55. A case for continuing tocilizumab beyond 12 months in giant cell arteritis?

INTRODUCTION: This case discusses a 60-year-old old gentleman who had aggressive disease and severe complications of giant cell arteritis. Shortly after diagnosis of GCA, he had an aortic dissection which was successfully repaired surgically. Medical therapy was escalated by increasing steroids and initiating tocilizumab, which was continued for one year as per NICE guidance. Within 4 weeks of ceasing tocilizumab, GCA flared symptomatically and serologically. He was promptly restarted on tocilizumab, to which he responded. 2 months later he collapsed, and resuscitation attempts were unsuccessful. Post mortem examination revealed ruptured aortic aneurysm. CASE DESCRIPTION: A 60-year-old old retired gentleman presented with left sided headache and blurred vision. CRP and ESR were 80 and 100 respectively. Temporal artery biopsy confirmed giant cell arteritis. He commenced 60mg prednisolone with good response and weaned according to BSR guidance. Past medical history included Barrett’s oesophagus. He was a non-smoker and had a strong family history of cardiovascular disease. 2 months later, he presented to A&E with central chest pain radiating to the groins and lower limb weakness. CT aortogram demonstrated Type A aortic dissection extending to the bifurcation. He was urgently transferred to a tertiary centre and underwent aortic root, ascending aorta and proximal aortic arch replacement with grafts. Rheumatology recommended pulsed IV methylprednisolone and tocilizumab due to aggressive disease. Histopathology from the dissected aorta reported ‘degenerative disease and no active GCA’. In rheumatology clinic 2 weeks later, he was in atrial fibrillation and commenced on apixiban and amiodarone. PET CT performed 6 weeks post-operatively did not show active vasculitis. He remained asymptomatic on tocilizumab with normal inflammatory markers. Prednisolone was weaned in accordance with GiACTa trial. He reverted to sinus rhythm; therefore apixiban and amiodarone were discontinued. 2 months later he developed acute left sided parasthesiae and weakness due to right thalamic infarct. He was in AF and CRP was <1. Over the following 6 months, he exhibited no features of active GCA. He suffered attacks of gout therefore prednisolone was increased to 5mg. He completed 12 months of tocilizumab, remaining on low dose prednisolone for gout. Within 1 month he relapsed with night sweats, arm claudication and ESR 97, CRP 247. Temporal ultrasound was negative. He received pulsed IV methylprednisolone and restarted tocilizumab, with prompt symptomatic and serological response. Two months later, he collapsed and suffered cardiac arrest. Post mortem revealed ruptured aortic aneurysm. DISCUSSION: This case highlights a severe case of GCA where the patient succumbed to a recognised but rare complication. Aortic involvement in GCA includes aortitis, dilatation, aneurysm and dissection. However, it is difficult to accurately report the incidence and prevalence as aortic involvement can be asymptomatic. Modern imaging studies have improved detection, demonstrating prevalence in up to 65% of newly diagnosed cases. Interestingly, this patient developed a dissection 2 months post diagnosis; whilst on 40mg prednisolone and demonstrating a clinical response. CRP was normal one week prior. The biopsy specimen did not find vasculitis suggesting the dissection occurred due to damage caused by previous activity. However, we later discovered only 1-2cm of resected aorta was examined, which may have missed patchy inflammation. Tocilizumab was licensed by NICE in 2017, so there are few patients that have received 12 months therapy and long-term remission rates beyond this are still being reported from the GiACTa trial. NICE recommends tocilizumab in refractory or relapsing disease and this should be stopped after 12 months. Considering he dissected relatively early after diagnosis whilst on 40mg prednisolone, tocilizumab was indicated for refractory disease and to reduce long term steroid burden. He achieved disease remission which was sustained while tapering steroids. However, on withdrawing tocilizumab at 12 months he quickly relapsed. The departmental decision was to restart tocilizumab. NICE implemented a 12-month stopping rule, therefore how to we proceed in these patients with aortic complications and high-risk disease? Stroke and TIA are also reported complications of large vessel vasculitis. Our patient’s CRP was normal at time of his stroke. He was in AF, and not on prophylaxis. Ultrasound Doppler’s were not performed at the time. It is difficult to conclude whether this was cardioembolic or related to vascular disease in the absence of any stenotic lesions. KEY LEARNING POINTS: Predicting patients at highest risk of aortic complications is challenging. Is there rationale to perform FDG PET in all patients to determine extent of disease? Clearly this isn’t feasible in the NHS, in which case should we determine some clear parameters to guide indications for imaging. Cardiovascular risk factors are the only other predictors of dissection in GCA. Retrospectively, we discovered a strong family history of sudden cardiac death from cardiovascular disease on his paternal side. One must assume he had asymptomatic active aortic disease some time before the onset of his cranial symptoms. This resulted in vascular damage by the time of biopsy, by which time he had been on steroids for a few weeks, and no active vasculitis was seen. Biopsy specimens require clear instruction to histopathology and sufficient sample length to avoid false negatives. He was awaiting CT angiogram to observe for further aortic manifestations but unfortunately suffered fatal aneurysm rupture only a few weeks prior. In a subset of patients deemed to be high risk, closer monitoring must be pursued and include imaging. Whilst on treatment, despite normal inflammatory markers and little symptoms, he was having subclinical damage which resulted in ruptured aneurysm. Interestingly, temporal/carotid/axillary artery ultrasound did not show features of vasculitis. Possibly his disease did not affect these vessels. We must also remember that tocilizumab lowers CRP and therefore ESR must be measured as well. As this case demonstrates, men in their 50’s and 60’s are prone to aggressive disease and relapse. NICE guidance implements a 12-month stopping policy; and doesn’t cater for these patients. Even though our patient appeared to be in remission, should tocilizumab be continued beyond 12 months in patients with prior aortic disease? We must make clinical decisions on a case by case basis. There is some evidence that abatacept carries less infection related morbidity when compared with tumour necrosis factor (TNF) inhibitors. The efficacy of addition of abatacept to prednisolone in reducing the risk of relapse of GCA is suggested in one study. Abatacept and prednisolone combination did not show higher rate of toxicity when compared to prednisolone alone, including rate of infection. In this context, could abatacept be a choice of treatment in this case? CONFLICTS OF INTEREST: The authors have declared no conflicts of interest.