Checkpoint inhibitor immunotherapy induced inflammatory arthritis secondary to Nivolumab and Ipilimumab: a pediatric first.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have expanded the arsenal of cancer therapeutics over the last decade but are associated with a spectrum of immune-related adverse events (irAEs), including inflammatory arthritis. While these complications are increasingly recognized in the adult population, no cases of inflammatory arthritis irAEs have been reported in the pediatric literature. CASE PRESENTATION: A 14-year-old female with metastatic epithelioid mesothelioma was referred to the pediatric rheumatology clinic after developing progressive inflammatory joint pain in her bilateral shoulders, hips, and small joints of hands following the second cycle of Nivolumab and Ipilimumab. Initial examinations showed bilateral shoulder joint line tenderness, positive FABERs test bilaterally, tenderness over bilateral greater trochanters, and bilateral second PIP effusions. Her serological profile was notable for positive HLA-B27, positive anti-CCP, negative Rheumatoid Factor, and negative ANA. PET-CT scan performed for disease response following immunotherapy showed symmetric increased metabolic activity primarily involving the supraspinatus, gluteus medius and minimus, and semimembranosus tendon insertions. Her presentation was consistent with a grade 1 irAE that worsened to a grade 2 irAE despite NSAID therapy, prompting a short course of oral prednisolone. She achieved clinical remission of her mesothelioma following six cycles of Nivolumab and Ipilimumab and her inflammatory arthritis was controlled on Celebrex monotherapy. CONCLUSIONS: To our knowledge, this is the first pediatric case of ICI-induced inflammatory arthritis and enthesitis. This case highlights the importance of increasing awareness of diagnosis and management of irAEs in children.

Prevalence and titres of antinuclear antibodies in juvenile idiopathic arthritis: A systematic review and meta-analysis.

BACKGROUND: Antinuclear antibodies (ANA) detected in juvenile idiopathic arthritis (JIA) sera are considered to be a biomarker for JIA-related uveitis. There is an unclear consensus on the screening dilutions of ANA as detected by the HEp-2 indirect immunofluorescence assay (IFA) that should be used when predicting the risk of uveitis in JIA. The primary aim of this systematic review and meta-analysis was to summarize the evidence regarding ANA prevalence and performance in JIA and JIA-associated uveitis. METHODS: A search of five databases identified 1766 abstracts, using the search terms juvenile idiopathic arthritis; pediatric; sensitivity or diagnostic; and ANA. Studies that met inclusion/exclusion criteria were analyzed for the proportion of JIA patients with a positive ANA. Forest plots and pooled estimates were generated for the proportion of JIA patients and those with uveitis who were positive for ANA stratified by screening dilution. Study heterogeneity was also assessed. RESULTS: Twenty-eight studies met inclusion criteria yielding 6250 unique patients; 5902 had JIA and 348 were healthy controls or were known to have other autoimmune diseases. The most reported IFA serum screening dilution was ≥1:80, representing 41.9% of patients and this screening dilution had the highest proportion of JIA ANA positivity (41.0%; 95% CI 25.0%-57.0%). ANA screening for JIA uveitis had a sensitivity and specificity of ANA at ≥1:40 of 75% (95% CI 46%-100%) and 66% (95% CI 39%-93%), respectively. There was significant study heterogeneity across both JIA subtypes and ANA titres. CONCLUSIONS: Although there was a large variation of ANA IFA screening dilutions used for investigation of JIA, the most common dilution was 1:80. The current literature has several important deficiencies that are identified in this review requiring additional studies to inform the ANA screening dilutions of clinical value in JIA and JIA-associated uveitis.

Can the Windkessel Hypothesis Explain Delayed Intraparenchymal Haemorrhage After Flow Diversion? A Case Report and Model-Based Analysis of Possible Mechanisms.

BACKGROUND: Delayed ipsilateral intraparenchymal haemorrhage is a recently recognised complication after endovascular flow diversion for intracranial aneurysms. Although the mechanism of this phenomenon is not understood, one proposed explanation (the windkessel hypothesis) is that removal of aneurysmal compliance increases distal pulse pressure. METHODS: We present a case of delayed haemorrhage after placement of a Pipeline stent, discuss the proposed mechanisms, and describe a novel electrical analogue model that was used to evaluate the likely haemodynamic effect of stent placement. RESULTS: Model-based analysis suggests that stenting is not likely to produce a significant change in distal pulse pressure. Moreover, basic fluid dynamics principles suggest that a local reduction in disturbed flow in the region of the aneurysm could produce only a minor increase in distal pressure (a few mmHg), which is unlikely to be the main cause of the observed haemorrhage. CONCLUSION: The windkessel hypothesis is unlikely to explain the occurrence of delayed ipsilateral intraparenchymal haemorrhage after flow diversion; however, other mechanisms involving altered haemodynamics distal to the treated aneurysm may play a role. Further studies involving the assessment of haemodynamic changes after flow diversion would be useful to understand, and eventually mitigate, this currently unpredictable risk.