Assessment of clinical, cellular and molecular determinants in sarcoidosis

Sarcoidosis is a complex, multisystem inflammatory disease with highly varied presentations, organ involvement and natural history. Its aetiology has remained enigmatic and previous attempts at investigating the cellular and genetic mechanisms that give rise to this disease have yielded conflicting and inconsistent results, largely due to the heterogeneous composition of patient cohorts studied. This project set out to address the problem of phenotypic heterogeneity in sarcoidosis in order to facilitate a more productive investigation into cellular and molecular determinants associated with this disease. We hypothesised that extreme or homogeneous presentations of sarcoidosis would be associated with distinct cellular and molecular characteristics. Through the establishment of a quaternary referral sarcoidosis clinic, patients with diverse presentations of sarcoidosis underwent clinical phenotyping to identify subgroups with consistent clinical characteristics and disease outcomes. Our phenotypic model identified 3 subgroups (neurosarcoidosis, sarcoid uveitis and hepatosplenic sarcoidosis) that were significantly associated with organ limited disease or associated with a distinct presentation that correlated with organ involvement. Patients with a newly described presentation of isolated tattoo and ocular inflammation were also studied as a distinct subgroup. Genetic analysis which focussed on NOD2 variants, demonstrated a significant association between the carriage of P268S and the development of sarcoid uveitis and multisystem disease. Patients with the extreme clinical phenotype of neurosarcoidosis were found to possess a baseline peripheral cellular signature consisting of reduced effector T regulatory cells and increased T effector memory, Th1 and Th2 cells, that was distinct from other clinical phenotypes of sarcoidosis. Finally, we identified global downregulation of chemokine receptor CXCR5 on lymphocyte populations in patients with active tattoo uveitis which normalised upon remission. This finding of chemokine receptor dysregulation is likely to be significant in a disease process that is characterised by organ restricted inflammation. Our results have demonstrated the utility of clinical phenotyping in heterogeneous disease processes. Further investigation will be required to clarify the mechanistic implications of the genetic and cellular associations identified

Successful cholecalciferol desensitisation in a case of delayed hypersensitivity

Hypersensitivity to cholecalciferol (vitamin D3) or its active metabolite, calcitriol, is an exceedingly rare clinical phenomenon, with only 2 previously reported cases of suspected immediate hypersensitivity. Diagnosis of delayed drug hypersensitivity reactions is inherently difficult due to the lack of any robust in vitro diagnostic assay, particularly in those patients for whom provocation testing confers an unacceptable risk. In these situations, diagnosis relies on reproducible clinical manifestations following administration of the culprit agent, resolution upon its withdrawal and exclusion of other potential differential diagnoses. Based on these criteria, we propose the first reported case of delayed hypersensitivity to cholecalciferol successfully managed with a desensitisation protocol to pure cholecalciferol

A Curious Case of Periodic Fevers, Avascular Necrosis and Inflammatory Nodules

We report a case of a 16-year-old Caucasian female with the explosive onset of fevers, arthralgias and refractory urticaria. Her history was signifi-cant for avascular necrosis of her wrists and feet four years prior to her presentation. Her clinical symptoms were associated with a marked inflammatory response but without serological evidence of autoimmunity. Her condition was initially responsive to colchicine and prednisolone, however, within a period of a few months became refractory. During this time, she developed unusual inflammatory nodules arising from her extensor digitorum, which became a feature of each clinical episode consisting of a tetrad of fevers, arthralgias, urticaria and tendon nodules. She had no evidence of uveitis or gut involvement. Her clinical phenotype suggested autoinflammatory disease but targeted gene sequencing did not reveal a known syndrome. Her family history was remarkable only for a brother with self-limiting erythema nodosum and a maternal grandmother with Crohn’s disease. Her clinical course has remained stormy but eventually she entered remission on a regimen of methotrexate 20 mg weekly and tocilizumab 400 mg monthly. The proband and her family have since undergone whole genome sequencing at the Centre for Personalised Immunology, which has provided insight into her diagnosis. Our patient demonstrates molecular and clinical features compatible with a recently described autoinflammatory syndrome; however, her presentation extends the described phenotype. This syndrome and potential pathogenic mechanisms will be discussed

Prominent subcutaneous oedema as a masquerading symptom of an underlying inflammatory myopathy

The inflammatory myopathies are a group of immune-mediated inflammatory muscle disorders that typically present with marked proximal muscle weakness. We report four cases of inflammatory myopathies with marked subcutaneous oedema as their main complaint. Three of the four patients had normal or low levels of creatine kinase, an enzyme often markedly elevated in these disorders. Magnetic resonance imaging of the muscles, followed by a muscle biopsy were used to make a definitive diagnosis