Background The diagnosis and therapeutic approach to early onset rheumatoid arthritis (RA) patients may be influenced by their access to specialized healthcare units. Objectives To assess diagnostic and therapeutic delays in RA in Catalonia (Spain) and their relationship with patient’s access to specialized healthcare units. Methods We carried out a cross-sectional epidemiological survey in 19 Catalonian Rheumatology Centres. Ten consecutive patients newly diagnosed with RA (according to physician criteria) during 2009 and 2010 were recruited from each centre. Together with demographic and clinical variables, several parameters related to diagnostic delay were recorded: 1) Time from first symptom to first rheumatologist appointment, 2) Referral time from General Practitioner (GP) evaluation to first rheumatologist appointment, 3) Time from first symptom onset to final RA diagnosis, 4) Time from first symptom to first DMARD started. The presence/absence of specialized healthcare units was evaluated in all centres: 1) Early arthritis units (EAU), 2) RA Units (RAU), 3) Rapid/preferential programming for RA, 4) Referral algorithms from GPs 5) Primary care (PC) rheumatology units (RUPC) and 6) Primary care rheumatology advisory programme (RAPPC). Results 183 patients (51M/132F) were included. Mean age 52.7±14 years, mean disease duration 27.3±20 months. Mean delays from the first symptom were; to first rheumatology appointment 10.2±12.7 months, to final RA diagnosis 11.3±13.2 months, and first DMARD 11.1±12.8 months. 34.4% of patients had access to an EAU, 37.2% to an RA unit, 66.1% were evaluated through rapid appointment programming and 31.1% through GP referral algorithms. RUPC and RAPPC were available for 61.7% and 31.7% of patients, respectively. Time from first symptom to first DMARD was associated with EAU (8.4±10.5 vs 12.6±13.7 without EAU, p=0.015) and there was a trend to significance for PC rheumatology units (9.1±10.3 vs. 12.1±13.7, p=0.056), but there was no association with RA units, rapid appointment programming, PC rheumatology advisory or referral algorithms from GP. EAU were associated with a shorter delay from first symptom to first rheumatology appointment (7.5±10 vs. 11.6±13.7; p=0.016) and to the final RA diagnosis (8.8±11.4 vs 12.6±13.7; p=0.046). RUPC and RAPPC were associated with a shorter time between both first symptom and first GP evaluation and time to final RA diagnosis. Preferential appointment programming and referral algorithms from GP were not associated with significant differences in delays. Conclusions The mean delay from symptom onset to RA diagnosis or initiation of the first DMARD in Catalonia was 11 months. Patient’s access to specialized units, especially early arthritis units, can improve early diagnosis and treatment of RA. Disclosure of Interest None Declared
GBA1 mutations result in excess storage of glucosylceramide (GC) and the induction of Gaucher disease (GD). GD is frequently associated with elevated levels of pro-inflammatory cytokines and the development of brain inflammation. The mechanisms underlying GC-driven brain inflammation in GD are ill-defined. Recently, we described immune complexes of GC-specific IgG autoantibodies in experimental and clinical GD, which induced massive complement activation and C5a generation. Further, we found that C5a-mediated activation of its cognate C5a receptor 1 (C5aR1) tips the balance between GC formation and degradation, thereby fueling excess GC accumulation and inflammation in visceral tissues in experimental and clinical GD. Previously, the C5a/C5aR1 axis was found to regulate the blood brain barrier integrity in systemic lupus and promote neurodegeneration in Alzheimer’s disease. Here, we determined the production of C5a in the brain of Gba1 D409V/knockout (9V/null) GD-prone mice. C5a production in the brain of 9V/null mice was markedly elevated, when compared to WT control mice. Also, 9V/null mice suffered from massive accumulation of GC in the brain and loss of neurons. To assess the relevance of C5a/C5aR1 axis activation for brain inflammation in GD, we targeted glucocerebrosidase (GCase) with conduritol B epoxide (CBE) in WT and C5aR1−/− mice. Strikingly, CBE-injected WT mice died within 30 days. In contrast, all C5aR1−/− mice survived the 60 days observation window, were protected from CBE-induced accumulation of GC in the brain, showed a marked reduction of microglial cell activation and only a minor loss of neurons. Our data suggest that the C5a/C5aR1 axis is a critical driver of neurodegeneration in experimental GD.
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