Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients.

Respiratory failure in the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is hypothesized to be driven by an overreacting innate immune response, where the complement system is a key player. In this prospective cohort study of 39 hospitalized coronavirus disease COVID-19 patients, we describe systemic complement activation and its association with development of respiratory failure. Clinical data and biological samples were obtained at admission, days 3 to 5, and days 7 to 10. Respiratory failure was defined as PO2/FiO2 ratio of ≤40 kPa. Complement activation products covering the classical/lectin (C4d), alternative (C3bBbP) and common pathway (C3bc, C5a, and sC5b-9), the lectin pathway recognition molecule MBL, and antibody serology were analyzed by enzyme-immunoassays; viral load by PCR. Controls comprised healthy blood donors. Consistently increased systemic complement activation was observed in the majority of COVID-19 patients during hospital stay. At admission, sC5b-9 and C4d were significantly higher in patients with than without respiratory failure (P = 0.008 and P = 0.034). Logistic regression showed increasing odds of respiratory failure with sC5b-9 (odds ratio 31.9, 95% CI 1.4 to 746, P = 0.03) and need for oxygen therapy with C4d (11.7, 1.1 to 130, P = 0.045). Admission sC5b-9 and C4d correlated significantly to ferritin (r = 0.64, P < 0.001; r = 0.69, P < 0.001). C4d, sC5b-9, and C5a correlated with antiviral antibodies, but not with viral load. Systemic complement activation is associated with respiratory failure in COVID-19 patients and provides a rationale for investigating complement inhibitors in future clinical trials.

Trends in all-cause and cardiovascular mortality in patients with incident rheumatoid arthritis: a 20-year follow-up matched case-cohort study.

OBJECTIVES: To examine all-cause and cardiovascular disease (CVD) mortality in consecutive cohorts of patients with incident RA, compared with population comparators. METHODS: The Oslo RA register inclusion criteria were diagnosis of RA (1987 ACR criteria) and residency in Oslo. Patients with disease onset 1994-2008 and 10 matched comparators for each case were linked to the Norwegian Cause of Death Registry. Hazard ratios for all-cause and CVD mortality were calculated for 5, 10, 15 and 20 years of observation using stratified cox-regression models. Mortality trends were estimated by multivariate cox-regression. RESULTS: 443, 479 and 469 cases with disease incidence in the periods 94-98, 99-03 and 04-08 were matched to 4430, 4790 and 4690 comparators, respectively. For cases diagnosed between 1994 and 2003, the all-cause mortality of cases diverged significantly from comparators after 10 years of disease duration [hazard ratio (95% CI) 94-98 cohort 1.42 (1.15-1.75): 99-03 cohort 1.37 (1.08-1.73)]. CVD related mortality was significantly increased after 5 years for the 94-98 cohort [hazard ratio (95% CI) 1.86 (1.16-2.98) and after 10 years for the 99-03 cohort 1.80 (1.20-2.70)]. Increased mortality was not observed in the 04-08 cohort where cases had significantly lower 10-year all-cause and CVD mortality compared with earlier cohorts. CONCLUSION: All-cause and CVD mortality were significantly increased in RA patients diagnosed from 1994 to 2003, compared with matched comparators, but not in patients diagnosed after 2004. This may indicate that modern treatment strategies have a positive impact on mortality in patients with RA.

Fibromyalgia in patients with rheumatoid arthritis. A 10-year follow-up study, results from the Oslo Rheumatoid Arthritis Register.

OBJECTIVES: To examine cross-sectional and longitudinal relationships between fibromyalgia (FM) and rheumatoid arthritis (RA) disease activity. METHODS: 636 patients in the observational Oslo RA register (ORAR) were invited to a clinical examination in 1999. 28-tender and swollen joint counts (TJC, SJC) and 18-tender points were assessed, the RA disease activity score (DAS-28) calculated. Fibromyalgia (FM) was diagnosed according to 1990 (FM-1990) and modified 2011 (mFM-2011) ACR criteria. At the 10-year follow-up patients completed the RA Disease Activity Index (RADAI) and Routine Assessment of Patient Index Data 3 (RAPID-3). Baseline and 10-year RA disease activity were compared across presence/absence of FM. Linear regression models were constructed with 10-year RADAI and RAPID-3 as outcome. RESULTS: 502 patients participated at baseline data-collection and 10-year data was available in 236. At baseline, mean (SD) age was 59.5 (12.5) years and 87% were female. 9% and 30% had FM-1990 and mFM-2011 respectively. RA-FM patients were predominantly female with higher SJC, TJC, and DAS-28 at baseline. Baseline RA-FM predicted higher levels of RADAI and RAPID-3 at the 10-year follow-up. CONCLUSIONS: RA-FM was associated with significantly higher levels of cross-sectional and longitudinal RA disease activity. FM should be considered in patients with RA not reaching remission.

Performance of the Rheumatoid Arthritis Impact of Disease (RAID) score in relation to other patient-reported outcomes in a register of patients with rheumatoid arthritis.

OBJECTIVE: Delegates at the Outcome Measures in Rheumatology (OMERACT) 10 conference (Borneo, 4-8 May 2010) questioned how the new seven-domain Rheumatoid Arthritis Impact of Disease (RAID) score performs as a global measure. Score distributions and associations between the RAID score and patient-reported outcomes (PROs) and demographic variables were examined in a large sample of rheumatoid arthritis (RA) patients. METHODS: 1086 patients in the Oslo RA Register responded to a postal survey with commonly used PROs. Bivariate associations between the RAID score and other measures are reported as Pearson correlation coefficients. RESULTS: The mean RAID was 3.37 ± 2.17. The distribution of the RAID score showed a slight floor effect: 17.5% had a score between 0 and 1, and 14.4% between 1 and 2, whereas only 1.0% and 0.3% had scores between 8 and 9, and 9 and 10, respectively. Correlations between the RAID score and the patient global assessment, Rheumatoid Arthritis Disease Activity Index, Short-Form (SF)-6D and EQ-5D were 0.82, 0.82, -0.77 and -0.73, respectively. Strong correlation was also seen between RAID and pain, the domain with highest weight, whereas correlations to measures of other RAID domains were moderate. The RAID score was higher in women than men (3.49 vs 2.95, p=0.001). CONCLUSION: The RAID score was correlated more strongly to other global measures than to PROs, reflecting single health domains.

Calcium supplementation and inflammation increase mortality in rheumatoid arthritis: A 15-year cohort study in 609 patients from the Oslo Rheumatoid Arthritis Register.

OBJECTIVE: To investigate whether osteoporosis or use of calcium supplementations predict all-cause mortality, or death from CVD, in a longitudinal cohort of patients with rheumatoid arthritis (RA). METHODS: Patients in the Oslo RA register (ORAR) were examined, and bone mineral density was measured in 1996. The cohort was linked to the Norwegian Cause of Death registry on December 31, 2010. Death from CVD was defined in 3 following different outcomes: (1) primary atherosclerotic death, (2) atherosclerotic death as one of the 5 listed causes of death, and (3) CVD according to World Health Organization (WHO) definition as primary cause of death. Baseline predictors of all-cause mortality and death from CVD were identified in separate Cox regression models, using backwards selection. Sensitivity analyses were performed including analyses of interactions and competing risk. RESULTS: A total of 609 patients were examined in 1996/1997. By December 31, 2010, 162 patients (27%) had died, resulting in 7439 observed patient-years. Of the deceased, 40 (24.7%) had primary atherosclerotic death. In the final model of all-cause mortality increased baseline ESR [hazard ratio (HR) 1.02 per mm/h, 95% CI: 1.01-1.03], calcium supplementation (1.74, 1.07-2.84), and osteoporosis, defined as a T score ≤2.5 SD at any location, (1.58, 1.07-2.32) predicted higher mortality rates, in models adjusted for age, gender, and a propensity score. In the final model of primary atherosclerotic death, increased ESR (1.03 per mm/h, 1.01-1.05) and calcium supplementation (3.39, 1.41-8.08), predicted higher mortality. CONCLUSIONS: Increased baseline ESR and use of calcium supplementation were predictors of increased all-cause mortality and risk of death from CVD in this longitudinal study of patients with RA.