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OBJECTIVES: Primary objective: To estimate the effect of corticosteroids compared with usual care or placebo on mortality up to 28 days after randomization. Secondary objectives: To examine whether the effect of corticosteroids compared with usual care or placebo on mortality up to 28 days after randomization varies between subgroups related to treatment characteristics, disease severity at the time of randomization, patient characteristics, or risk of bias. To examine the effect of corticosteroids compared with usual care or placebo on serious adverse events.STUDY DESIGN: Prospective meta-analysis of randomized controlled trials. Both placebo-controlled and open-label trials are eligible.PARTICIPANTS: Hospitalised, critically ill patients with suspected or confirmed COVID-19.INTERVENTION AND COMPARATOR: Intervention groups will have received therapeutic doses of a steroid (dexamethasone, hydrocortisone or methylprednisolone) with IV or oral administration immediately after randomization. The comparator groups will have received standard of care or usual care or placebo.MAIN OUTCOME: All-cause mortality up to 28 days after randomization.SEARCH METHODS: Systematic searching of clinicaltrials.gov , EudraCT, the WHO ISRCTN registry, and the Chinese clinical trials registry. Additionally, research and WHO networks will be asked for relevant trials.RISK OF BIAS ASSESSMENTS: These will be based on the Cochrane RoB 2 tool, and will use structured information provided by the trial investigators on a form designed for this prospective meta-analysis. We will use GRADE to assess the certainty of the evidence.STATISTICAL ANALYSES: Trial investigators will provide data on the numbers of participants who did and did not experience each outcome according to intervention group, overall and in specified subgroups. We will conduct fixed-effect (primary analysis) and random-effects (Paule-Mandel estimate of heterogeneity and Hartung

OBJECTIVES: Primary objective: To estimate the effect of corticosteroids compared with usual care or placebo on mortality up to 28 days after randomization. Secondary objectives: To examine whether the effect of corticosteroids compared with usual care or placebo on mortality up to 28 days after randomization varies between subgroups related to treatment characteristics, disease severity at the time of randomization, patient characteristics, or risk of bias. To examine the effect of corticosteroids compared with usual care or placebo on serious adverse events.STUDY DESIGN: Prospective meta-analysis of randomized controlled trials. Both placebo-controlled and open-label trials are eligible.PARTICIPANTS: Hospitalised, critically ill patients with suspected or confirmed COVID-19.INTERVENTION AND COMPARATOR: Intervention groups will have received therapeutic doses of a steroid (dexamethasone, hydrocortisone or methylprednisolone) with IV or oral administration immediately after randomization. The comparator groups will have received standard of care or usual care or placebo.MAIN OUTCOME: All-cause mortality up to 28 days after randomization.SEARCH METHODS: Systematic searching of clinicaltrials.gov , EudraCT, the WHO ISRCTN registry, and the Chinese clinical trials registry. Additionally, research and WHO networks will be asked for relevant trials.RISK OF BIAS ASSESSMENTS: These will be based on the Cochrane RoB 2 tool, and will use structured information provided by the trial investigators on a form designed for this prospective meta-analysis. We will use GRADE to assess the certainty of the evidence.STATISTICAL ANALYSES: Trial investigators will provide data on the numbers of participants who did and did not experience each outcome according to intervention group, overall and in specified subgroups. We will conduct fixed-effect (primary analysis) and random-effects (Paule-Mandel estimate of heterogeneity and Hartung

OBJECTIVE: To investigate the clinical and radiographic status, and to identify baseline predictors of functional status and erosive progression at 11 years' follow-up of early rheumatoid arthritis (RA) patients.METHODS: Patients enrolled in the Danish investigator-initiated randomized controlled CIMESTRA trial, which investigated a 2 year treat-to-target intervention with methotrexate and intra-articular glucocorticoids with or without cyclosporine, were followed up. The 28-joint Disease Activity Score (DAS28), Health Assessment Questionnaire (HAQ) score, and total Sharp van der Heijde score (TSS) were assessed at baseline and 11 years. Baseline magnetic resonance imaging (MRI) of unilateral wrists was scored (OMERACT RAMRIS). Multivariable linear regression analyses of baseline variables [TSS, HAQ, DAS28, age, anti-cyclic citrullinated peptide (anti-CCP) status, gender, MRI erosion score, MRI synovitis score, MRI bone marrow oedema score] were performed in 96 patients with HAQ11yrs and ∆TSS0-11yrs as dependent variables. Since outcomes were similar in the two treatment arms, data were pooled.RESULTS: In total, 120 of 160 patients completed 11 years' follow-up. They were 63 (55-72) years old, 68% were in DAS28 remission (≤ 2.4), HAQ11yrs was 0.25 (0-0.75), mean ∆TSS0-11yrs was 0.96 ± 1.52 units/year; 53%, 20%, and 27% received conventional treatment, biologics, and no treatment, respectively; and 34% had not progressed radiographically since baseline. Increased DAS28 (p = 0.02) and anti-CCP (p = 0.03) predicted HAQ11yrs, whereas anti-CCP (p = 0.03) and MRI bone marrow oedema (p = 0.01) predicted ∆TSS0-11yrs in multivariable analyses.CONCLUSIONS: Early and strict synovitis suppression with methotrexate and intra-articular glucocorticoids led to persistently high remission rates and limited erosive progression at 11 years. In this well-treated cohort, baseline anti-CCP status, DAS28, and MRI bone marrow oedema predicted functional status and/o

OBJECTIVE: To investigate the clinical and radiographic status, and to identify baseline predictors of functional status and erosive progression at 11 years' follow-up of early rheumatoid arthritis (RA) patients.METHODS: Patients enrolled in the Danish investigator-initiated randomized controlled CIMESTRA trial, which investigated a 2 year treat-to-target intervention with methotrexate and intra-articular glucocorticoids with or without cyclosporine, were followed up. The 28-joint Disease Activity Score (DAS28), Health Assessment Questionnaire (HAQ) score, and total Sharp van der Heijde score (TSS) were assessed at baseline and 11 years. Baseline magnetic resonance imaging (MRI) of unilateral wrists was scored (OMERACT RAMRIS). Multivariable linear regression analyses of baseline variables [TSS, HAQ, DAS28, age, anti-cyclic citrullinated peptide (anti-CCP) status, gender, MRI erosion score, MRI synovitis score, MRI bone marrow oedema score] were performed in 96 patients with HAQ11yrs and ∆TSS0-11yrs as dependent variables. Since outcomes were similar in the two treatment arms, data were pooled.RESULTS: In total, 120 of 160 patients completed 11 years' follow-up. They were 63 (55-72) years old, 68% were in DAS28 remission (≤ 2.4), HAQ11yrs was 0.25 (0-0.75), mean ∆TSS0-11yrs was 0.96 ± 1.52 units/year; 53%, 20%, and 27% received conventional treatment, biologics, and no treatment, respectively; and 34% had not progressed radiographically since baseline. Increased DAS28 (p = 0.02) and anti-CCP (p = 0.03) predicted HAQ11yrs, whereas anti-CCP (p = 0.03) and MRI bone marrow oedema (p = 0.01) predicted ∆TSS0-11yrs in multivariable analyses.CONCLUSIONS: Early and strict synovitis suppression with methotrexate and intra-articular glucocorticoids led to persistently high remission rates and limited erosive progression at 11 years. In this well-treated cohort, baseline anti-CCP status, DAS28, and MRI bone marrow oedema predicted functional status and/o

OBJECTIVE: The spectrum of antinuclear antibodies (ANAs) is changing to include both nuclear staining as well as cytoplasmic and mitotic cell patterns (CMPs) and accordingly a change is occurring in terminology to anticellular antibodies. This study examined the prevalence of indirect immunofluorescence (IIF) anticellular antibody staining using the Systemic Lupus International Collaborating Clinics inception cohort.METHODS: Anticellular antibodies were detected by IIF on HEp-2000 substrate using the baseline serum. Three serologic subsets were examined: ANA positive (presence of either nuclear or mixed nuclear/CMP staining), anticellular antibody negative (absence of any intracellular staining), and isolated CMP staining. The odds of being anticellular antibody negative versus ANA or isolated CMP positive was assessed by multivariable analysis.RESULTS: A total of 1,137 patients were included; 1,049 (92.3%) were ANA positive, 71 (6.2%) were anticellular antibody negative, and 17 (1.5%) had an isolated CMP. The isolated CMP-positive group did not differ from the ANA-positive or anticellular antibody-negative groups in clinical, demographic, or serologic features. Patients who were older (odds ratio [OR] 1.02 [95% confidence interval (95% CI) 1.00, 1.04]), of white race/ethnicity (OR 3.53 [95% CI 1.77, 7.03]), or receiving high-dose glucocorticoids at or prior to enrollment (OR 2.39 [95% CI 1.39, 4.12]) were more likely to be anticellular antibody negative. Patients on immunosuppressants (OR 0.35 [95% CI 0.19, 0.64]) or with anti-SSA/Ro 60 (OR 0.41 [95% CI 0.23, 0.74]) or anti-U1 RNP (OR 0.43 [95% CI 0.20, 0.93]) were less likely to be anticellular antibody negative.CONCLUSION: In newly diagnosed systemic lupus erythematosus, 6.2% of patients were anticellular antibody negative, and 1.5% had an isolated CMP. The prevalence of anticellular antibody-negative systemic lupus erythematosus will likely decrease as emerging nomenclature guidelines rec

BACKGROUND: The optimal way to home-monitor patients with inflammatory bowel disease (IBD) for disease progression or relapse remains to be found.AIM: To determine whether an electronic health (eHealth) screening procedure for disease activity in IBD should be implemented in clinical practice, scheduled every third month (3M) or according to patient own decision, on demand (OD).METHODS: Adult IBD patients were consecutively randomized to 1-year open-label eHealth interventions (3M vs OD). Both intervention arms were screening for disease activity, quality of life and fatigue and were measuring medical compliance with the constant care web-application according to the screening interventions OD or 3M. Disease activity was assessed using home measured fecal calprotectin (FC) and a disease activity score.RESULTS: In total, 102 patients were randomized (n = 52/50 3M/OD) at baseline, and 88 patients completed the 1-year study (n = 43 3M; n = 45 OD). No difference in the two screening procedures could be found regarding medical compliance (P = 0.58), fatigue (P = 0.86), quality of life (P = 0.17), mean time spent in remission (P > 0.32), overall FC relapse rates (P = 0.49), FC disease courses (P = 0.61), FC time to a severe relapse (P = 0.69) and remission (P = 0.88) during 1 year. Median (interquartile range) numbers of FC home-monitoring test-kits used per patient were significantly different, 3M: 6.0 (5.0-8.0) and OD: 4.0 (2.0-9.0), P = 0.04.CONCLUSION: The two eHealth screening procedures are equally good in capturing a relapse and bringing about remission. However, the OD group used fewer FC home test-kits per patient. Individualized screening procedures can be recommended for adult IBD patients in clinical web-practice.

BACKGROUND: The optimal way to home-monitor patients with inflammatory bowel disease (IBD) for disease progression or relapse remains to be found.AIM: To determine whether an electronic health (eHealth) screening procedure for disease activity in IBD should be implemented in clinical practice, scheduled every third month (3M) or according to patient own decision, on demand (OD).METHODS: Adult IBD patients were consecutively randomized to 1-year open-label eHealth interventions (3M vs OD). Both intervention arms were screening for disease activity, quality of life and fatigue and were measuring medical compliance with the constant care web-application according to the screening interventions OD or 3M. Disease activity was assessed using home measured fecal calprotectin (FC) and a disease activity score.RESULTS: In total, 102 patients were randomized (n = 52/50 3M/OD) at baseline, and 88 patients completed the 1-year study (n = 43 3M; n = 45 OD). No difference in the two screening procedures could be found regarding medical compliance (P = 0.58), fatigue (P = 0.86), quality of life (P = 0.17), mean time spent in remission (P > 0.32), overall FC relapse rates (P = 0.49), FC disease courses (P = 0.61), FC time to a severe relapse (P = 0.69) and remission (P = 0.88) during 1 year. Median (interquartile range) numbers of FC home-monitoring test-kits used per patient were significantly different, 3M: 6.0 (5.0-8.0) and OD: 4.0 (2.0-9.0), P = 0.04.CONCLUSION: The two eHealth screening procedures are equally good in capturing a relapse and bringing about remission. However, the OD group used fewer FC home test-kits per patient. Individualized screening procedures can be recommended for adult IBD patients in clinical web-practice.

BACKGROUND AND OBJECTIVE: Dysfunctional breathing (DB) is a respiratory disorder, which involves a pattern of breathing too deeply, too superficially and/or too rapidly. In asthma patients, DB may lead to an overestimation of the severity of asthma symptoms, and hence potentially to overtreatment. However, it is not known to which degree DB may affect estimates of asthma control, in a specialist clinical setting.METHODS: The MAPOut-study examined all patients referred consecutively over a 12-months period for specialist assessment of asthma at the Respiratory Outpatient Clinic at Bispebjerg Hospital in Copenhagen. All patients were examined with the Nijmegen questionnaire with a DB defined as a score ≥23 and the ACQ questionnaire. Linear regression analysis of predictors of ACQ score was performed. Asthma was defined as asthma symptoms and a positive asthma test.RESULTS: Of the 256 patients referred to the lung clinic, data on both the Nijmegen questionnaire and ACQ score was obtained in 127 patients, who were included in the present analysis. Median (range) age: 30 (15-63) years, and 76 (59.8%) were females. DB was found in 31 (24.4%). Asthmatic patients with co-existing DB had a poorer asthma control compared to asthmatics without DB (Median (range) ACQ score: 2.40 (0.20-4.60) vs 1.20 (0.00-4.40); p < 0.001.). A regression analysis showed that the effect of DB on asthma control was independent of airway hyperresponsiveness or airway inflammation in patients with DB.CONCLUSION: Dysfunctional breathing is common among asthma patients in a specialist setting, and results in a clinically significant underestimation of asthma control, which may potentially lead to overtreatment.

We describe a family in which the mother died of unresolved lung disease and whose 5 children, some of whom had previous signs of asthma, were subsequently affected by extrinsic allergic alveolitis caused by contact with wild city pigeon antigens. The children received systemic corticosteroids for 1 month and inhaled steroids for 24 months, while antigen exposure was reduced as much as feasible. This was followed by a quick clinical recovery and a slow normalization of chest radiographs and pulmonary function indices, especially of diffusion capacity, during a follow-up of 24 months. Because pigeon-breeder's lung caused by free-roaming city pigeons has not been previously described, it remains unclear whether this family developed the disease because of high antigen exposure or because of increased susceptibility. None of the supposedly high-risk human leukocyte antigen types were found in the children. Whether human leukocyte antigen B7 in 1 child played a role in the course of the illness remains speculative. It is unknown to what extent pigeon-breeder's lung caused by nondomestic birds remains undetected and misdiagnosed as difficult or steroid-resistant asthma. The question remains whether free-roaming city pigeons are indeed a public health risk. We suggest that atypical outdoor antigens be considered in all patients with nonresolving chest disease or therapy-resistant asthma.

A regional inception cohort of 1161 ulcerative colitis (UC) patients was followed up from diagnosis to the end of 1987. The follow-up rate for death and occurrence of cancer was 99.9% (median observation time, 11.7 years; range, 0-26 years). One hundred forty-one deaths were observed, 26 caused by UC or complications thereof. No significant excess mortality was found after the first year, but in the year of diagnosis the relative risk of death was 2.4 (P < 0.001). The cumulative colectomy rate 25 years after diagnosis was 32.4%. The initial extent of disease significantly influenced the colectomy probability, being 35% in total colitis, 19% in substantial colitis, and 9% in distal colitis within the first 5 years after diagnosis. Six patients developed colorectal cancer within the observation period. Compared with the expected number of 6.6, the relative risk for patients with UC was 0.9. The calculated cumulative cancer incidence was 3.1% after 25 years (95% confidence limits, 0.0-6.8). The calculated lifetime risk (0-74 years) for development of colorectal cancer was 3.5% for UC patients compared with 3.7% for the Danish population. It is concluded that with an active approach to medical and surgical treatment, as practiced here, patients whose colons are left intact bear no significantly increased risk of colorectal malignancy.

A regional inception cohort of 1161 ulcerative colitis (UC) patients was followed up from diagnosis to the end of 1987. The follow-up rate for death and occurrence of cancer was 99.9% (median observation time, 11.7 years; range, 0-26 years). One hundred forty-one deaths were observed, 26 caused by UC or complications thereof. No significant excess mortality was found after the first year, but in the year of diagnosis the relative risk of death was 2.4 (P < 0.001). The cumulative colectomy rate 25 years after diagnosis was 32.4%. The initial extent of disease significantly influenced the colectomy probability, being 35% in total colitis, 19% in substantial colitis, and 9% in distal colitis within the first 5 years after diagnosis. Six patients developed colorectal cancer within the observation period. Compared with the expected number of 6.6, the relative risk for patients with UC was 0.9. The calculated cumulative cancer incidence was 3.1% after 25 years (95% confidence limits, 0.0-6.8). The calculated lifetime risk (0-74 years) for development of colorectal cancer was 3.5% for UC patients compared with 3.7% for the Danish population. It is concluded that with an active approach to medical and surgical treatment, as practiced here, patients whose colons are left intact bear no significantly increased risk of colorectal malignancy.

Ulcerative colitis and Crohn's disease are chronic inflammatory bowel diseases. The most widely prescribed drug for treatment of these diseases, sulfasalazine, has been shown to inhibit the activity of free radicals, as the active moiety of sulfasalazine, 5-aminosalicylic acid, is a radical scavenger. This effect of 5-aminosalicylic acid may be of clinical relevance, as a recent study has shown that 5-aminosalicylic acid reacts with oxygen-derived free radicals formed in the intestine in this disease. Reaction with free radicals does not, however, occur in patients with rheumatoid arthritis treated with the same agent. Furthermore, a significant correlation exists between the activity in the intestine of free radicals, as measured by the rate of lipid peroxidation, and the disease activity.

Ulcerative colitis and Crohn's disease are chronic inflammatory bowel diseases. The most widely prescribed drug for treatment of these diseases, sulfasalazine, has been shown to inhibit the activity of free radicals, as the active moiety of sulfasalazine, 5-aminosalicylic acid, is a radical scavenger. This effect of 5-aminosalicylic acid may be of clinical relevance, as a recent study has shown that 5-aminosalicylic acid reacts with oxygen-derived free radicals formed in the intestine in this disease. Reaction with free radicals does not, however, occur in patients with rheumatoid arthritis treated with the same agent. Furthermore, a significant correlation exists between the activity in the intestine of free radicals, as measured by the rate of lipid peroxidation, and the disease activity.