Use of biologic agents in generalized myasthenia gravis is generally limited to therapy-refractory cases; benefit in new-onset disease is unknown.
To assess rituximab in refractory and new-onset ...generalized myasthenia gravis and rituximab vs conventional immunotherapy in new-onset disease.
A retrospective cohort study with prospectively collected data was conducted on a county-based community sample at Karolinska University Hospital, Stockholm, Sweden. Participants included 72 patients with myasthenia gravis, excluding those displaying muscle-specific tyrosine kinase antibodies, initiating rituximab treatment from January 1, 2010, to December 31, 2018, and patients with new-onset disease initiating conventional immunotherapy from January 1, 2003, to December 31, 2012, with 12 months or more of observation time. The present study was conducted from March 1, 2019, to January 31, 2020.
Treatment with low-dose rituximab (most often 500 mg every 6 months) or conventional immunosuppressants.
Time to remission (main outcome) as well as use of rescue therapies or additional immunotherapies and time in remission (secondary outcomes).
Of the 72 patients included, 31 patients (43%) were women; mean (SD) age at treatment start was 60 (18) years. Twenty-four patients had received rituximab within 12 months of disease onset and 48 received rituximab at a later time, 34 of whom had therapy-refractory disease. A total of 26 patients (3 12% women; mean SD age, 68 11 years at treatment start) received conventional immunosuppressant therapy. Median time to remission was shorter for new-onset vs refractory disease (7 vs 16 months: hazard ratio HR, 2.53; 95% CI, 1.26-5.07; P = .009 after adjustment for age, sex, and disease severity) and for rituximab vs conventional immunosuppressant therapies (7 vs 11 months: HR, 2.97; 95% CI, 1.43-6.18; P = .004 after adjustment). In addition, fewer rescue therapy episodes during the first 24 months were required (mean SD, 0.38 1.10 vs 1.31 1.59 times; mean difference, -1.26; 95% CI, -1.97 to -0.56; P < .001 after adjustment), and a larger proportion of patients had minimal or no need of additional immunotherapies (70% vs 35%; OR, 5.47; 95% CI, 1.40-21.43; P = .02 after adjustment). Rates of treatment discontinuation due to adverse events were lower with rituximab compared with conventional therapies (3% vs 46%; P < .001 after adjustment).
Clinical outcomes with rituximab appeared to be more favorable in new-onset generalized myasthenia gravis, and rituximab also appeared to perform better than conventional immunosuppressant therapy. These findings suggest a relatively greater benefit of rituximab earlier in the disease course. A placebo-controlled randomized trial to corroborate these findings is warranted.
A convenient way of dealing with confounding is the sibling comparison design, where the outcome in exposed individuals is compared with the outcome in their unexposed siblings. The standard analysis ...of sibling comparison designs assumes that the exposure and outcome of an individual do not affect the exposure and outcome of his/her siblings, sometimes referred to as an absence of sibling carryover or contagion effects. Unfortunately, there are many situations where carryover effects are likely to be present. In this article, we explore the consequences of carryover effects for sibling comparison designs. We show, using causal diagrams, when and why carryover effects lead to bias, and we investigate the sign and magnitude of this bias under various scenarios.
Objective
To estimate familial aggregation of rheumatoid arthritis (RA) in 3 large population‐representative samples and to test if familial aggregation is affected by rheumatoid factor ...(RF)/anti–citrullinated protein antibody (ACPA) status, type of relative, sex, and age at onset of RA.
Methods
A register‐based nested case–control study was performed in the Swedish total population. Data on patients with RA were ascertained through the nationwide Swedish Patient Register (n = 88,639), the clinical Swedish Rheumatology Quality Register (n = 11,519), and the Epidemiological Investigation of Rheumatoid Arthritis case–control study (n = 2,871). Data on first‐ and second‐degree relatives were obtained through the Swedish Multigeneration Register. Familial risks were calculated using conditional logistic regression.
Results
Consistent across data sources, the familial odds ratio for RA was ∼3 in first‐degree relatives of RA patients and 2 in second‐degree relatives. Familial risks were similar among siblings, parents, and offspring. Familial aggregation was not modified by sex, but was higher in RA patients with early‐onset disease and in RF/ACPA‐positive RA patients. The observed familial risks were consistent with a heritability of ∼50% for ACPA‐positive RA and ∼20% for ACPA‐negative RA.
Conclusion
The pattern of risks suggests that familial factors influence RA in men and women equally and that these factors are of less importance for late‐onset RA. Familial factors are more important for seropositive RA, but there is significant familial overlap between seropositive RA and seronegative RA. Even if the familial risk is assumed to be completely due to genetics, the observed risks suggest that heritability of RA is lower than previously reported, in particular for ACPA‐negative RA.
Prenatal environmental factors such as maternal adiposity may influence the risk of offspring autism spectrum disorders (ASD), though current evidence is inconsistent. The objective of this study was ...to assess the relationship of parental BMI and gestational weight gain (GWG) with risk of offspring ASD in a population-based cohort study using family-based study designs.
The cohort was based in Stockholm County, Sweden, including 333,057 individuals born 1984-2007, of whom 6420 were diagnosed with an ASD. We evaluated maternal body mass index (BMI) at first antenatal visit, GWG and paternal BMI at the time of conscription into the Swedish military as exposures using general estimating equation (GEE) models with logit link.
At the population level, maternal overweight/obesity was associated with increased risk of offspring ASD odds ratio (OR)25 ≤ BMI < 30 1.31, 95% confidence interval = 1.21-1.41; ORBMI ≥ 30 1.94, 1.72-2.17, as was paternal underweight (ORBMI < 18.5, 1.19, 1.06-1.33) and obesity (ORBMI ≥ 30 1.47, 1.12-1.92) in mutually adjusted models. However, in matched sibling analyses, the relationship between elevated maternal BMI and ASD risk was not apparent. GWG had a U-shaped association with offspring ASD at the population level (ORinsufficient 1.22, 1.07-1.40; ORexcessive 1.23, 1.08-1.40). Matched sibling analyses were suggestive of elevated risk with excessive GWG (ORinsufficient 1.12, 0.68-1.84; ORexcessive 1.48, 0.93-2.38).
Whereas population-level results suggested that maternal BMI was associated with ASD, sibling analyses and paternal BMI analyses indicate that maternal BMI may also be a proxy marker for other familial risk factors. Evidence is stronger for a direct link between GWG and ASD risk.
Background
The Apgar score consists of five components: heart rate, respiratory effort, muscle tone, reflex irritability, and colour. Although the Apgar score has been used for 60 years, the specific ...contribution of the Apgar score components with respect to risks and prediction of neonatal mortality remains unknown. Likewise, the value of reduced scores (including less than five Apgar score components) has rarely been investigated.
Methods
In a population‐based cohort study of 148 765 liveborn singleton infants in Sweden 2008–2013, we investigated components of Apgar score at 5 min with respect to relative risks and prediction (using ROC curves, sensitivity, and positive predictive values) of neonatal mortality.
Results
Reduced values (0–1) of heart rate, respiratory effort, and colour were independently associated with increased relative risks of neonatal mortality. For the full Apgar score, the sensitivity and positive predictive values of neonatal mortality (cut‐off ≤3) were by gestational age: ≤31 weeks: 56.1% and 49.2%; 32–36 weeks: 25.0% and 18.2%; and ≥37 weeks: 35.2% and 9.3%, respectively. When only heart rate and respiratory effort were considered (range 0–4; cut‐off ≤2), corresponding values were 66.7% and 34.9%; 37.5% and 13.0%; and 46.3% and 7.6%, respectively.
Conclusions
A reduced Apgar score has generally the same predictability of neonatal mortality as the full Apgar score. The full Apgar score or reduced scores may be better predictors of neonatal mortality in very preterm infants (≤31 weeks) than in infants with longer gestations.
In this issue of the Journal, von Ehrenstein et al. (Am J Epidemiol. 2021;190(5):728–737) add to the large and growing literature on the potentially causal association between prenatal exposure to ...maternal smoking and neuropsychiatric health. In addition to statewide, prospectively collected data, a particular strength was their ability to perform a sibling-comparison design, contrasting the rate of autism spectrum disorder in siblings discordantly exposed to maternal smoking. Unfortunately, the estimate from the sibling pairs could neither confirm nor refute the conclusions based on the full cohort. Interpretation was hampered by broad confidence limits, and even had power been higher, the authors acknowledge a range of potential biases that would have made it difficult to draw any firm conclusions from a similarity or difference in the sibling-pair estimate and estimate from the full cohort. Was the addition of the sibling comparison actually worth the effort? In this commentary, I will briefly summarize the benefits and limitations of this design, and, with some caveats, argue that its inclusion in the study by von Ehrenstein et al. was indeed a strength and not just an ornamentation.
Anti-citrullinated protein antibodies (ACPA) are highly specific for rheumatoid arthritis (RA), but the diagnostic accuracy of ACPA in the general population has not been thoroughly assessed. We ...aimed to assess the diagnostic accuracy of ACPA for RA in the general population and to further characterise the citrullinated peptide recognition pattern.
Serum samples from a large population-representative twin cohort consisting of 12 590 individuals were analysed for the presence of ACPA using anti-CCP2 ELISA. All ACPA-positive samples were further tested on ELISAs for four peptide-specific ACPA. RA cases were identified by linkage to the Swedish National Patient Register at inclusion and after a median follow-up of 37 months (IQR 31-49).
350 out of 12 590 individuals had a positive anti-CCP2 test, measuring ACPA. Of these, 103 had an RA diagnosis at the time of blood donation and inclusion. During a median follow-up of 3 years, an additional 21 of the remaining 247 ACPA-positive individuals developed RA. Overall, a positive anti-CCP2 test had a positive predictive value of 29% for prevalent RA at inclusion (negative predictive value of 99.6%). High titres (>3× cut-off) of anti-CCP2 increased the positive predictive value to 48% (negative predictive value of 99.5%). ACPA-positive individuals without RA had lower anti-CCP2 titres and fewer peptide-specific ACPA than ACPA-positive patients with RA and higher C reactive protein levels than ACPA-negative individuals without RA.
Presence of ACPA and especially high titres of anti-CCP2 have a high diagnostic accuracy for an RA diagnosis in a population setting.
We compared the incidence of cardiovascular disease (CVD) in transgender participants with a diagnosis of gender dysphoria (GD) with and without gender-affirming hormone therapy (GAHT) to the ...incidence observed in the general population.
The population-based cohort included all individuals >10 years in Sweden linked to Swedish nationwide healthcare Registers (2006-16). Two comparator groups without GD/GAHT were matched (1:10) on age, county of residence, and on male and female birth-assigned sex, respectively. Cox proportional models provided hazard ratios (HRs) and 95% confidence intervals (CI) for CVD outcomes. Among 1779 transgender individuals 48% birth-assigned males (AMAB), 52% birth-assigned females (AFAB), 18 developed CVD, most of which were conduction disorders. The incidence of CVD for AFAB individuals with GD was 3.7 per 1000 person-years (95% CI: 1.4-10.0). Assigned male at birth individuals with GD had an incidence of CVD event of 7.1 per 1000 person-years (95% CI: 4.2-12.0). The risk of CVD event was 2.4 times higher in AMAB individuals (HR: 2.4, 95% CI: 1.3-4.2) compared with cisgender women, and 1.7 higher compared with cisgender men (HR: 1.7, 95% CI: 1.0-2.9). Analysis limited to transgender individuals without GAHT yielded similar results to those with GAHT treatment.
The incidence of CVD among GD/GAHT individuals was low, although increased compared with matched individuals without GD and similar to the incidence among GD/no GAHT individuals, thus not lending support for a causal relationship between treatment and CVD outcomes. Larger studies with longer follow-up are needed to verify these findings, as well as possible effect modification by comorbidity.
Abstract
Objective
Observational studies have reported an increased risk of infections associated with glucocorticoids in RA, not supported by evidence from randomized controlled trials. ...Inappropriately accommodating time-varying exposure and confounding in observational studies might explain the conflicting results. Therefore, we compared the incidence of serious infections between different oral glucocorticoid dose patterns over three years in a prospective inception cohort, adjusting for time-varying confounders in marginal structural models.
Methods
We included 9654 newly diagnosed RA patients from the Swedish Rheumatology Quality Register between 2007–2018 and followed them for three years after the first rheumatology visit. Follow-up was divided into 90-day periods. A mean oral prednisone daily dose was calculated for each period and categorized into ‘no use’, ‘low’ (≤10 mg/day) and ‘high’ (>10 mg/day) doses. The incidence of serious infections (hospitalization for infection) over follow-up periods was modelled by pooled logistic regression allowing separate effects for recent and past exposure.
Results
An increased incidence of serious infections was associated with higher compared with lower doses and with more recent compared with past glucocorticoid exposure. Over 3 years of follow-up, the marginal structural models predicted one additional serious infection for every 83 individuals treated with low GC doses for the first 6 months, and for every 125 individuals treated with high GC doses for the first 3 months, compared with no GC use.
Conclusion
Our results broadly agree with previous observational studies showing a dose dependent increased risk of infection associated with (recent) use of oral glucocorticoids.
Abstract
The aim of this study was to examine the validity of the Gender Dysphoria (GD) diagnoses in the Swedish National Patient Register (NPR), to discuss different register-based definitions of GD ...and to investigate incidence trends. We collected data on all individuals with registered GD diagnoses between 2001 and 2016 as well as data on the coverage in the NPR. We regarded gender confirming medical intervention (GCMI) as one proxy for a clinically valid diagnosis and calculated the positive predictive value (PPV) for receiving GCMI for increasing number of registered GD diagnoses. We assessed crude and coverage-adjusted time trends of GD during 2004–2015 with a Poisson regression, using assigned sex and age as interaction terms. The PPV for receiving GCMI was 68% for ≥ 1 and 79% for ≥ 4 GD-diagnoses. The incidence of GD was on average 35% higher with the definition of ≥ 1 compared to the definition of ≥ 4 diagnoses. The incidence of GD, defined as ≥ 4 diagnoses increased significantly during the study period and mostly in the age categories 10–17 and 18–30 years, even after adjusting for register coverage. We concluded that the validity of a single ICD code denoting clinical GD in the Swedish NPR can be questioned. For future research, we propose to carefully weight the advantages and disadvantages of different register-based definitions according to the individual study’s needs, the time periods involved and the age-groups under study.
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