Long-term clinical and radiological effectiveness and safety of ultralow doses of rituximab in rheumatoid arthritis: observational extension of the REDO trial.

BACKGROUND: The REDO trial (REtreatment with Rituximab in RhEmatoid arthritis: Disease Outcome after Dose Optimisation) showed similar disease activity for retreatment with ultralow doses (200 mg and 500 mg per 6 months) compared with standard low-dose rituximab (RTX, 1000 mg per 6 months). We performed an observational extension study of the REDO trial to assess long-term effectiveness. METHODS: Patients from the REDO trial were followed from start of the trial to censoring in April 2021. RTX use was at the discretion of patient and rheumatologist using treat to target. The primary outcome was disease activity (disease activity score in 28 joints C-reactive protein (DAS28-CRP)), analysed using a longitudinal mixed model by original randomisation and time-varying RTX dose. The original DAS28-CRP non-inferiority (NI) margin of 0.6 was used. RTX dose and persistence, safety and radiological outcomes were also assessed. FINDINGS: Data from 126 of 142 REDO patients was collected from 15 December 2016, up to 30 April 2021. Drop-outs continued treatment elsewhere (n=3) or did not consent (n=13).Disease activity did not differ by original randomisation group: 1000 mg mean DAS28-CRP (95% CI) of 2.2 (2.0 to 2.5), 500 mg 2.3 (2.1 to 2.4) and 200 mg 2.4 (2.2 to 2.5). Lower time-varying RTX dose was associated with higher DAS28-CRP (0.22 (95% CI 0.05 to 0.40) higher for 200 mg/6 months compared with 1000 mg/6 months), but remained within the NI-margin. RTX persistence was 93%. Median RTX dose was 978 mg (IQR 684-1413) per year, and no association was found between RTX dose and adverse events or radiological damage. INTERPRETATION: Long-term use of ultralow doses of RTX is effective in patients with rheumatoid arthritis responding to standard dose RTX.

Parenting problems postpartum can be detected early in pregnancy in patients with rheumatoid arthritis.

OBJECTIVE: To describe parenting disability postpartum in patients with rheumatoid arthritis (RA) using the Parenting Disability Index and to determine early in pregnancy which patients will face parenting problems postpartum. METHODS: Data were collected from a prospective study on pregnancy and RA (Pregnancy induced Amelioration of Rheumatoid Arthritis study). Postpartum visits were performed at 6, 12 and 26 weeks after delivery. Domains causing parenting difficulties were identified. A multivariate logistic regression model to identify which patients develop parenting disabilities postpartum with patient characteristics in the first trimester as covariates was performed. RESULTS: 148 patients were eligible for this study. The domains carrying, hygiene, feeding, getting up and down, and household/shopping were frequently scored as difficult. Maintaining discipline, taking care of the children when sick, listening and having other children over caused the least problems. 30.1% of patients with RA report low parenting disability, 30.9% reports intermediate disability and 39.0% reports high disability. Patients with a low Health Assessment Questionnaire (HAQ)-score in the first trimester (OR 9.2, 95% CI 3.0 to 27.7, p<0.001) and low disease activity in the first trimester (Disease Activity Score 28-joint count C reactive protein<3.2) (OR 4.8, 95% CI 1.8 to 12.9, p=0.002) were likely to report low parenting disability postpartum. Patients with a longer disease duration (OR 0.87, 95% CI 0.79 to 0.95, p=0.003) were less likely to report low parenting disability postpartum. A high HAQ-score in the first trimester (OR 4.54, 95% CI 1.99 to 10.34, p<0.001) and erosive disease (OR 2.32, 95% CI 1.00 to 5.35, p=0.049) increased the risk of high parenting disability postpartum. CONCLUSION: Physical domains of parenting postpartum are most commonly affected in patients with RA. When counselling patients with RA, a HAQ-score in the first trimester is the most reliable marker to identify patients that develop parenting disability after delivery.

MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease.

BACKGROUND: Given the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA. METHODS: Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls. RESULTS: Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7×10-17). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7×10-35) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3×10-49). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4×10-5), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5×10-6). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. CONCLUSIONS: We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Société Française de Rhumatologie and others.).

Psychosocial predictors of DMARD adherence in the first three months of treatment for early arthritis.

OBJECTIVES: To induce disease remission, early arthritis patients should adhere to their disease-modifying antirheumatic drugs (DMARD) in the first months after diagnosis. It remains unknown why some patients are non-adherent. We aimed to identify patients at risk for non-adherence in the first 3 months of treatment. METHODS: Adult DMARD-naive early arthritis patients starting synthetic DMARDs filled out items on potential adherence predictors at baseline. Adherence was measured continuously. Non-adherence was defined as not opening the electronically monitored pill bottle when it should have been. Items were reduced and clustered using principal component analysis. The most discriminating items were identified with latent trait models. We used a multivariable logistic regression model to find non-adherence predictors. RESULTS: 301 patients agreed to participate. Adherence was high and declined over time. Principal component analysis led to 7 dimensions, while subsequent latent trait models analyses led to 15 dimensions. Two dimensions were associated with adherence, one dimension was associated with non-adherence. CONCLUSIONS: Information seeking behavior and positive expectations about the course of the disease are associated with adherence. Patients who become passive because of pain are at risk for non-adherence. PRACTICE IMPLICATIONS: Rheumatologists have cues to identify non-adherence, and may intervene on non-adherence through implementing shared decision making techniques.

Disease activity or remission of rheumatoid arthritis before, during and following pregnancy.

PURPOSE OF REVIEW: Disease activity of rheumatoid arthritis (RA) can ameliorate spontaneously during pregnancy; however, adequate measurement of disease activity during pregnancy is a challenge, as is quantifying disease improvement during pregnancy and disease flare postpartum. Adverse pregnancy outcomes may be related to high disease activity during pregnancy, the full extent of which remains to be fully defined. RECENT FINDINGS: Disease activity might best be measured during pregnancy with DAS28-CRP without visual analogue scale (VAS) general health. Pregnancy outcome seems to be worse in patients with RA compared with healthy controls. High disease activity of RA may contribute importantly both to the longer time to conceive and worse pregnancy outcome. SUMMARY: Low disease activity of RA before, during and after pregnancy may be best for both mother and child. Counselling of patients on reproductive health and preconception treat-to-target management may help to achieve lower disease activity. This may result in better pregnancy outcomes.

[Acute liver injury in a patient with anorexia nervosa]. / Een anorexiapatiënt met acute leverproefstoornissen.

BACKGROUND: Anorexia nervosa is associated with somatic complications. Mildly abnormal liver tests are frequently seen; however, severe acute liver injury is rare in anorexia. CASE DESCRIPTION: A 23-year-old woman was admitted with acutely elevated liver enzymes and hypoglycemia. All diagnostic tests for acute hepatitis were negative. Therefore, we made the diagnosis of 'acute liver injury due to anorexia'. With supportive care such as rehydration, drip-feed and infusions with glucose, the patient recovered and her liver tests improved. CONCLUSION: Severe acute liver injury is a rare but life-threatening complication of anorexia nervosa. Its aetiology is unknown. Autophagy of hepatocytes, hypoperfusion of the liver and oxidative stress may play a role in the pathogenesis. Treatment consists of rehydration and nutritional support.

Construct and criterion validity of several proposed DAS28-based rheumatoid arthritis flare criteria: an OMERACT cohort validation study.

BACKGROUND: To describe rheumatoid arthritis (RA) worsening that leads to change or re-initiation of treatment, several Disease Activity Score 28 (DAS28)-based flare criteria have been described, but none validated. METHODS: Six previously published DAS28-based flare criteria ((1) increase in DAS28 >1.2, or >0.6 if DAS28 >5.1; (2) increase in DAS28 >1.2, or >0.6 if DAS28 ≥3.2; (3) increase >0.6 or DAS28 >3.2; (4) increase in DAS28 >1.2; (5) DAS28 >3.2; (6) DAS28 >2.6) were tested against five hypotheses concerning criterion and construct validity: (1+2) Sensitivity and specificity >70% compared with patient's/physician's judgment; (3) difference in proportion with disease modifying anti-rheumatic drug/corticosteroid initiation/increase >0.2; (4) mean difference in C-reactive protein (CRP) >10 mg/l; and (5) no statistical difference in Short Form-36 Mental Health subscale change. Three different RA patient databases in which flare might occur were used. Sensitivity/specificity, χ(2) and two-sample student t test analyses were done. RESULTS: The analyses included 51, 147 and 744 RA patients, from the three databases. Criterion 2 fulfilled most hypotheses: 4 out of 5. Sensitivity and specificity varied between 63%-78% and 84%-92%. Construct validity was demonstrated with 23% more treatment change, higher mean CRP (11.4 mg/l) and depression scale change of -5. Criteria 3, 5 and 6 were more sensitive, criteria 1, 2 and 4 more specific. CONCLUSIONS: An increase in DAS28 >1.2 or >0.6 if DAS28 ≥3.2 appears most discriminating and valid by our predefined validation criteria. Considering the other criteria, sensitivity and specificity shown here might facilitate use in different settings.

Circulating maternal cytokines influence fetal growth in pregnant women with rheumatoid arthritis.

BACKGROUND: High rheumatoid arthritis (RA) disease activity during pregnancy is associated with a lower birth weight. Active RA is characterised by high circulating levels of cytokines, which can mediate placental growth and remodelling. OBJECTIVES: To assess the influence of maternal serum cytokine levels on birth weight in RA pregnancy. METHODS: This study is embedded in the PARA Study, a prospective study on RA and pregnancy. In the present study, 161 pregnant women with RA and 32 healthy pregnant women were studied. The main outcome measures were birth weight SD score (birth weight SDS) in relation to maternal serum levels of interleukin-10 (IL-10), interleukin-6 (IL-6) and tumour necrosis factor-α (TNFα) at three different time points: preconception and during the first and third trimester. Single-nucleotide polymorphisms (SNPs) in the corresponding cytokine genes were also studied. RESULTS: During the first trimester, IL-10 was detectable in 16% of patients with RA, IL-6 in 71%, and TNFα in all patients with RA. Mean birth weight SDS of children born to mothers with RA was higher when IL-10 level was high compared with low (difference=0.75; p=0.04), and lower when IL-6 was high compared with low (difference=0.50; p<0.01) in the first trimester. No correlation was seen at the other time points studied or with TNFα. Cytokine levels were not related to their corresponding SNPs. CONCLUSIONS: Maternal IL-10 and IL-6 levels are associated with fetal growth in RA. In the first trimester, high IL-10 levels are associated with higher birth weight SDS, and high IL-6 levels are associated with lower birth weight SDS, even after correction for disease activity.

Glucocorticoid receptor gene polymorphisms and disease activity during pregnancy and the postpartum period in rheumatoid arthritis.

INTRODUCTION: The mechanism underlying the spontaneous improvement of rheumatoid arthritis (RA) during pregnancy and the subsequent postpartum flare is incompletely understood, and the disease course varies widely between pregnant RA patients. In pregnancy, total and free levels of cortisol increase gradually, followed by a postpartum decrease to prepregnancy values. The glucocorticoid receptor (GR) polymorphisms BclI and N363S are associated with relatively increased glucocorticoid (GC) sensitivity, whereas the 9ß and ER22/23EK polymorphisms of the GR gene are associated with a relatively decreased GC sensitivity. We examined the relation between the presence of these GR polymorphisms and level of disease activity and disease course of RA during pregnancy and postpartum. METHODS: We studied 147 participants of the PARA study (Pregnancy-Induced Amelioration of Rheumatoid Arthritis study), a prospective study investigating the natural improvement during pregnancy and the postpartum flare in women with RA. Patients were visited, preferably before pregnancy, at each trimester and at three postpartum time points. On all occasions, disease activity was scored by using DAS28. All patients were genotyped for the GR polymorphisms BclI, N363S, 9ß, and ER22/23EK and divided in groups harboring either polymorphisms conferring increased GC sensitivity (BclI and N363S; GC-S patients) or polymorphisms conferring decreased GC sensitivity (9ß or 9ß + ER22/23EK; GC-I patients). Data were analyzed by using a mixed linear model, comparing GC-S patients with GC-I patients with respect to improvement during pregnancy and the postpartum flare. The cumulative disease activity was calculated by using time-integrated values (area under the curve, AUC) of DAS28 in GC-I patients versus GC-S patients. Separate analyses were performed according to the state of GC use. RESULTS: GC-S patients treated with GC had a significantly lower AUC of DAS28 in the postpartum period than did GC-I patients. This difference was not observed in patients who were not treated with GCs. During pregnancy, GC-S and GC-I patients had comparable levels of disease activity and course of disease. CONCLUSIONS: Differences in relative GC sensitivity, as determined by GR polymorphisms, are associated with the level of disease activity in the postpartum period in GC-treated patients, but they do not seem to influence the course of the disease per se.

[Rheumatic diseases need more attention in case of the desire to have children and during pregnancy]. / Reumatische ziekten bij kinderwens en zwangerschap. Extra aandacht vereist.

Treatment of rheumatic diseases, such as rheumatoid arthritis, systemic lupus erythematosus and Bechterew's disease is still improving and the number of fertile patients with a wish to conceive will probably increase. New knowledge regarding the course of rheumatic diseases during pregnancy and post partum herald a change in the support of women with rheumatic diseases who desire to have children. Justified use of antirheumatic drugs before, during and after pregnancy is a key issue for a successful pregnancy. The newer agents such as tumour necrosis factor (TNF) alpha blocking agents can also be of use. Specific preconception care should be offered to women with rheumatic diseases to optimize and increase chances of a successful pregnancy.

Mannose-binding lectin does not explain the course and outcome of pregnancy in rheumatoid arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) improves during pregnancy and flares after delivery. It has been hypothesized that high levels of the complement factor mannose-binding lectin (MBL) are associated with a favourable disease course of RA by facilitating the clearance of pathogenic immunoglobulin G (IgG) lacking galactose sugar moieties. During pregnancy, increased galactosylation of IgG and simultaneously increased MBL levels can be observed, with the latter being strictly related to maternal MBL genotypes. Therefore, increased MBL levels in concert with increased IgG galactosylation may be associated with pregnancy-induced improvement of RA. The objective of this study was to investigate whether MBL genotypes are associated with changes in RA disease activity and with changes in IgG galactosylation during pregnancy and in the postpartum period. We also studied the association between MBL genotypes and pregnancy outcomes in RA. METHODS: Serum from 216 patients with RA and 31 healthy controls participating in the Pregnancy-induced Amelioration of Rheumatoid Arthritis (PARA) Study was collected before, during and after pregnancy. IgG galactosylation was determined by performing matrix-assisted laser desorption/ionization time of flight mass spectrometry. Disease activity was determined using the internationally recognized Disease Activity Score 28 (DAS28). MBL genotypes were determined. The pregnancy outcome measures studied were gestational age, birth weight, miscarriage and hypertensive disorders. RESULTS: No association was found between the MBL genotype groups and changes in RA disease activity (P = 0.89) or changes in IgG galactosylation (patients, P = 0.75, and controls, P = 0.54) during pregnancy and in the postpartum period. Furthermore, MBL genotype groups were not related to the studied pregnancy outcome measures. CONCLUSIONS: This study does not provide evidence for a role for MBL in the improvement of RA during pregnancy or for a role for MBL in pregnancy outcome.

Immunoglobulin G galactosylation and sialylation are associated with pregnancy-induced improvement of rheumatoid arthritis and the postpartum flare: results from a large prospective cohort study.

INTRODUCTION: Improvement of rheumatoid arthritis (RA) during pregnancy has been causatively associated with increased galactosylation of immunoglobulin G (IgG) N-glycans. Since previous studies were small, did not include the postpartum flare and did not study sialylation, these issues were addressed in the present study. METHODS: Serum from 148 RA cases and 32 healthy controls was collected at several time points before, during and after pregnancy. Improvement during pregnancy and postpartum flare were determined according to the European League Against Rheumatism (EULAR) response criteria. Galactosylation and sialylation of Immunoglobulin G (IgG) and the presence of bisecting N-acetylglucosamine (GlcNAc) were analyzed by matrix-assisted laser desorption/ionization - time of flight - mass spectrometry (MALDI-TOF-MS). RESULTS: IgG1 and IgG2 galactosylation of the cases and controls increased during pregnancy with a maximum in the third trimester. Galactosylation decreased directly postpartum. IgG galactosylation of controls was at a higher level than cases (P < 0.001 at all time points) and a similar pattern was observed for sialylation. Moreover, there was a good association between galactosylation and sialylation. The increase in galactosylation was significantly more pronounced for cases with improvement than cases without improvement during pregnancy. The reverse was true for deteriorators and non-deteriorators postpartum. The presence of bisecting GlcNAc was not significantly influenced by pregnancy or postpartum for cases and controls. CONCLUSIONS: This large cohort study demonstrates the association of changes in galactosylation with both pregnancy-induced improvement and postpartum flare in RA-patients, suggesting a role for changes in glycosylation in the pregnancy-induced improvement of RA.

Association of higher rheumatoid arthritis disease activity during pregnancy with lower birth weight: results of a national prospective study.

OBJECTIVE: To determine the outcome of pregnancy in women with rheumatoid arthritis (RA) in relation to disease activity and medication use during the pregnancy. METHODS: In a prospective study, pregnant women with RA were evaluated before conception (when possible), during each trimester of the pregnancy, and postpartum. Clinical characteristics, disease activity, medication use, and pregnancy outcome were analyzed. To examine the independent influence of prednisone use and disease activity on birth weight, regression analyses were performed, with adjustments for gestational age of the child at delivery, the sex of the newborn, and the mother's smoking status, education level, parity, and use of an assisted reproduction technique. Kaplan-Meier curve analyses were performed to examine the association between medication use and gestational age at delivery. RESULTS: Data from 152 Caucasian RA patients with singleton pregnancies were available. Both the mean +/- SD birth weight (3,379 +/- 564 gm) and the mean +/- SD birth weight standard deviation score (SDS; +0.1 +/- 1.1), which is the birth weight adjusted for the gestational age and sex of the newborn, were comparable with those in the general population. On multiple linear regression analyses of birth weight and birth weight SDS, both of which were adjusted for covariates, only disease activity was associated with lower birth weight (P = 0.025). The gestational age at delivery was significantly lower in women who were taking prednisone (38.8 versus 39.9 weeks; P = 0.001), and their delivery was more often premature (<37 weeks; P = 0.004). CONCLUSION: Pregnancy outcome in women with well-controlled RA is comparable with that in the general population. The effect of prednisone on birth weight is mediated by a lower gestational age at delivery, whereas a higher level of disease activity independently influences birth weight negatively, suggesting an immune-mediated mechanism.

Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study.

OBJECTIVE: According to common knowledge and retrospective studies, approximately 75-90% of patients with rheumatoid arthritis (RA) will improve during pregnancy. Prospective data on disease activity during pregnancy are limited. Therefore, this study aimed to prospectively determine the disease activity during pregnancy in RA patients treated in an era of new treatment options. METHODS: For 84 RA patients (American College of Rheumatology criteria), a Disease Activity Score in 28 joints (DAS28) and medication use were obtained, before conception if possible, at each trimester of pregnancy and at 6, 12, and 26 weeks postpartum. Improvement and deterioration were determined by assessing changes in DAS28 and by applying the DAS28-derived European League Against Rheumatism (EULAR) response criteria. RESULTS: Disease activity decreased with statistical significance (P = 0.035) during pregnancy and increased postpartum. In patients with at least moderate disease activity in the first trimester (n = 52), at least 48% had a moderate response during pregnancy according to EULAR-defined response criteria. In patients with low disease activity in the first trimester (n = 32), disease activity was stable during pregnancy. Thirty-nine percent of patients had at least a moderate flare postpartum according to reversed EULAR response criteria. Less medication was used during pregnancy compared with before conception and compared with postpartum. CONCLUSION: This study demonstrates that patients achieve remission during pregnancy and deteriorate postpartum, although less frequently than previously described.

Measuring disease activity and functionality during pregnancy in patients with rheumatoid arthritis.

OBJECTIVE: Pregnancy has a favorable effect on the course of rheumatoid arthritis (RA), although the magnitude of this effect is equivocal because RA assessment tools have never been validated in pregnancy. The goal of this study was to assess how pregnancy influences the scoring of the Disease Activity Score in 28 joints (DAS28) and the Health Assessment Questionnaire (HAQ), and how both scores perform in pregnant patients with RA. METHODS: Thirty-two healthy women and 30 pregnant patients with RA were prospectively studied during pregnancy and at postpartum. At each trimester and postpartum the components of the DAS28 (global health [GH], erythrocyte sedimentation rate [ESR], and C-reactive protein level [CRP]) and HAQ scores were determined. Maximal influences of healthy pregnancy on each component of the DAS28 were calculated. The performances of different DAS28 scores and the HAQ were also determined in RA patients. Furthermore, variants of the HAQ were developed within the HAQ scoring rules. RESULTS: The components of the DAS28 were influenced by healthy pregnancy, with average increases in DAS28 score of 0.22 (GH), 1.1 (ESR), and 0.25 (CRP). The DAS28 calculated with CRP (DAS28-CRP) and without GH performed the best in pregnant RA patients. In healthy pregnancy, the median HAQ increased to 0.50 in the third trimester and was reduced by the HAQ variants to 0.25. CONCLUSION: Pregnancy considerably influences the scoring of the DAS28 and HAQ. RA disease activity in pregnant patients should preferably be calculated with DAS28-CRP without GH. Even with HAQ variants, influences of pregnancy on the assessment of functionality cannot be precluded.