Medication regimens using conditioning via variable reinforcement have shown similar or improved therapeutic effects as full pharmacological treatment, but evidence in patient populations is scarce... Show moreMedication regimens using conditioning via variable reinforcement have shown similar or improved therapeutic effects as full pharmacological treatment, but evidence in patient populations is scarce. This proof-of-principle double-blind randomized clinical trial examined whether treatment effects in recent-onset rheumatoid arthritis (RA) can be optimized through pharmacological conditioning. After four months of standardized treatment (n = 46), patients in clinical remission (n = 19) were randomized to the Control group (C), continuing standardized treatment (n = 8), or the Pharmacological Conditioning (PC) group, receiving variable treatment according to conditioning principles (n = 11). After eight months, treatment was tapered and discontinued linearly (C) or variably (PC). Standard treatment led to large improvements in disease activity and HRQoL in both groups. The groups did not differ in the percentage of drug-free clinical remission obtained after conditioning or continued standard treatment. The PC group did show a larger decrease in self-reported disease activity (Cohen's d = 0.9) and a smaller increase in TNF-alpha levels (Cohen's d = 0.7) than the C group. During all phases, more differences between groups were found for the patients who followed protocol than for the intention-to-treat sample. Although the results are not conclusive, pharmacological conditioning may have some advantages in terms of disease progression and stability, especially during the conditioning phase, compared with standard clinical treatment. The effects may be particularly beneficial for patients who show a good initial response to increased medication dosages. Show less
Almayali, A.A.H.; Boers, M.; Hartman, L.; Opris, D.; Bos, R.; Kok, M.R.; ... ; Wee, M.M. ter 2023
Objective The randomised placebo-controlled GLORIA (Glucocorticoid LOw-dose in RheumatoId Arthritis) trial evaluated the benefits and harms of prednisolone 5 mg/day added to standard care for 2... Show moreObjective The randomised placebo-controlled GLORIA (Glucocorticoid LOw-dose in RheumatoId Arthritis) trial evaluated the benefits and harms of prednisolone 5 mg/day added to standard care for 2 years in patients aged 65+ years with rheumatoid arthritis (RA). Here, we studied disease activity, flares and possible adrenal insufficiency after blinded withdrawal of study medication.Methods Per protocol, patients successfully completing the 2-year trial period linearly tapered and stopped blinded study medication in 3 months. We compared changes in disease activity after taper between treatment groups (one-sided testing). Secondary outcomes (two-sided tests) comprised disease flares (DAS28 (Disease Activity Score 28 joints) increase >0.6, open-label glucocorticoids or disease-modifying antirheumatic drug (DMARD) increase/switch after week 4 of tapering) and symptoms/signs of adrenal insufficiency. In a subset of patients from 3 Dutch centres, cortisol and ACTH were measured in spot serum samples after tapering.Results 191 patients were eligible; 36 met treatment-related flare criteria and were only included in the flare analysis. Mean (SD) DAS28 change at follow-up: 0.2 (1.0) in the prednisolone group (n=76) vs 0.0 (1.2) in placebo (n=79). Adjusted for baseline, the between-group difference in DAS28 increase was 0.16 (95% confidence limit –0.06, p=0.12). Flares occurred in 45% of prednisolone patients compared with 33% in placebo, relative risk (RR) 1.37 (95% CI 0.95 to 1.98; p=0.12). We found no evidence for adrenal insufficiency.Conclusions Tapering prednisolone moderately increases disease activity to the levels of the placebo group (mean still at low disease activity levels) and numerically increases the risk of flare without evidence for adrenal insufficiency. This suggests that withdrawal of low-dose prednisolone is feasible and safe after 2 years of administration. Show less
Liem, S.I.E.; Ciaffi, J.; Leeuwen, N.M. van; Boonstra, M.; Ahmed, S.; Voorde, L.J.J. van de; ... ; Vries-Bouwstra, J. de 2023
Background: Since 2009, Dutch patients with a confirmed diagnosis/suspicion of systemic sclerosis (SSc) can be referred to the Leiden Combined Care in Systemic Sclerosis (CCISS) cohort. This study... Show moreBackground: Since 2009, Dutch patients with a confirmed diagnosis/suspicion of systemic sclerosis (SSc) can be referred to the Leiden Combined Care in Systemic Sclerosis (CCISS) cohort. This study evaluated whether early recognition of SSc has improved over time and whether disease characteristics and survival has changed over time. Methods: 643 SSc patients fulfilling American College of Rheumatology/European Alliance of Associations for Rheumatology 2013 SSc criteria were included and categorised into three groups based on cohort-entry year: (1) 2010-2013 (n=229 (36%)), (2) 2014-2017 (n=207 (32%)) and (3) 2018-2021 (n=207 (32%)). Variables including disease duration, interstitial lung disease (ILD), digital ulcers (DU), diffuse cutaneous SSc (dcSSc), antitopoisomerase (ATA) and anticentromere (ACA) antibodies, and survival from disease onset were compared between cohort-entry groups, including analyses stratified for sex and autoantibodies. Results: Over time, duration between onset of disease symptoms and cohort entry decreased in males and females, but was always longer in females than in males.The proportion of patients presenting with DU decreased, especially in ACA+SSc patients. Almost no ACA+ patients presented with ILD, while in ATA+ patients this proportion was 25% in 2010-2013 and decreased to 19% in 2018-2021. A reduction in patients presenting with clinically meaningful ILD and dcSSc was observed.Overall 8-year survival for males was 59% (95% CI 40% to 73%) and for females 89% (95% CI 82% to 93%). Eight-year survival showed a trend for improvement over time, and was always worse in males. Conclusion: We observed a decrease in disease duration in Leiden CCISS cohort at cohort entry, possibly indicating more timely diagnosis of SSc. This could provide opportunities for early interventions. While symptom duration at presentation is longer in females, mortality is consistently higher in males, underlining the urge for sex-specific treatment and follow-up. Show less
Pol, J.A. van der; Akdemir, G.; Broek, M. van den; Dirven, L.; Kerstens, P.J.S.M.; Lems, W.F.; ... ; Allaart, C.F. 2023
Objectives: To investigate whether repair of erosions and joint space narrowing (JSN) in rheumatoid arthritis (RA) occurs and whether clinical variables predict this. Methods: Eight-year follow-up... Show moreObjectives: To investigate whether repair of erosions and joint space narrowing (JSN) in rheumatoid arthritis (RA) occurs and whether clinical variables predict this. Methods: Eight-year follow-up data of the BeSt-study were used. Patients with recent onset RA (1987 criteria) were randomised to four treatment strategies and treated-to-target (Disease Activity Score (DAS)<= 2.4). Yearly radiographs of hands and feet were scored in non-chronological order by four independent readers, using the Sharp/van der Heijde score (SHS). Damage repair was defined as a negative Delta SHS in an individual joint, seen by >= 3 out of 4 readers and persisting >= 2 consecutive years. Associations between repair and DAS, prednisone use, infliximab use, anticitrullinated protein antibody, gender, age, body mass index, symptom duration and randomisation arm were investigated with logistic regression analyses, corrected for mean SHS. Results: Repair was seen in 17 patients (5.3%); 10 had regression of JSN, 7 of erosions, none had both. There were no significant associations in any of the regression analyses. Conclusion: After 8 years of treatment to target DAS <= 2.4 in 508 patients with recent onset RA, repair of JSN and erosions was seen in 17/320 patients (5.3%). Probably due to the rarity of repair, we found no associations with suppression of disease activity or other predictors and repair. Show less
Liem, S.I.E.; Ciaffi, J.; Leeuwen, N.M. van; Boonstra, M.; Ahmed, S.; Voorde, L.J.J. van de; ... ; Vries-Bouwstra, J. de 2023
Background Since 2009, Dutch patients with a confirmed diagnosis/suspicion of systemic sclerosis (SSc) can be referred to the Leiden Combined Care in Systemic Sclerosis (CCISS) cohort. This study... Show moreBackground Since 2009, Dutch patients with a confirmed diagnosis/suspicion of systemic sclerosis (SSc) can be referred to the Leiden Combined Care in Systemic Sclerosis (CCISS) cohort. This study evaluated whether early recognition of SSc has improved over time and whether disease characteristics and survival has changed over time.Methods 643 SSc patients fulfilling American College of Rheumatology/European Alliance of Associations for Rheumatology 2013 SSc criteria were included and categorised into three groups based on cohort-entry year: (1) 2010–2013 (n=229 (36%)), (2) 2014–2017 (n=207 (32%)) and (3) 2018–2021 (n=207 (32%)). Variables including disease duration, interstitial lung disease (ILD), digital ulcers (DU), diffuse cutaneous SSc (dcSSc), antitopoisomerase (ATA) and anticentromere (ACA) antibodies, and survival from disease onset were compared between cohort-entry groups, including analyses stratified for sex and autoantibodies.Results Over time, duration between onset of disease symptoms and cohort entry decreased in males and females, but was always longer in females than in males.The proportion of patients presenting with DU decreased, especially in ACA+SSc patients. Almost no ACA+ patients presented with ILD, while in ATA+ patients this proportion was 25% in 2010–2013 and decreased to 19% in 2018–2021. A reduction in patients presenting with clinically meaningful ILD and dcSSc was observed.Overall 8-year survival for males was 59% (95% CI 40% to 73%) and for females 89% (95% CI 82% to 93%). Eight-year survival showed a trend for improvement over time, and was always worse in males.Conclusion We observed a decrease in disease duration in Leiden CCISS cohort at cohort entry, possibly indicating more timely diagnosis of SSc. This could provide opportunities for early interventions. While symptom duration at presentation is longer in females, mortality is consistently higher in males, underlining the urge for sex-specific treatment and follow-up. Show less
Pol, J.A. van der; Akdemir, G.; Broek, M. van den; Dirven, L.; Kerstens, P.J.S.M.; Lems, W.F.; ... ; Allaart, C.F. 2023
Objectives To investigate whether repair of erosions and joint space narrowing (JSN) in rheumatoid arthritis (RA) occurs and whether clinical variables predict this.Methods Eight-year follow-up... Show moreObjectives To investigate whether repair of erosions and joint space narrowing (JSN) in rheumatoid arthritis (RA) occurs and whether clinical variables predict this.Methods Eight-year follow-up data of the BeSt-study were used. Patients with recent onset RA (1987 criteria) were randomised to four treatment strategies and treated-to-target (Disease Activity Score (DAS)≤2.4). Yearly radiographs of hands and feet were scored in non-chronological order by four independent readers, using the Sharp/van der Heijde score (SHS). Damage repair was defined as a negative ΔSHS in an individual joint, seen by ≥3 out of 4 readers and persisting ≥2 consecutive years. Associations between repair and DAS, prednisone use, infliximab use, anticitrullinated protein antibody, gender, age, body mass index, symptom duration and randomisation arm were investigated with logistic regression analyses, corrected for mean SHS.Results Repair was seen in 17 patients (5.3%); 10 had regression of JSN, 7 of erosions, none had both. There were no significant associations in any of the regression analyses.Conclusion After 8 years of treatment to target DAS≤2.4 in 508 patients with recent onset RA, repair of JSN and erosions was seen in 17/320 patients (5.3%). Probably due to the rarity of repair, we found no associations with suppression of disease activity or other predictors and repair. Show less
Hepatotoxicity is a serious adverse drug reaction related to methotrexate (MTX). However, the cause of drug-induced liver injury (DILI) is still unclear and unpredictable. Genetic risk factors may... Show moreHepatotoxicity is a serious adverse drug reaction related to methotrexate (MTX). However, the cause of drug-induced liver injury (DILI) is still unclear and unpredictable. Genetic risk factors may predispose for MTX-DILI. Therefore, we conducted a nested case-control genome-wide association study to explore genetic risk factors associated with MTX-DILI. Seven international groups contributed blood samples and data of patients with rheumatoid arthritis who used MTX. MTX-DILI was defined as an alanine aminotransferase (ALT) level of at least three times the upper limit of normal (ULN), to increase contrast controls ALT levels did not raise above two times the ULN. Per study site, control subjects and patients with MTX-DILI (ratio 3:1) were matched for age, gender, and duration of MTX use. Patients were genotyped using Illumina GSA MD-24v1-0 and data were imputed using the 1000 Genomes reference panel. Single-nucleotide polymorphisms (SNPs) were analyzed using an additive genetic model, corrected for sex, country, and age. A P-value of <= 5 x 10(-8) was considered significant, whereas a P-value of <= 5 x 10(-6) was considered suggestive. A total of 108 MTX-DILI cases and 311 controls were included for association analysis. None of the SNPs were significantly associated with MTX-DILI. However, we found seven suggestive genetic variants associated with MTX-DILI (P-values 7.43 x 10(-8) to 4.86 x 10(-6)). Of those, five SNPs were in the intronic protein-coding regions of FTCDNL1, BCOR, FGF14, RBMS3, and PFDN4/DOK5. Investigation of candidates SPATA9 (rs72783407), PLCG2 (rs60427389), RAVER2 (rs72675408), JAK1 (rs72675451), PTPN2 (rs2476601), MTHFR C677T (rs1801133), and into the HLA region did not show significant findings. No genetic variants associated with MTX-DILI were found, whereas suggestive SNPs need further investigation. Show less
Introduction: Early diagnosis of systemic sclerosis (SSc) is important to start therapeutic interventions timely. Important risk factors for progression to SSc are the SSc-specific autoantibodies,... Show moreIntroduction: Early diagnosis of systemic sclerosis (SSc) is important to start therapeutic interventions timely. Important risk factors for progression to SSc are the SSc-specific autoantibodies, of whom anti-centromere antibodies (ACA) and anti-topoisomerase I antibodies (ATA) are the most frequent. ATA is associated with a severe disease course. A more detailed characterisation of the ATA-response in SSc might increase insights in preclinical disease stages and improve prognostication. To address this we identified all patients with suspected very early ATA-positive SSc, defined as all patients who are ATA-positive not fulfilling American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 criteria, in the Leiden Combined Care in Systemic Sclerosis (CCISS)-cohort and found very low numbers. Methods This triggered us to search the literature on the ATA prevalence in patients with suspected very early SSc and contribution of the SSc-specific autoantibodies to progression from suspected very early to definite SSc. To increase insights on the ATA-response in suspected very early SSc, we then evaluated the association between the ATA-response and time between onset of Raynaud's phenomenon (RP) and first non-RP symptom, as a proxy for progressing to definite SSc, in all patients with ATA-positive SSc from the Leiden CCISS-cohort. Results: In short, included studies show that prevalence of ATA is much lower in suspected very early SSc than in populations fulfilling ACR/EULAR 2013 criteria. After 1-15 years of follow-up, only 52% of the patients with suspected very early SSc progress to definite SSc. ATA-IgG levels tend to be higher in patients with ATA-positive SSc with more rapid disease progression. Conclusion: Although a role of ATA in disease progression is suggested, more studies on the ATA response in suspected very early SSc are warranted. Show less
Objectives: To investigate whether meticulously following a treat-to-target (T2T)-strategy in daily clinical practice will lead to less radiographic progression in patients with active RA who start... Show moreObjectives: To investigate whether meticulously following a treat-to-target (T2T)-strategy in daily clinical practice will lead to less radiographic progression in patients with active RA who start (new) DMARD-therapy. Methods: Patients with RA from 10 countries starting/changing conventional synthetic or biologic DMARDs because of active RA, and in whom treatment intensification according to the T2T principle was pursued, were assessed for disease activity every 3 months for 2 years (RA-BIODAM cohort). The primary outcome was the change in Sharp-van der Heijde (SvdH) score, assessed every 6 months. Per 3-month interval DAS44-T2T could be followed zero, one or two times (in a total of two visits). The relation between T2T intensity and change in SvdH-score was modelled by generalized estimating equations. Results: In total, 511 patients were included [mean (s.d.) age: 56 (13) years; 76% female]. Mean 2-year SvdH progression was 2.2 (4.1) units (median: 1 unit). A stricter application of T2T in a 3-month interval did not reduce progression in the same 6-month interval [parameter estimates (for yes vs no): +0.15 units (95% CI: -0.04, 0.33) for 2 vs 0 visits; and +0.08 units (-0.06; 0.22) for 1 vs 0 visits] nor did it reduce progression in the subsequent 6-month interval. Conclusions: In this daily practice cohort, following T2T principles more meticulously did not result in less radiographic progression than a somewhat more lenient attitude towards T2T. One possible interpretation of these results is that the intention to apply T2T already suffices and that a more stringent approach does not further improve outcome. Show less
Ramiro, S.; Landewé, R.; Heijde, D. van der; Sepriano, A.; FitzGerald, O.; Ostergaard, M.; ... ; Maksymowych, W.P. 2023
ObjectivesTo investigate whether meticulously following a treat-to-target (T2T)-strategy in daily clinical practice will lead to less radiographic progression in patients with active RA who start ... Show moreObjectivesTo investigate whether meticulously following a treat-to-target (T2T)-strategy in daily clinical practice will lead to less radiographic progression in patients with active RA who start (new) DMARD-therapy.MethodsPatients with RA from 10 countries starting/changing conventional synthetic or biologic DMARDs because of active RA, and in whom treatment intensification according to the T2T principle was pursued, were assessed for disease activity every 3 months for 2 years (RA-BIODAM cohort). The primary outcome was the change in Sharp-van der Heijde (SvdH) score, assessed every 6 months. Per 3-month interval DAS44-T2T could be followed zero, one or two times (in a total of two visits). The relation between T2T intensity and change in SvdH-score was modelled by generalized estimating equations.ResultsIn total, 511 patients were included [mean (s.d.) age: 56 (13) years; 76% female]. Mean 2-year SvdH progression was 2.2 (4.1) units (median: 1 unit). A stricter application of T2T in a 3-month interval did not reduce progression in the same 6-month interval [parameter estimates (for yes vs no): +0.15 units (95% CI: −0.04, 0.33) for 2 vs 0 visits; and +0.08 units (−0.06; 0.22) for 1 vs 0 visits] nor did it reduce progression in the subsequent 6-month interval.ConclusionsIn this daily practice cohort, following T2T principles more meticulously did not result in less radiographic progression than a somewhat more lenient attitude towards T2T. One possible interpretation of these results is that the intention to apply T2T already suffices and that a more stringent approach does not further improve outcome. Show less
Objectives: To compare the cumulative incidence and disease severity of reported SARS-CoV-2 omicron breakthrough infections between patients with immune-mediated inflammatory diseases (IMID) on... Show moreObjectives: To compare the cumulative incidence and disease severity of reported SARS-CoV-2 omicron breakthrough infections between patients with immune-mediated inflammatory diseases (IMID) on immunosuppressants and controls, and to investigate determinants for breakthrough infections. Methods: Data were used from an ongoing national prospective multicentre cohort study on SARS-CoV-2 vaccination responses in patients with IMID in the Netherlands (Target-to-B! (T2B!) study). Patients wih IMID on immunosuppressants and controls (patients with IMID not on immunosuppressants and healthy controls) who completed primary immunisation were included. The observation period was between 1 January 2022 and 1 April 2022, during which the SARS-CoV-2 omicron (BA.1 and BA.2 subvariant) was dominant. A SARS-CoV-2 breakthrough infection was defined as a reported positive PCR and/or antigen test at least 14 days after primary immunisation. A multivariate logistic regression model was used to investigate determinants. Results: 1593 patients with IMID on immunosuppressants and 579 controls were included. The cumulative incidence of breakthrough infections was 472/1593 (29.6%; 95% CI 27% to 32%) in patients with IMID on immunosuppressants and 181/579 (31.3%; 95% CI 28% to 35%) in controls (p=0.42). Three (0.5%) participants had severe disease. Seroconversion after primary immunisation (relative risk, RR 0.71; 95% CI 0.52 to 0.96), additional vaccinations (RR 0.61; 95% CI 0.49 to 0.76) and a prior SARS-CoV-2 infection (RR 0.60; 95% CI 0.48 to 0.75) were associated with decreased risk of breakthrough infection. Conclusions: The cumulative incidence of reported SARS-CoV-2 omicron breakthrough infections was high, but similar between patients with IMID on immunosuppressants and controls, and disease severity was mostly mild. Additional vaccinations and prior SARS-CoV-2 infections may reduce the incidence of breakthrough infections. Show less
Krijbolder, D.I.; Verstappen, M.; Dijk, B.T. van; Dakkak, Y.J.; Burgers, L.E.; Boer, A.C.; ... ; Helm-van Mil, A.H.M. van der 2022
Background: Rheumatoid arthritis is the most common autoimmune disease worldwide and requires long-term treatment to suppress inflammation. Currently, treatment is started when arthritis is... Show moreBackground: Rheumatoid arthritis is the most common autoimmune disease worldwide and requires long-term treatment to suppress inflammation. Currently, treatment is started when arthritis is clinically apparent. We aimed to evaluate whether earlier intervention, in the preceding phase of arthralgia and subclinical joint inflammation, could prevent the development of clinical arthritis or reduce the disease burden. Methods: We conducted a randomised, double-blind, placebo-controlled, proof-of-concept-trial at the Leiden University Medical Centre, Leiden, Netherlands. Adults aged 18 years or older with arthralgia clinically suspected of progressing to rheumatoid arthritis and MRI-detected subclinical joint inflammation were eligible for enrolment across 13 rheumatology outpatient clinics in the southwest region of the Netherlands and randomly assigned (1:1) to a single intramuscular glucocorticoid injection (120 mg) and a 1-year course of oral methotrexate (up to 25 mg/week), or placebo (single injection and tablets for 1 year). Participants and investigators were masked to group assignment. Follow-up continued for 1 year after the end of the 1-year treatment period. The primary endpoint was development of clinical arthritis (fulfilling the 2010 rheumatoid arthritis classification criteria or involving two or more joints) that persisted for at least 2 weeks. Patient-reported physical functioning, symptoms, and work productivity were secondary endpoints, which were measured every 4 months. Additionally, the course of MRI-detected inflammation was studied. All participants entered the intention-to-treat analysis. This trial is registered with EudraCT, 2014-004472-35, and the Netherlands Trial Register, NTR4853-trial-NL4599. Findings: Between April 16, 2015, and Sept 11, 2019, 901 patients were assessed for eligibility and 236 were enrolled and randomly assigned to active treatment (n=119) or placebo (n=117). At 2 years, the frequency of the primary endpoint was similar between the groups (23 [19%] of 119 participants in the treatment group vs 21 [18%] of 117 in the placebo group; hazard ratio 0middot81, 95% CI 0middot45 to 1middot48). Physical functioning improved more in the treatment group during the first 4 months and remained better than in the placebo group (mean between-group difference in Health Assessment Questionnaire disability index over 2 years: -0middot09, 95% CI -0middot16 to -0middot03; p=0middot0042). Similarly, pain (on scale 0-100, mean between-group difference: -8, 95% CI -12 to -4; p < 0middot0001), morning stiffness of joints (-12, -16 to -8; p < 0middot0001), presenteeism (-8%, -13 to -3; p=0middot0007), and MRI-detected joint inflammation (-1middot4 points, -2middot0 to -0middot9; p < 0middot0001) showed sustained improvement in the treatment group compared with the placebo group. The number of serious adverse events was equal in both groups; adverse events were consistent with the known safety profile for methotrexate. Interpretation: Methotrexate, the cornerstone treatment of rheumatoid arthritis, initiated at the pre-arthritis stage of symptoms and subclinical inflammation, did not prevent the development of clinical arthritis, but modified the disease course as shown by sustained improvement in MRI-detected inflammation, related symptoms, and impairments compared with placebo. Copyright (C) 2022 Elsevier Ltd. All rights reserved. Show less
Ouwerkerk, L. van; Woude, D. van der; Rispens, T.; Allaart, C.F.; Huizinga, T.W.J. 2022
Objective To evaluate the relationship between reported coronavirus disease 2019 (COVID-19)-like symptoms and the presence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibodies... Show moreObjective To evaluate the relationship between reported coronavirus disease 2019 (COVID-19)-like symptoms and the presence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibodies in patients with an immune-mediated inflammatory disorder or post-solid organ transplantation (IMIDT) with and without immunosuppressive medication (imed) and controls. Method The IENIMINI cohort was a prospective cohort study set up in the Netherlands in March 2020, with 2 monthly (paper) or weekly (online) questionnaires about COVID-19-like symptoms. Participants from this cohort who reported these symptoms between March 2020 and November 2020 were approached for this substudy. SARS-CoV-2 antibodies were tested using a total antibody assay. Results Of the 1203 participants approached, 629 agreed to participate and were sent a fingerprick test; 565 participants collected a capillary blood sample, of which 562 were usable. Analysis showed that 57/202 (28.2%) of the tested IMIDT group with imed, 48/16 3(29.4%) of the IMIDT group without imed, and 69/197 (35.0%) of the control group tested positive for SARS-CoV-2 antibodies. Seroprevalences of SARS-CoV-2 antibodies between males and females, biological disease-modifying anti-rheumatic drug users and non-users, and those who had had a serious disease period (defined as an episode with dyspnoea and fever) and those who had not, were not statistically different between the three groups. Conclusions Approximately 30% of patients who had reported COVID-19-like symptoms had SARS-CoV-2 antibodies. The seroprevalence of SARS-CoV-2 antibodies after reported COVID-19-like symptoms was similar in IMIDT patients with and without imed compared to controls. Show less
Meulen, C. van der; Stadt, L.A. van de; Kroon, F.P.B.; Kortekaas, M.C.; Boonen, A.E.R.C.H.; Bohringer, S.; ... ; Kloppenburg, M. 2022
Background: Pain is common in hand osteoarthritis (OA) and multiple types may occur. We investigated the prevalence, associated patient characteristics, influence on health-related quality of life ... Show moreBackground: Pain is common in hand osteoarthritis (OA) and multiple types may occur. We investigated the prevalence, associated patient characteristics, influence on health-related quality of life (HR-QoL) and response to anti-inflammatory treatment of neuropathic-like pain in inflammatory hand OA. Methods: Data were analysed from a 6-week, randomized, double-blind, placebo-controlled trial investigating prednisolone treatment in 92 patients with painful inflammatory hand OA. Neuropathic-like pain was measured with the painDETECT questionnaire. Associations between baseline characteristics and baseline neuropathic-like pain were analysed with ordinal logistic regression, association of baseline neuropathic-like pain symptoms with baseline HR-QoL with linear regression, painDETECT and visual analogue scale (VAS) change from baseline to week 6 and interaction of painDETECT with prednisolone efficacy on VAS pain change from baseline to week 6 with generalized estimating equations (GEE). Results: Of 91 patients (79% female, mean age 64) with complete painDETECT data at baseline, 53% were unlikely to have neuropathic-like pain, 31% were indeterminate and 16% were likely to have neuropathic-like pain. Neuropathic-like pain was associated with female sex, less radiographic damage and more comorbidities. Patients with neuropathic-like pain had lower HR-QoL (PCS-6.5 [95% CI -10.4 to -2.6]) than those without. Neuropathic-like pain symptoms remained under prednisolone treatment and no interaction was seen between painDETECT and prednisolone efficacy on VAS pain. Conclusions: In this study, 16% of inflammatory hand OA patients had neuropathic-like pain. They were more often female, had more comorbidities and had lower QoL than those without. Neuropathic-like pain symptoms remained despite prednisolone treatment and did not seem to affect the outcome of prednisolone treatment. Significance: Pain is the dominant symptom in hand OA, with an unclear aetiology. In this study, we found that neuropathic-like pain may play a role in hand OA, that it showed associations with female sex, younger age and more comorbidities and that it lowered health-related quality of life in hand OA. Neuropathic-like pain in hand OA seems resistant to prednisolone therapy but did not seem to interfere with the treatment of inflammatory pain with prednisolone. Show less
Background: Concerns have been raised regarding the risks of SARS-CoV-2 breakthrough infections in vaccinated patients with immune-mediated inflammatory diseases treated with immunosuppressants,... Show moreBackground: Concerns have been raised regarding the risks of SARS-CoV-2 breakthrough infections in vaccinated patients with immune-mediated inflammatory diseases treated with immunosuppressants, but clinical data on breakthrough infections are still scarce. The primary objective of this study was to compare the incidence and severity of SARS-CoV-2 breakthrough infections between patients with immune-mediated inflammatory diseases using immunosuppressants, and controls (patients with immune-mediated inflammatory diseases not taking immunosuppressants and healthy controls) who had received full COVID-19 vaccinations. The secondary objective was to explore determinants of breakthrough infections of the delta (B.1.617.2) variant of SARS-CoV-2, including humoral immune responses after vaccination. Methods: In this substudy, we pooled data collected in two large ongoing prospective multicentre cohort studies conducted in the Netherlands (Target to-B! [T2B!] study and Amsterdam Rheumatology Center COVID [ARC-COVID] study). Both studies recruited adult patients (age >= 18 years) with immune-mediated inflammatory diseases and healthy controls. We sourced clinical data from standardised electronic case record forms, digital questionnaires, and medical files. We only included individuals who were vaccinated against SARS-CoV-2. For T2B!, participants were recruited between Feb 2 and Aug 1, 2021, and for ARC-COVID, participants were recruited between April 26, 2020, and March 1, 2021. In this study we assessed data on breakthrough infections collected between July 1 and Dec 15, 2021, a period in which the delta SARS-CoV-2 variant was the dominant variant in the Netherlands. We defined a SARS-CoV-2 breakthrough infection as a PCR-confirmed or antigen test-confirmed SARS-CoV-2 infection that occurred at least 14 days after vaccination. All breakthrough infections during this period were assumed to be due to the delta variant due to its dominance during the study period. We analysed post-vaccination serum samples for anti-receptor binding domain (RBD) antibodies to assess the humoral vaccination response (T2B! study only) and anti-nucleocapsid antibodies to identify asymptomatic breakthrough infections (ARC-COVID study only). We used multivariable logistic regression analyses to explore potential clinical and humoral determinants associated with the odds of breakthrough infections. The T2B! study is registered with the Dutch Trial Register, Trial ID NL8900, and the ARC-COVID study is registered with Dutch Trial Register, trial ID NL8513. Findings: We included 3207 patients with immune-mediated inflammatory diseases who receive immunosuppressants, and 1807 controls (985 patients with immune-mediated inflammatory disease not on immunosuppressants and 822 healthy controls). Among patients receiving immunosuppressants, mean age was 53 years (SD 14), 2042 (64%) of 3207 were female and 1165 (36%) were male; among patients not receiving immunosuppressants, mean age was 54 years (SD 14), 598 (61%) of 985 were female and 387 (39%) were male; and among healthy controls, mean age was 57 years (SD 13), 549 (67%) of 822 were female and 273 (33%) were male. The cumulative incidence of PCR-test or antigen-test confirmed SARS-CoV-2 breakthrough infections was similar in patients on immunosuppressants (148 of 3207; 4.6% [95% CI 3.9-5.4]), patients not on immunosuppressants (52 of 985; 5.3% [95% CI 4.0-6.9]), and healthy controls (33 of 822; 4.0% [95% CI 2.8-5.6]). There was no difference in the odds of breakthrough infection for patients with immune-mediate inflammatory disease on immunosuppressants versus combined controls (ie, patients not on immunosuppressants and healthy controls; adjusted odds ratio 0.88 [95% CI 0.66-1.18]). Seroconversion after vaccination (odds ratio 0.58 [95% CI 0.34-0.98]; T2B! cohort only) and SARS-CoV-2 infection before vaccination (0.34 [0.18-0.56]) were associated with a lower odds of breakthrough infections. Interpretation: The incidence and severity of SARS-CoV-2 breakthrough infections in patients with immune-mediated inflammatory diseases on immunosuppressants was similar to that in controls. However, caution might still be warranted for those on anti-CD20 therapy and those with traditional risk factors. Copyright (C) 2022 Elsevier Ltd. All rights reserved. Show less
Objective. The autoimmune response in rheumatoid arthritis (RA) is marked by the presence of anti-citrullinated protein antibodies (ACPAs). A notable feature of IgG ACPA is the abundant expression... Show moreObjective. The autoimmune response in rheumatoid arthritis (RA) is marked by the presence of anti-citrullinated protein antibodies (ACPAs). A notable feature of IgG ACPA is the abundant expression of N-linked glycans in the variable domain. However, the presence of ACPA variable domain glycosylation (VDG) across disease stages, and its response to therapy, are poorly described. To understand its dynamics, we investigated the abundance of IgG ACPA VDG in 1,498 samples from individuals in different clinical stages. Methods. Using liquid chromatography, we analyzed IgG ACPA VDG profiles in 7 different cohorts from Japan, Canada, The Netherlands, and Sweden. We assessed 106 healthy individuals, 228 individuals with presymptomatic RA, 277 individuals with arthralgia, 307 patients with new-onset/early RA, and 117 RA patients after prespecified treatment regimens. Additionally, we measured VDG in 234 samples from patients with RA who did or did not achieve long-term drug-free remission (DFR) during up to 16 years follow-up. Results. IgG ACPA VDG significantly increased (P < 0.0001) toward disease onset and was associated with ACPA levels and epitope spreading prior to diagnosis. A slight increase in VDG was observed in patients with established RA, with a moderate influence of treatment (P = 0.007). In patients in whom DFR was later achieved, IgG ACPA VDG was already reduced at the time of RA onset. Conclusion. The abundance of IgG ACPA VDG increases toward RA onset and correlates with maturation of the ACPA response. While IgG ACPA VDG levels are fairly stable in established disease, a lower degree of VDG at RA onset correlates with DFR. Although the underlying biologic mechanisms remain elusive, our data support the concept that VDG relates to an expansion of the ACPA response in the pre-disease phase and contributes to disease development. Show less
Boers, M.; Hartman, L.; Opris-Belinski, D.; Bos, R.; Kok, M.R.; Silva, J.A.P. da; ... ; GLORIA Trial Consortium 2022
Background: Low-dose glucocorticoid (GC) therapy is widely used in rheumatoid arthritis (RA) but the balance of benefit and harm is still unclear. Methods: The GLORIA (Glucocorticoid LOw-dose in... Show moreBackground: Low-dose glucocorticoid (GC) therapy is widely used in rheumatoid arthritis (RA) but the balance of benefit and harm is still unclear. Methods: The GLORIA (Glucocorticoid LOw-dose in Rheumatoid Arthritis) pragmatic double-blind randomised trial compared 2 years of prednisolone, 5 mg/day, to placebo in patients aged 65+ with active RA. We allowed all cotreatments except long-term open label GC and minimised exclusion criteria, tailored to seniors. Benefit outcomes included disease activity (disease activity score; DAS28, coprimary) and joint damage (Sharp/van der Heijde, secondary). The other coprimary outcome was harm, expressed as the proportion of patients with >= 1 adverse event (AE) of special interest. Such events comprised serious events, GC-specific events and those causing study discontinuation. Longitudinal models analysed the data, with one-sided testing and 95% confidence limits (95% CL). Results: We randomised 451 patients with established RA and mean 2.1 comorbidities, age 72, disease duration 11 years and DAS28 4.5. 79% were on disease-modifying treatment, including 14% on biologics. 63% prednisolone versus 61% placebo patients completed the trial. Discontinuations were for AE (both, 14%), active disease (3 vs 4%) and for other (including covid pandemic-related disease) reasons (19 vs 21%); mean time in study was 19 months. Disease activity was 0.37 points lower on prednisolone (95% CL 0.23, p<0.0001); joint damage progression was 1.7 points lower (95% CL 0.7, p=0.003). 60% versus 49% of patients experienced the harm outcome, adjusted relative risk 1.24 (95% CL 1.04, p=0.02), with the largest contrast in (mostly non-severe) infections. Other GC-specific events were rare. Conclusion: Add-on low-dose prednisolone has beneficial long-term effects in senior patients with established RA, with a trade-off of 24% increase in patients with mostly non-severe AE; this suggests a favourable balance of benefit and harm. Show less
