Publications by authors named "Tom W J Huizinga"

449 Publications

Cross-reactivity of IgM anti-modified protein antibodies in rheumatoid arthritis despite limited mutational load.

Arthritis Res Ther 2021 Sep 3;23(1):230. Epub 2021 Sep 3.

Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.

Background: Anti-modified protein antibodies (AMPA) targeting citrullinated, acetylated and/or carbamylated self-antigens are hallmarks of rheumatoid arthritis (RA). Although AMPA-IgG cross-reactivity to multiple post-translational modifications (PTMs) is evident, it is unknown whether the first responding B cells, expressing IgM, display similar characteristics or if cross-reactivity is crucially dependent on somatic hypermutation (SHM). We now studied the reactivity of (germline) AMPA-IgM to further understand the breach of B cell tolerance and to identify if cross-reactivity depends on extensive SHM. Moreover, we investigated whether AMPA-IgM can efficiently recruit immune effector mechanisms.

Methods: Polyclonal AMPA-IgM were isolated from RA patients and assessed for cross-reactivity towards PTM antigens. AMPA-IgM B cell receptor sequences were obtained by single cell isolation using antigen-specific tetramers. Subsequently, pentameric monoclonal AMPA-IgM, their germline counterparts and monomeric IgG variants were generated. The antibodies were analysed on a panel of PTM antigens and tested for complement activation.

Results: Pentameric monoclonal and polyclonal AMPA-IgM displayed cross-reactivity to multiple antigens and different PTMs. PTM antigen recognition was still present, although reduced, after reverting the IgM into germline. Valency of AMPA-IgM was crucial for antigen recognition as PTM-reactivity significantly decreased when AMPA-IgM were expressed as IgG. Furthermore, AMPA-IgM was 15- to 30-fold more potent in complement-activation compared to AMPA-IgG.

Conclusions: We provide first evidence that AMPA-IgM are cross-reactive towards different PTMs, indicating that PTM (cross-)reactivity is not confined to IgG and does not necessarily depend on extensive somatic hypermutation. Moreover, our data indicate that a diverse set of PTM antigens could be involved in the initial tolerance breach in RA and suggest that AMPA-IgM can induce complement-activation and thereby inflammation.
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http://dx.doi.org/10.1186/s13075-021-02609-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413699PMC
September 2021

Joint inflammation tends to recur in the same joints during the rheumatoid arthritis disease course.

Ann Rheum Dis 2021 Aug 30. Epub 2021 Aug 30.

Rheumatology, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands.

Objectives: We investigated whether local joint swelling recurs in the same joints over time in patients with rheumatoid arthritis (RA) who are treated to target.

Methods: Patients with newly diagnosed RA participating in the Behandel-Strategieën, "treatment strategies" (BeSt) study (n=508) were followed for median 10 years while receiving Disease Activity Score (DAS) ≤2.4 steered treatment. Every 3 months 68 joints were assessed for the presence of swelling. We evaluated whether baseline local joint swelling was predictive for swelling in the same joint during follow-up using a multilevel mixed-effect logistic regression model. Different strategies were used to account for missing data. A permutation test was performed to assess if joint swelling was better predicted by baseline swelling of the joint itself than by baseline swelling of randomly selected other joints.

Results: In 46% of the joints that were swollen at baseline, joint swelling later recurred at least once during follow-up. Joint swelling at baseline was statistically significantly associated with swelling in the same joint during follow-up (OR 2.37, 95% CI 2.30 to 2.43, p<0.001), and also specifically with recurrent swelling in the same joint (OR 1.73, 95% CI 1.37 to 1.59, p<0.001). Local joint swelling was better predicted by baseline swelling of that particular joint than by baseline swelling of other joints (p<0.001).

Conclusion: Joint swelling tends to recur locally in the joints swollen at RA onset. This suggests that local factors influence the manifestation of joint inflammation over time.
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http://dx.doi.org/10.1136/annrheumdis-2021-220882DOI Listing
August 2021

A Polymorphism in C-C Chemokine Receptor 5 (CCR5) Associates with Löfgren's Syndrome and Alters Receptor Expression as well as Functional Response.

Cells 2021 Aug 3;10(8). Epub 2021 Aug 3.

Department of Science, University College Roosevelt, P.O. Box 94, 4330 AB Middelburg, The Netherlands.

C-C chemokine receptor 5 (CCR5) and polymorphisms in gene are associated with sarcoidosis and Löfgren's syndrome. Löfgren's syndrome is an acute and usually self-remitting phenotype of sarcoidosis. We investigated whether the single nucleotide polymorphism (SNP) rs1799987 is associated with susceptibility for Löfgren's syndrome and has an effect on CCR5 expression on monocytes and function of CCR5. A total of 106 patients with Löfgren's syndrome and 257 controls were genotyped for rs1799987. Expression of CCR5 on monocytes was measured by flowcytometry. We evaluated calcium influx kinetics following stimulation upon N-formylmethionyl-leucyl-phenylalanine (fMLP) and macrophage inflammatory protein-1α (MIP-1α) on monocytes by measuring the median fluorescence intensity (MFI). The frequency of the G allele of rs1799987 was significantly higher in Löfgren's syndrome than in healthy controls ( = 0.0015, confidence interval (CI) 1.22-2.32, odds ratio (OR) 1.680). Patients with a GG genotype showed higher CCR5 expression on monocytes than patients with the AA genotype ( = 0.026). A significantly ( = 0.027) lower count of patients with the GG genotype showed a calcium influx reaction to simulation upon MIP-1 α, compared with patients with the AA genotype. The rs1799987 G allele in gene is associated with susceptibility to Löfgren's syndrome and with quantitative and qualitative changes in CCR5, potentially effecting the inflammatory response.
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http://dx.doi.org/10.3390/cells10081967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394428PMC
August 2021

Glucocorticoid discontinuation in patients with early rheumatoid and undifferentiated arthritis: a post-hoc analysis of the BeSt and IMPROVED studies.

Ann Rheum Dis 2021 09 28;80(9):1124-1129. Epub 2021 May 28.

Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.

Objectives: To evaluate the success rate of glucocorticoid discontinuation and to study which factors are associated with successful discontinuation.

Methods: Data from two treat-to-target studies, BeSt (target Disease Activity Score (DAS) ≤2.4) and IMPROVED (target DAS <1.6), were evaluated for all patients initially treated with a tapered high dose of prednisone with conventional synthetic disease-modifying antirheumatic drugs. Prednisone was discontinued when DAS ≤2.4 was maintained for 28 weeks in BeSt and as soon as DAS was <1.6 in IMPROVED. Discontinuation was considered successful if the target was maintained at the next visit. Logistic regression analyses were performed to identify predictors of successful discontinuation. A mixed effects logistic regression model was used to assess whether primary versus secondary discontinuation was as successful.

Results: In the BeSt study, 40% (47 of 93) of patients flared after primary prednisone discontinuation, and of the other 60% (56 of 93), 38% had to restart later. Of those who restarted (secondary discontinuation), 47% (17 of 35) again flared. In IMPROVED, after primary discontinuation 39% (158 of 400) flared, and of the other 61% (242 of 400), 40% had to restart later. After secondary discontinuation 49% (68 of 139) flared. Only in IMPROVED a secondary attempt was less successful (BeSt OR 0.71, p=0.45; IMPROVED OR 0.60, p=0.01). A lower DAS both at baseline and stop visit and male gender (in IMPROVED) were associated with successful primary discontinuation.

Conclusion: Primary glucocorticoid discontinuation resulted in direct loss of disease control in approximately 40% and secondary in 50% of patients. 'Standard' baseline characteristics seem insufficient to personalise the duration of temporary glucocorticoid bridging, but the DAS at the time of discontinuation might provide guidance.
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http://dx.doi.org/10.1136/annrheumdis-2021-220403DOI Listing
September 2021

Anti-centromere antibody levels and isotypes and the development of systemic sclerosis.

Arthritis Rheumatol 2021 May 27. Epub 2021 May 27.

Leiden University Medical Centre, Department of Rheumatology, Leiden, The Netherlands.

Objectives: Little is known on the disease course of very early systemic sclerosis (SSc). It is unknown whether anti-centromere antibody (ACA) isotype levels can serve as biomarkers for future SSc development and for organ involvement. We aim to evaluate whether ACA-IgG, -IgM and -IgA levels in ACA-IgG positive patients associate with disease severity and/or progression from very early SSc to definite SSc.

Methods: ACA-IgG positive patients with very early SSc and ACA-IgG positive patients fulfilling the 2013 ACR/EULAR criteria for SSc from five different cohorts were included. A diagnosis of very early SSc was based on the presence of ACA-IgG AND Raynaud and/or puffy fingers and/or abnormal nailfold capillaroscopy but not fulfilling the 2013 ACR/EULAR criteria. Multivariable regression analyses were performed to determine the association between baseline isotype levels and progression to SSc and organ involvement.

Results: Six hundred twenty-five ACA-IgG positive patients were included of whom 138 (22%) fulfilled very early SSc criteria and 487 (78%) had definite SSc. ACA-IgG (Odds Ratio (OR) 2.5 (1.8-3.7)) and ACA-IgM (OR 1.8 (1.3 -2.3)) levels were significantly higher in definite SSc patients. Of 115 very early SSc patients with follow-up, 48 (42%) progressed to definite SSc within five years. Progression to definite SSc was associated with higher ACA-IgG levels at baseline (OR 4.3 (1.7-10.7)).

Conclusion: ACA isotype levels might serve as a biomarker to identify very early SSc patients at risk for progression to definite SSc.
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http://dx.doi.org/10.1002/art.41814DOI Listing
May 2021

Effectiveness of a multidisciplinary clinical pathway for women with systemic lupus erythematosus and/or antiphospholipid syndrome.

Lupus Sci Med 2021 05;8(1)

Nephrology, Leiden University Medical Center, Leiden, The Netherlands.

Objectives: SLE and/or antiphospholipid syndrome (SLE/APS) are complex and rare systemic autoimmune diseases that predominantly affect women of childbearing age. Women with SLE/APS are at high risk of developing complications during pregnancy. Therefore, clinical practice guidelines recommend that patients with SLE/APS should receive multidisciplinary counselling before getting pregnant. We investigated the clinical effectiveness of implementing a multidisciplinary clinical pathway including prepregnancy counselling of patients with SLE/APS.

Methods: A clinical pathway with specific evaluation and prepregnancy counselling for patients with SLE/APS was developed and implemented in a tertiary, academic hospital setting. Patients were prospectively managed within the clinical pathway from 2014 onwards and compared with a retrospective cohort of patients that was not managed in a clinical pathway. Primary outcome was a combined outcome of disease flares for SLE and thromboembolic events for APS. Secondary outcomes were maternal and fetal pregnancy complications.

Results: Seventy-eight patients with 112 pregnancies were included in this study. The primary combined outcome was significantly lower in the pathway cohort (adjusted OR (aOR) 0.20 (95% CI 0.06 to 0.75)) which was predominantly determined by a fivefold risk reduction of SLE flares (aOR 0.22 (95% CI 0.04 to 1.09)). Maternal and fetal pregnancy complications were not different between the cohorts (respectively, aOR 0.91 (95% CI 0.38 to 2.17) and aOR 1.26 (95% CI 0.55 to 2.88)).

Conclusions: The outcomes of this study suggest that patients with SLE/APS with a pregnancy wish benefit from a multidisciplinary clinical pathway including prepregnancy counselling.
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http://dx.doi.org/10.1136/lupus-2020-000472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103373PMC
May 2021

Different phenotypes of neuropsychiatric systemic lupus erythematosus are related to a distinct pattern of structural changes on brain MRI.

Eur Radiol 2021 Apr 30. Epub 2021 Apr 30.

Department of Radiology, Leiden University Medical Center (LUMC), Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.

Objectives: The underlying structural brain correlates of neuropsychiatric involvement in systemic lupus erythematosus (NPSLE) remain unclear, thus hindering correct diagnosis. We compared brain tissue volumes between a clinically well-defined cohort of patients with NPSLE and SLE patients with neuropsychiatric syndromes not attributed to SLE (non-NPSLE). Within the NPSLE patients, we also examined differences between patients with two distinct disease phenotypes: ischemic and inflammatory.

Methods: In this prospective (May 2007 to April 2015) cohort study, we included 38 NPSLE patients (26 inflammatory and 12 ischemic) and 117 non-NPSLE patients. All patients underwent a 3-T brain MRI scan that was used to automatically determine white matter, grey matter, white matter hyperintensities (WMH) and total brain volumes. Group differences in brain tissue volumes were studied with linear regression analyses corrected for age, gender, and total intracranial volume and expressed as B values and 95% confidence intervals.

Results: NPSLE patients showed higher WMH volume compared to non-NPSLE patients (p = 0.004). NPSLE inflammatory patients showed lower total brain (p = 0.014) and white matter volumes (p = 0.020), and higher WMH volume (p = 0.002) compared to non-NPSLE patients. Additionally, NPSLE inflammatory patients showed lower white matter (p = 0.020) and total brain volumes (p = 0.038) compared to NPSLE ischemic patients.

Conclusion: We showed that different phenotypes of NPSLE were related to distinct patterns of underlying structural brain MRI changes. Especially the inflammatory phenotype of NPSLE was associated with the most pronounced brain volume changes, which might facilitate the diagnostic process in SLE patients with neuropsychiatric symptoms.

Key Points: • Neuropsychiatric systemic lupus erythematosus (NPSLE) patients showed a higher WMH volume compared to SLE patients with neuropsychiatric syndromes not attributed to SLE (non-NPSLE). • NPSLE patients with inflammatory phenotype showed a lower total brain and white matter volume, and a higher volume of white matter hyperintensities, compared to non-NPSLE patients. • NPSLE patients with inflammatory phenotype showed lower white matter and total brain volumes compared to NPSLE patients with ischemic phenotype.
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http://dx.doi.org/10.1007/s00330-021-07970-2DOI Listing
April 2021

Light chain skewing in autoantibodies and B-cell receptors of the citrullinated antigen-binding B-cell response in rheumatoid arthritis.

PLoS One 2021 30;16(3):e0247847. Epub 2021 Mar 30.

Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting 1% of the world population. RA is associated with the presence of autoantibodies, of which anti-citrullinated protein antibodies (ACPA) are most prominent. ACPA are produced by citrullinated antigen-binding B cells that have presumably survived tolerance checkpoints. So far, it is unclear how and when such autoreactive B cells emerge. Light chain (LC) rearrangement and mutation rates can be informative with regard to selection steps during B-cell development. Therefore, we studied LC characteristics of ACPA-expressing B cells and secreted ACPA with the aim to better understand the development of this disease-specific, autoreactive B-cell response. Paired ACPA-IgG and ACPA-depleted IgG were isolated from serum (n = 87) and synovial fluid (SF, n = 21) of patients with established RA. We determined the LC composition for each fraction by ELISA using kappa(Igκ)- and lambda(Igλ) LC-specific antibodies. Cellular LC expression was determined using flow cytometry. In addition, we used a B-cell receptor (BCR)-specific PCR to obtain LC variable region sequences of citrullinated antigen- and tetanus toxoid (TT)-binding B cells. In serum, we observed an increased frequency of lambda LC in ACPA-IgG (1.64:1) compared to control IgG (2.03:1) and to the κ/λ ratio reported for healthy individuals (2:1). A similar trend towards higher frequencies of lambda LCs was observed for ACPA-IgG in SF (1.84:1). Additionally, the percentage of Igλ-expressing B cells was higher for citrullinated antigen-binding B cells (51%) compared to TT-specific (43%) and total CD19+CD20+ B cells (36%). Moreover, an increased Igλ percentage was observed in BCR-sequences derived from ACPA-expressing (49%) compared to TT-specific B cells (34%). Taken together, we report an enhanced frequency of lambda LCs in the secreted ACPA-IgG repertoire and, on the cellular level, in BCR sequences of ACPA-expressing B cells compared to control. This skewing in the autoreactive B-cell repertoire could reflect a process of active selection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247847PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009422PMC
March 2021

Onset of rheumatoid arthritis after COVID-19: coincidence or connected?

Ann Rheum Dis 2021 Mar 1. Epub 2021 Mar 1.

Department of Rheumatology, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands.

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http://dx.doi.org/10.1136/annrheumdis-2021-219859DOI Listing
March 2021

Phenotype and treatment of elderly onset compared to younger onset rheumatoid arthritis patients in international daily practice.

Rheumatology (Oxford) 2021 Feb 4. Epub 2021 Feb 4.

Objective: To identify possible differences in baseline characteristics, initial treatment and treatment response between rheumatoid arthritis (RA) patient subgroups based on age at disease onset.

Methods: Daily practice data from the worldwide METEOR registry were used. Patients (7,912) were stratified into three age-groups (age at disease diagnosis <45 years; 45-65 years; >65 years). Initial treatment was compared between the different age-groups. With Cox regression analyses the effect of age-group on time-to-switch from first to second treatment was investigated, and with linear mixed models differences in response to treatment (DAS and HAQ) between the age-groups were assessed, after correction for potential confounders.

Results: The >65 years age-group included more men, more seronegative RA with somewhat higher inflammatory markers. Initial treatment choices differed only slightly between the age-groups, and the time-to-switch from initial treatment to the next was similar. DAS and HAQ improvement were dependent on the age-group, reflected by a significant interaction between age-group and outcome. The stratified analysis showed a difference of -0.02 and -0.05 DAS points and, -0.01 and 0.02, HAQ points per month in the <45y and 45-65y age-groups as compared to the >65y age group. A difference that did not seem clinically relevant.

Conclusion: In this international study on worldwide clinical practice, patients with RA onset >65 years include more men and seronegative arthritis, and were initially treated slightly different than younger patients. We observed no clinically relevant differences in timing of a next treatment step, or response to treatment measured by DAS and HAQ.
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http://dx.doi.org/10.1093/rheumatology/keab102DOI Listing
February 2021

Correction to: Earlier chronotype in patients with rheumatoid arthritis.

Clin Rheumatol 2021 Jun;40(6):2519

Health, Medical, and Neuropsychology Unit, Institute of Psychology, Leiden University, Wassenaarseweg 52, 2333 AK, Leiden, the Netherlands.

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http://dx.doi.org/10.1007/s10067-021-05606-wDOI Listing
June 2021

Longitudinal changes in cerebral white matter microstructure in newly diagnosed systemic lupus erythematosus patients.

Rheumatology (Oxford) 2021 06;60(6):2678-2687

Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.

Objectives: To evaluate longitudinal variations in diffusion tensor imaging (DTI) metrics of different white matter (WM) tracts of newly diagnosed SLE patients, and to assess whether DTI changes relate to changes in clinical characteristics over time.

Methods: A total of 17 newly diagnosed SLE patients (19-55 years) were assessed within 24 months from diagnosis with brain MRI (1.5 T Philips Achieva) at baseline, and after at least 12 months. Fractional anisotropy, mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity values were calculated in several normal-appearing WM tracts. Longitudinal variations in DTI metrics were analysed by repeated measures analysis of variance. DTI changes were separately assessed for 21 WM tracts. Associations between longitudinal alterations of DTI metrics and clinical variables (SLEDAI-2K, complement levels, glucocorticoid dosage) were evaluated using adjusted Spearman correlation analysis.

Results: Mean MD and RD values from the normal-appearing WM significantly increased over time (P = 0.019 and P = 0.021, respectively). A significant increase in RD (P = 0.005) and MD (P = 0.012) was found in the left posterior limb of the internal capsule; RD significantly increased in the left retro-lenticular part of the internal capsule (P = 0.013), and fractional anisotropy significantly decreased in the left corticospinal tract (P = 0.029). No significant correlation was found between the longitudinal change in DTI metrics and the change in clinical measures.

Conclusion: Increase in diffusivity, reflecting a compromised WM tissue microstructure, starts in initial phases of the SLE disease course, even in the absence of overt neuropsychiatric (NP) symptoms. These results indicate the importance of monitoring NP involvement in SLE, even shortly after diagnosis.
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http://dx.doi.org/10.1093/rheumatology/keaa677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213425PMC
June 2021

Earlier chronotype in patients with rheumatoid arthritis.

Clin Rheumatol 2021 Jun 16;40(6):2185-2192. Epub 2021 Jan 16.

Health, Medical, and Neuropsychology Unit, Institute of Psychology, Leiden University, Wassenaarseweg 52, 2333, Leiden, AK, the Netherlands.

Objectives: Rheumatoid arthritis (RA) patients show an earlier circadian rhythm (i.e. serum melatonin peaks earlier during the night, indicating an earlier timing of the internal circadian pacemaker). In the current study, we examined whether the chronotype, which is influenced by the circadian rhythm, is also earlier. In addition, we explored whether chronotype is related to disease activity and patient-reported outcomes.

Methods: The chronotype (Munich Chronotype Questionnaire) of patients with RA (n = 121; mean age 60 years, 73% female) was compared with that of subjects from the general population (norm group; n = 1695) with a one-sample t test. In addition, we investigated chronotype in relation to disease activity (Disease Activity Score; DAS), reported morning stiffness, fatigue (Checklist Individual Strength), and health-related quality of life (RAND-36).

Results: The chronotype of patients with RA was, on average, 23 min (95% CI, 15 to 31 min) earlier than that of the norm group (t(115) = - 5.901, p < 0.001, d = 0.55). Chronotype was not related to disease activity or patient-reported outcomes (p > 0.05).

Conclusion: As expected, chronotype was earlier in RA patients. However, in this correlational study, chronotype was not related to disease activity or patient-reported outcomes. An experimental study is needed to examine whether delaying the circadian rhythm has a positive influence on these outcomes. This insight could improve our understanding of the pathophysiology of RA and contribute to exploring new treatment possibilities. Key Points • This is the first study examining chronotype in patients with rheumatoid arthritis, and how chronotype relates to disease activity and patient-reported outcomes. • We found an earlier chronotype in patients with rheumatoid arthritis than in subjects from the general population. • In this correlational study, chronotype was not related to disease activity or patient-reported outcomes. An experimental study is needed to examine whether delaying the circadian rhythm positively influences these outcomes.
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http://dx.doi.org/10.1007/s10067-020-05546-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121723PMC
June 2021

Health-related quality of life in patients with systemic sclerosis: evolution over time and main determinants.

Rheumatology (Oxford) 2021 08;60(8):3646-3655

Rheumatology Department, Leiden University Medical Center, Leiden, The Netherlands.

Objectives: In SSc patients, disease specific determinants that influence health-related quality of life (HRQoL) over time have not been described. We aim to, in patients with SSc, (i) evaluate if and how HRQoL changes over time, and (ii) assess how different SSc domains and functional impairments contribute to changes in HRQoL over time.

Methods: All SSc patients from the Leiden SSc cohort were included; patients with disease duration <24 months were classified as incident cases. HRQoL was assessed prospectively on an annual basis using the EQ-5D and the SF36. To assess baseline associations between clinical characteristics and HRQoL, linear regressions were performed. To identify possible associations between SSc characteristics and HRQoL change over time, linear mixed models were performed in both incident and prevalent cases.

Results: In total, 492 SSc patients were included (n = 202 incident cases), with a median follow-up duration of 3.4 years. At baseline, presence of organ involvement was independently associated with a worse SF36 physical component score and lower EQ-5D score. Over time, gastrointestinal symptoms, Raynaud and digital ulcers were independently associated with deterioration of HRQoL in both incident and prevalent cases. In prevalent cases, pulmonary arterial hypertension (PAH) was associated with a decrease in HRQoL over time. Worse functioning as measured by six-min walking distance, mouth-opening, finger-to-palm distance and grip-strength contributed significantly to deterioration of HRQoL over time.

Conclusion: In SSc, key clinical burdens that contribute to worsening of HRQoL over time include digital ulcers, Raynaud and gastrointestinal involvement. In addition, PAH is a significant burden in prevalent disease.
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http://dx.doi.org/10.1093/rheumatology/keaa827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328503PMC
August 2021

Suspected Transverse Myelitis with Normal MRI and CSF Findings in a Patient with Lupus: What to Do? A Case Series and Systematic Review.

Neuropsychiatr Dis Treat 2020 22;16:3173-3186. Epub 2020 Dec 22.

Department of Rheumatology, Leiden University Medical Center (LUMC), Leiden, the Netherlands.

Purpose: To evaluate the use of immunosuppressive treatment, clinical outcome and diagnostic strategy in patients with systemic lupus erythematosus (SLE) presenting with clinical features of transverse myelitis (TM), but normal MRI of the spinal cord (sMRI) and normal cerebrospinal fluid (CSF) assessment, and to suggest a clinical guideline.

Patients And Methods: All patients with SLE and clinical features compatible with (sub)acute TM visiting the NPSLE clinic of the LUMC between 2007 and 2020 were included. Information on baseline characteristics, investigations, treatment and outcomes was collected from electronic medical records. In addition, a systematic review of individual participant data was performed up to April 2020 in PubMed, Embase and Web of Science, identifying all patients with TM, SLE and sMRI assessment. Data regarding sMRI, CSF analysis, treatment and outcome were extracted, and outcome was compared between patients with normal sMRI and CSF (sMRI-/CSF-) and patients with abnormalities.

Results: Twelve SLE patients with a clinical diagnosis of TM were identified: four sMRI-/CSF- and one sMRI- with CSF not available. All patients received immunosuppressive treatment, but outcome in sMRI-/CSF- patients was worse: no recovery (n=1) or partial recovery (n=3) compared to partial recovery (n=4) and (nearly) complete recovery (n=3) in MRI+ patients. The systematic literature review yielded 146 articles eligible for inclusion, 90% case reports. A total of 427 SLE patients with TM were identified, of which only four cases were sMRI-/CSF- (1%), showing no improvement (n=1), partial improvement (n=2) and complete recovery (n=1) after immunosuppressive treatment.

Conclusion: Outcome in SLE patients presenting with clinically suspected TM with normal sMRI and CSF is less favorable, despite treatment with immunosuppressive therapy. Taking a functional neurological disorder into consideration may be helpful in order to start other therapeutic strategies. We suggest prescribing immunosuppressive treatment for a restricted period of time to evaluate its effect in cases where a functional disorder initially is considered unlikely.
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http://dx.doi.org/10.2147/NDT.S267000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764958PMC
December 2020

Association Between Bone Mineral Density and Autoantibodies in Patients With Rheumatoid Arthritis.

Arthritis Rheumatol 2021 06 10;73(6):921-930. Epub 2021 May 10.

Leiden University Medical Center, Leiden, The Netherlands.

Objective: Autoantibodies, such as anti-citrullinated protein antibodies (ACPAs), have been described as inducing bone loss in rheumatoid arthritis (RA), which can also be reflected by bone mineral density (BMD). We therefore examined the association between osteoporosis and autoantibodies in two independent RA cohorts.

Methods: Dual x-ray absorptiometry (DXA) of the lumbar spine and left hip was performed in 408 Dutch patients with early RA during 5 years of follow-up and in 198 Swedish patients with early RA during 10 years of follow-up. The longitudinal effect of ACPAs and other autoantibodies on several BMD measures was assessed using generalized estimating equations.

Results: In the Dutch cohort, significantly lower BMD at baseline was observed in ACPA-positive patients compared to ACPA-negative patients, with an estimated marginal mean BMD in the left hip of 0.92 g/cm (95% confidence interval [95% CI] 0.91-0.93) versus 0.95 g/cm (95% CI 0.93-0.97) (P = 0.01). In line with this, significantly lower Z scores at baseline were noted in the ACPA-positive group compared to the ACPA-negative group (estimated marginal mean Z score in the left hip of 0.18 [95% CI 0.08-0.29] versus 0.48 [95% CI 0.33-0.63]) (P < 0.01). However, despite clear differences at baseline, ACPA positivity was not associated with greater decrease in absolute BMD or Z scores over time. Furthermore, there was no association between BMD and higher levels of ACPAs or other autoantibodies (rheumatoid factor and anti-carbamylated protein antibodies). In the Swedish cohort, ACPA-positive patients tended to have a higher prevalence of osteopenia at baseline (P = 0.04), but again, ACPA positivity was not associated with an increased prevalence of osteopenia or osteoporosis over time.

Conclusion: The presence of ACPAs is associated with significantly lower BMD at baseline, but not with greater BMD loss over time in treated RA patients. These results suggest that ACPAs alone do not appear to contribute to bone loss after disease onset when disease activity is well-managed.
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http://dx.doi.org/10.1002/art.41623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251600PMC
June 2021

Adalimumab Biosimilars in the Treatment of Rheumatoid Arthritis: A Systematic Review of the Evidence for Biosimilarity.

Rheumatol Ther 2021 Mar 1;8(1):41-61. Epub 2020 Dec 1.

Mylan Inc., Canonsburg, PA, USA.

Although treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) has significantly improved clinical outcomes in patients with rheumatoid arthritis (RA), many patients do not have access to these treatments. As cost-effective alternatives to their reference products (RPs), biosimilars provide an opportunity to increase access to bDMARDs. The European Medicines Agency and the US Food and Drug Administration have detailed pathways for the approval of biosimilars based on establishing the similarity of the biosimilar to the RP in terms of structure and function, pharmacokinetics (PK), efficacy, safety, and immunogenicity. A number of biosimilars of adalimumab, infliximab, etanercept, and rituximab RPs have been approved in the United States and/or European Union. This article is focused on the seven adalimumab biosimilars. A review of the data for the biosimilars FKB327, ABP 501, BI 695501, GP2017, MSB11022, PF-06410293, and SB5 confirm that these products are highly similar to the adalimumab RP with regard to structure, physicochemical and biological properties, PK, safety, immunogenicity, and efficacy in the treatment of RA and other chronic immune-mediated, inflammatory conditions. Data from several switching studies showed no changes in efficacy, safety, trough serum drug concentration, or immunogenicity between the biosimilars and their RP.Trial registration: ClinicalTrials.gov identifiers: NCT02260791, NCT02405780, NCT01970475, NCT02137226, NCT02045979, NCT02744755, NCT02144714, NCT02167139, NCT03014947, NCT02114931, NCT02640612, NCT02167139, NCT03052322, NCT02480153. EudraCT numbers: 2012-005140-23, 2012-000785-37, 2013-003722-84, 2015-000579-28, 2014-002879-29, 2014-000662-21, 2013-004654-13, 2015-002634-41, 2014-005229-11, 2016-002852-26, 2014-000352-29.
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http://dx.doi.org/10.1007/s40744-020-00259-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991039PMC
March 2021

Machine Learning Electronic Health Record Identification of Patients with Rheumatoid Arthritis: Algorithm Pipeline Development and Validation Study.

JMIR Med Inform 2020 Nov 30;8(11):e23930. Epub 2020 Nov 30.

Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands.

Background: Financial codes are often used to extract diagnoses from electronic health records. This approach is prone to false positives. Alternatively, queries are constructed, but these are highly center and language specific. A tantalizing alternative is the automatic identification of patients by employing machine learning on format-free text entries.

Objective: The aim of this study was to develop an easily implementable workflow that builds a machine learning algorithm capable of accurately identifying patients with rheumatoid arthritis from format-free text fields in electronic health records.

Methods: Two electronic health record data sets were employed: Leiden (n=3000) and Erlangen (n=4771). Using a portion of the Leiden data (n=2000), we compared 6 different machine learning methods and a naïve word-matching algorithm using 10-fold cross-validation. Performances were compared using the area under the receiver operating characteristic curve (AUROC) and the area under the precision recall curve (AUPRC), and F1 score was used as the primary criterion for selecting the best method to build a classifying algorithm. We selected the optimal threshold of positive predictive value for case identification based on the output of the best method in the training data. This validation workflow was subsequently applied to a portion of the Erlangen data (n=4293). For testing, the best performing methods were applied to remaining data (Leiden n=1000; Erlangen n=478) for an unbiased evaluation.

Results: For the Leiden data set, the word-matching algorithm demonstrated mixed performance (AUROC 0.90; AUPRC 0.33; F1 score 0.55), and 4 methods significantly outperformed word-matching, with support vector machines performing best (AUROC 0.98; AUPRC 0.88; F1 score 0.83). Applying this support vector machine classifier to the test data resulted in a similarly high performance (F1 score 0.81; positive predictive value [PPV] 0.94), and with this method, we could identify 2873 patients with rheumatoid arthritis in less than 7 seconds out of the complete collection of 23,300 patients in the Leiden electronic health record system. For the Erlangen data set, gradient boosting performed best (AUROC 0.94; AUPRC 0.85; F1 score 0.82) in the training set, and applied to the test data, resulted once again in good results (F1 score 0.67; PPV 0.97).

Conclusions: We demonstrate that machine learning methods can extract the records of patients with rheumatoid arthritis from electronic health record data with high precision, allowing research on very large populations for limited costs. Our approach is language and center independent and could be applied to any type of diagnosis. We have developed our pipeline into a universally applicable and easy-to-implement workflow to equip centers with their own high-performing algorithm. This allows the creation of observational studies of unprecedented size covering different countries for low cost from already available data in electronic health record systems.
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http://dx.doi.org/10.2196/23930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735897PMC
November 2020

Persistently activated, proliferative memory autoreactive B cells promote inflammation in rheumatoid arthritis.

Sci Transl Med 2020 11;12(570)

Department of Rheumatology, Leiden University Medical Center, 2300RC Leiden, Netherlands.

Autoreactive B cells mediate autoimmune pathology, but exactly how remains unknown. A hallmark of rheumatoid arthritis (RA), a common autoimmune disease, is the presence of disease-specific anticitrullinated protein antibodies (ACPAs). Here, we showed that ACPA-positive B cells in patients with RA strongly expressed T cell-stimulating ligands, produced abundant proinflammatory cytokines, and were proliferative while escaping inhibitory signals. This activated state was found at different degrees in different stages of disease: highest in patients with recent-onset RA, moderate in patients with established RA, and far less pronounced in ACPA-positive individuals "at risk" for developing disease. The activated autoreactive B cell response persisted in patients who achieved clinical remission with conventional treatment. ACPA-positive B cells in blood and synovial fluid secreted increased amounts of the chemoattractant interleukin-8, which attracted neutrophils, the most abundant immune cell in arthritic joints. Tetanus toxoid-specific B cells from the same patients exhibited properties of memory B cells without the activation and proliferation phenotype, but these cells transiently acquired a similar proliferative phenotype upon booster vaccination. Together, these data indicated that continuous antigenic triggering of autoreactive B cells occurs in human autoimmune disease and support the emerging concept of immunological activity that persists under treatment even in clinical remission, which may revise our current concept of treatment targets for future therapeutic interventions. In addition, our data pointed to a pathogenic role of ACPA-positive B cells in the inflammatory disease process underlying RA and favor approaches that aim at their antigen-specific inactivation or depletion.
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http://dx.doi.org/10.1126/scitranslmed.aaz5327DOI Listing
November 2020

Mortality in patients with systemic lupus erythematosus and neuropsychiatric involvement: A retrospective analysis from a tertiary referral center in the Netherlands.

Lupus 2020 Dec 20;29(14):1892-1901. Epub 2020 Oct 20.

Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.

Objective: We aimed to evaluate all-cause and cause-specific mortality in patients with systemic lupus erythematosus (SLE) and neuropsychiatric (NP) symptoms in the Netherlands between 2007-2018.

Methods: Patients visiting the tertiary referral NPSLE clinic of the Leiden University Medical Center were included. NP symptoms were attributed to SLE requiring treatment (major NPSLE) or to other and mild causes (minor/non-NPSLE). Municipal registries were checked for current status (alive/deceased). Standardized mortality ratios (SMRs) and 95% confidence intervals (CI) were calculated using data from the Dutch population. Rate ratio (RR) and 95% CI were calculated using direct standardization to compare mortality between major NPSLE and minor/non-NPSLE.

Results: 351 patients were included and 149 patients were classified as major NPSLE (42.5%). Compared with the general population, mortality was increased in major NPSLE (SMR 5.0 (95% CI: 2.6-8.5)) and minor/non-NPSLE patients (SMR 3.7 (95% CI: 2.2-6.0)). Compared with minor/non-NPSLE, mortality was similar in major NPSLE patients (RR: 1.0 (95% CI: 0.5-2.0)). Cause-specific mortality rates demonstrated an increased risk of death due to infections in both groups, whereas death due to cardiovascular disease was only increased in minor/non-NPSLE patients.

Conclusion: Mortality was increased in both major NPSLE and minor/non-NPSLE patients in comparison with the general population. There was no difference in mortality between major NPSLE and minor/non-NPSLE patients.
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http://dx.doi.org/10.1177/0961203320963815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684795PMC
December 2020

Anti-Inflammatory and Proresolving Effects of the Omega-6 Polyunsaturated Fatty Acid Adrenic Acid.

J Immunol 2020 11 2;205(10):2840-2849. Epub 2020 Oct 2.

Department of Rheumatology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.

Polyunsaturated fatty acids (PUFAs) and their metabolites are potent regulators of inflammation. Generally, omega ()-3 PUFAs are considered proresolving whereas -6 PUFAs are classified as proinflammatory. In this study, we characterized the inflammatory response in murine peritonitis and unexpectedly found the accumulation of adrenic acid (AdA), a poorly studied -6 PUFA. Functional studies revealed that AdA potently inhibited the formation of the chemoattractant leukotriene B (LTB), specifically in human neutrophils, and this correlated with a reduction of its precursor arachidonic acid (AA) in free form. AdA exposure in human monocyte-derived macrophages enhanced efferocytosis of apoptotic human neutrophils. In vivo, AdA treatment significantly alleviated arthritis in an LTB-dependent murine arthritis model. Our findings are, to our knowledge, the first to indicate that the -6 fatty acid AdA effectively blocks production of LTB by neutrophils and could play a role in resolution of inflammation in vivo.
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http://dx.doi.org/10.4049/jimmunol.1801653DOI Listing
November 2020

Evolution of interstitial lung disease one year after hematopoietic stem cell transplantation or cyclophosphamide for systemic sclerosis.

Arthritis Care Res (Hoboken) 2020 Sep 22. Epub 2020 Sep 22.

Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.

Objectives: Hematopoietic stem cell transplantation (HSCT) and cyclophosphamide (CYC) are treatment options for progressive interstitial lung disease associated with systemic sclerosis (SSc-ILD). The aims of our retrospective observational study were to evaluate: 1) the evolution of SSc-ILD assessed by high-resolution computed tomography (HRCT) in SSc patients treated with HSCT. A group of patients treated with CYC was included as frame of reference; 2) how pulmonary function tests (PFTs) associate with HRCT findings; 3) which factors predict ILD reduction.

Methods: We semi-quantitatively scored total ILD extent, reticulations and ground glass opacities (GGO) on baseline and 1-year HRCTs of SSc patients treated with HSCT or CYC. Linear association between HRCT and PFT changes, and predictors of ILD improvement, were studied.

Results: We included 51 patients (HSCT n=20; CYC n=31). Mean change in total ILD score was -5.1% (95%CI -10.2 to 0.0) in HSCT (p=0.050), and -1.0% (95%CI -4.3 to 2.3) in CYC group (p=0.535). For all patients, evolution of HRCT scores was weakly associated with relative changes in PFTs. In univariate logistic regression, higher GGO and total ILD scores, and lower diffusing capacity of the lungs for carbon monoxide at baseline (DLCO), predicted improvement of ILD extent after treatment, but a multivariable model could not be built to assess independency of predictors.

Conclusion: One year after treatment with HSCT, a non-significant, but clear, reduction of SSc-ILD extent was observed. Changes in PFTs were associated with changes in HRCT scores but the correlation was weak and cannot be considered conclusive.
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http://dx.doi.org/10.1002/acr.24451DOI Listing
September 2020

Enhanced treatment strategies and distinct disease outcomes among autoantibody-positive and -negative rheumatoid arthritis patients over 25 years: A longitudinal cohort study in the Netherlands.

PLoS Med 2020 09 22;17(9):e1003296. Epub 2020 Sep 22.

Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands.

Background: Based on different genetic and environmental risk factors and histology, it has been proposed that rheumatoid arthritis (RA) consists of 2 types: autoantibody-positive and autoantibody-negative RA. However, until now, this remained hypothetical. To assess this hypothesis, we studied whether the long-term outcomes differed for these 2 groups of RA patients.

Methods And Findings: In the Leiden Early Arthritis Clinic cohort, 1,285 consecutive RA patients were included between 1993 and 2016 and followed yearly. Treatment protocols in routine care improved over time, irrespective of autoantibody status, and 5 inclusion periods were used as instrumental variables: 1993-1996, delayed mild disease-modifying antirheumatic drug (DMARD) initiation (reference period); 1997-2000, early mild DMARDs; 2001-2005, early methotrexate; 2006-2010, early methotrexate followed by treat-to-target adjustments; 2011-2016, similar to 2006-2010 plus additional efforts for very early referral. Three long-term outcomes were studied: sustained DMARD-free remission (SDFR) (persistent absence of clinical synovitis after DMARD cessation), mortality, and functional disability measured by yearly Health Assessment Questionnaire (HAQ). Treatment response in the short term (disease activity) was measured by Disease Activity Score-28 with erythrocyte sedimentation rate (DAS28-ESR). Linear mixed models and Cox regression were used, stratified for autoantibody positivity, defined as IgG anti-CCP2 and/or IgM rheumatoid factor positivity. In total, 823 patients had autoantibody-positive RA (mean age 55 years, 67% female); 462 patients had autoantibody-negative RA (age 60 years, 64% female). Age, gender, and percentage of autoantibody-positive patients were stable throughout the inclusion periods. Disease activity significantly decreased over time within both groups. SDFR rates increased after introduction of treat-to-target (hazard ratio [HR] 2006-2010 relative to 1993-1996: 3.35 [95% CI 1.46 to 7.72; p = 0.004]; HR 2011-2016: 4.57 [95% CI 1.80 to 11.6; p = 0.001]) in autoantibody-positive RA, but not in autoantibody-negative RA. In autoantibody-positive RA, mortality decreased significantly after the introduction of treat-to-target treatment adjustments (HR 2006-2010: 0.56 [95% CI 0.34 to 0.92; p = 0.023]; HR 2011-2016: 0.33 [95% CI 0.14 to 0.77; p = 0.010]), but not in autoantibody-negative RA (HR 2006-2010: 0.79 [95% CI 0.40 to 1.56; p = 0.50]; HR 2011-2016: 0.36 [95% CI 0.10 to 1.34; p = 0.13]). Similarly, functional disability improved in autoantibody-positive RA for the periods after 2000 relative to 1993-1996 (range -0.16 [95% CI -0.29 to -0.03; p = 0.043] to -0.32 [95% CI -0.44 to -0.20; p < 0.001] units of improvement), but not in autoantibody-negative RA (range 0.10 [95% CI -0.12 to 0.31; p = 0.38] to -0.13 [95% CI -0.34 to 0.07; p = 0.20] units of improvement). Limitations to note were that treatment was not randomized-but it was protocolized and instrumental variable analysis was used to obtain comparable groups-and that a limited spread of ethnicities was included.

Conclusions: Although disease activity has improved in both autoantibody-positive and autoantibody-negative RA in recent decades, the response in long-term outcomes differed. We propose that it is time to subdivide RA into autoantibody-positive RA (type 1) and autoantibody-negative RA (type 2), in the hope that this leads to stratified treatment in RA.
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http://dx.doi.org/10.1371/journal.pmed.1003296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508377PMC
September 2020

Interpreting big-data analysis of retrospective observational data.

Lancet Rheumatol 2020 Nov 21;2(11):e652-e653. Epub 2020 Aug 21.

Department or Rheumatology, Leiden University Medical Center, Leiden, Netherlands.

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http://dx.doi.org/10.1016/S2665-9913(20)30289-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442429PMC
November 2020

Association of Anti-Topoisomerase I Antibodies of the IgM Isotype With Disease Progression in Anti-Topoisomerase I-Positive Systemic Sclerosis.

Arthritis Rheumatol 2020 11 29;72(11):1897-1904. Epub 2020 Sep 29.

Leiden University Medical Center, Leiden, The Netherlands.

Objective: Anti-topoisomerase I (anti-topo I) autoantibodies in systemic sclerosis (SSc) are associated with diffuse skin involvement and interstitial lung fibrosis. Thus far, however, the relationship between anti-topo I antibody response and disease course has not yet been fully evaluated. This study was undertaken to gain insight into the association between characteristics of the anti-topo I antibody response and clinical disease course in SSc patients positive for anti-topo I antibodies.

Methods: Levels of anti-topo I IgG, anti-topo I IgM, and anti-topo I IgA were assessed in consecutive serum samples obtained from patients at baseline who were positive for anti-topo I IgG in the Leiden Combined Care In Systemic Sclerosis (CCISS) cohort. One-year disease progression was defined by a relevant increase in modified Rodnan skin thickness score (MRSS), decline in pulmonary function, development of digital ulcers, renal crisis, and pulmonary hypertension, and/or mortality. Validation was performed in SSc patients who were positive for anti-topo I from the Oslo University Hospital and University Hospital Zurich.

Results: Of the 103 patients with anti-topo I IgG in the CCISS cohort, clinical data were available to assess 1-year disease progression in 81 patients. Of these 81 patients, 23 (28%) had disease progression. At baseline, patients with disease progression were significantly more often anti-topo I IgM-positive than those who did not experience disease progression (21 [91%] of 23 versus 33 [57%] of 58; P < 0.01). This finding was confirmed in the independent validation samples.

Conclusion: In SSc patients who were anti-topo I IgG-positive, presence of anti-topo I IgM, which might be considered as a surrogate for an ongoing autoreactive B cell immune response, is associated with disease progression.
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http://dx.doi.org/10.1002/art.41403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702063PMC
November 2020

Body mass index and treatment survival in patients with RA starting treatment with TNFα-inhibitors: long-term follow-up in the real-life METEOR registry.

RMD Open 2020 06;6(2)

Rheumatology, Leiden University Medical Center, Leiden, Netherlands.

Objectives: To study whether there is an association between body mass index (BMI) category and survival of various tumour necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA) patients in a real-life longitudinal international registry.

Methods: Data from 5230 patients with RA starting treatment with any TNFi were selected from the METEOR registry. Patients were divided into six BMI categories: 3.7% underweight, BMI<18.5 kg/m; 46% normal weight, BMI 18.5-25 kg/m; 32% pre-obesity, BMI 25-30 kg/m; 13% obesity class I, BMI 30-35 kg/m; 3.4% obesity class II, BMI 35-40 kg/m; and 1.6% obesity class III, BMI >40 kg/m. Time on treatment in the different BMI categories was compared for all TNFi combined and for the infliximab, adalimumab and etanercept separately, using Kaplan-Meier curves and Cox regression analyses. Cox regression analyses were adjusted for potential confounders, with follow-up censored at 5000 days.

Results: Patients in obesity class II (HR 1.28, 95% CI 1.06 to 1.54) and III (HR 1.67, 95% CI 1.29 to 2.18) and underweight patients (HR 1.30, 95% CI 1.07 to 1.58) showed statistically significantly shorter TNFi survival than normal weight patients. The effect in underweight patients was strongest for infliximab (HR 1.82, 95% CI 1.20 to 2.76), the effect in overweight patients was strongest for infliximab (category II (HR 1.49, 95% CI 0.98 to 2.26); category III (HR 1.46, 95% CI 0.79 to 2.71)) and etanercept (category II (HR 1.27 95% CI 0.98 to 1.65); category III (HR 1.79, 95% CI 1.25 to 2.55)). No significant effect modification from reported pain was found.

Conclusion: Both underweight and overweight patients discontinued TNFi treatment earlier than normal weight patients, without evidence of reported pain as the main determinant. It remains uncertain what determines TNFi survival in individual patients.
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http://dx.doi.org/10.1136/rmdopen-2020-001203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299513PMC
June 2020

Association Between Centromere- and Topoisomerase-specific Immune Responses and the Degree of Microangiopathy in Systemic Sclerosis.

J Rheumatol 2021 03 1;48(3):402-409. Epub 2020 Jun 1.

N.M. van Leeuwen, MD, C.M. Wortel, MSc, C.M. Fehres, PhD, H.U. Scherer, MD, PhD, R.E.M Toes, Professor, MSc, PhD, T.W. Huizinga, Professor, MD, PhD, J.K. de Vries-Bouwstra, MD, PhD, Department of Rheumatology, Leiden University Medical Center.

Objective: Autoreactive antibody responses, including the use of several isotypes of autoantibodies, have been shown to be associated with clinical outcome in several rheumatic autoimmune diseases. The goals of this study were to evaluate whether (1) anticentromere antibody (ACA)- and antitopoisomerase antibody (ATA)-specific isotype expression, and (2) organ involvement are associated with the degree of microangiopathy in systemic sclerosis (SSc).

Methods: ACA and ATA IgG, IgM, and IgA levels were measured in baseline serum samples of ACA IgG-positive (+) and ATA IgG+ patients with SSc. The degree of microangiopathy was determined based on nailfold videocapillaroscopy (NVC) images collected at the same point in time. Logistic regression analyses with autoantibodies, clinical characteristics, isotype expression, and ACA and ATA IgG, IgM, and IgA levels as independent variables, and NVC pattern as the dependent variable were performed.

Results: In 164 patients, isotype levels and degree of microangiopathy were evaluated. Logistic regression confirmed the association of the degree of microangiopathy with the presence of digital ulcers (OR 3.07, 95% CI 1.43-6.60), interstitial lung disease (OR 3.41, 95% CI 1.11-10.61), and pulmonary arterial hypertension (OR 5.58, 95% CI 2.05-17.81). ATA positivity was associated with more severe microangiopathy (OR 2.09, 95% CI 1.05-4.13). Patients who expressed solely ACA IgG showed a trend towards less severe microangiopathy compared to patients also expressing ACA IgM and/or IgA. Levels of ACA IgG and ATA IgM were found to be associated with microangiopathy severity.

Conclusion: We observed an association between ACA and ATA responses and the degree of microangiopathy in SSc. These findings might indicate that the breadth of the autoimmune response, as reflected by autoantibody production and microvascular damage, interacts in the pathophysiology of SSc.
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http://dx.doi.org/10.3899/jrheum.191331DOI Listing
March 2021

Increasing incidence of autoantibody-negative RA is replicated and is partly explained by an aging population.

Ann Rheum Dis 2020 May 29. Epub 2020 May 29.

Rheumatology, Leiden University Medical Center, Leiden, Zuid-Holland, Netherlands.

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http://dx.doi.org/10.1136/annrheumdis-2020-217609DOI Listing
May 2020

Earlier is better when treating rheumatoid arthritis: but can we detect a window of opportunity?

RMD Open 2020 05;6(1)

Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands.

Objectives: The window of opportunity (WOO) hypothesis suggests a limited time frame to stop rheumatoid arthritis (RA). We hypothesised that a WOO could either be represented by a hyperbolic ('curved') decline in the chance to achieve the outcome sustained drug-free remission (sDFR) over time, after which achieving sDFR is not possible anymore, or by a more gradual linear decline approaching zero chance to achieve sDFR.

Methods: Patients with RA (symptom duration <2 years) were included from two randomised trials: BehandelStrategieën (BeSt), n=508 and Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED), n=479. Cox-regression was performed to assess the shape of the association between symptom duration and sDFR (Disease Activity Score<1.6, no disease-modifying anti-rheumatic drugs for ≥1 year) for patients starting slow-acting monotherapy (IMPROVED, BeSt) or fast-acting combination therapy (BeSt). Likelihood ratio tests were used to compare the fit of linear and non-linear models in both databases separately. Predictions from the best fitting models were used to assess whether the absolute risk to achieve sDFR approaches zero with increasing symptom duration.

Results: In BeSt and IMPROVED, 54/226 and 110/421 patients achieved sDFR with fast-acting treatment, and 53/243 (BeSt) with slow-acting treatment. Non-linear models did not fit better than linear models (fast-acting treatment BeSt p=0.743, IMPROVED p=0.337; slow-acting treatment BeSt p=0.609). After slow-acting monotherapy, linear models declined steeper. None of the models approached zero chance to achieve sDFR over time.

Conclusions: The chance to achieve sDFR decreased gradually over time, and decreased fastest in patients starting slow-acting monotherapy. In both treatment groups, we found no evidence for a WOO within 2 years symptom duration.
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http://dx.doi.org/10.1136/rmdopen-2020-001242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299505PMC
May 2020
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