Presence of SARS-CoV-2 antibodies in patients with COVID-19 like symptoms from the IENIMINI cohort.

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 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.

NT-proBNP and sRAGE levels in early rheumatoid arthritis.

OBJECTIVE: Several biomarkers of cardiovascular function are found to be increased in rheumatoid arthritis (RA), with some suggesting a relationship with disease activity and improvement with adequate anti-rheumatic treatment. Promising biomarkers include N-terminal pro-brain natriuretic peptide (NT-proBNP) and the soluble receptor form of advanced glycation end-products (sRAGE). The objective of this study was to investigate associations between NT-proBNP and sRAGE levels and markers of inflammation and disease activity in early RA patients and their changes during (effective) anti-rheumatic treatment. METHOD: Data from 342 consecutive early RA patients participating in the 'Parelsnoer' cohort were used. At baseline and after 6 months' disease activity, NT-proBNP and sRAGE levels were assessed. RESULTS: After 6 months, NT-proBNP decreased from 83 pmol/L (mean) at baseline to 69 pmol/L at follow-up (p < 0.001), while sRAGE increased from 997 pg/mL to 1125 pg/mL (p < 0.001). A larger decrease in erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) was associated with larger changes in NT-proBNP and sRAGE. For every point decrease in ESR, there was a 1.7-point decrease in NT-proBNP and a 2.2-point increase in sRAGE. For CRP, these values were 1.7 and 2.7, respectively (p < 0.001). CONCLUSION: Suppressing inflammation, independently of achieving remission, increases sRAGE levels and decreases NT-proBNP levels significantly. Whether this translates into a decrease in incident cardiovascular disease remains to be elucidated.

Antibodies and B cells recognising citrullinated proteins display a broad cross-reactivity towards other post-translational modifications.

OBJECTIVE: Autoantibodies against antigens carrying distinct post-translational modifications (PTMs), such as citrulline, homocitrulline or acetyllysine, are hallmarks of rheumatoid arthritis (RA). The relation between these anti-modified protein antibody (AMPA)-classes is poorly understood as is the ability of different PTM-antigens to activate B-cell receptors (BCRs) directed against citrullinated proteins (CP). Insights into the nature of PTMs able to activate such B cells are pivotal to understand the 'evolution' of the autoimmune response conceivable underlying the disease. Here, we investigated the cross-reactivity of monoclonal AMPA and the ability of different types of PTM-antigens to activate CP-reactive BCRs. METHODS: BCR sequences from B cells isolated using citrullinated or acetylated antigens were used to produce monoclonal antibodies (mAb) followed by a detailed analysis of their cross-reactivity towards PTM-antigens. Ramos B-cell transfectants expressing CP-reactive IgG BCRs were generated and their activation on stimulation with PTM-antigens investigated. RESULTS: Most mAbs were highly cross-reactive towards multiple PTMs, while no reactivity was observed to the unmodified controls. B cells carrying CP-reactive BCRs showed activation on stimulation with various types of PTM-antigens. CONCLUSIONS: Our study illustrates that AMPA exhibit a high cross-reactivity towards at least two PTMs indicating that their recognition pattern is not confined to one type of modification. Furthermore, our data show that CP-reactive B cells are not only activated by citrullinated, but also by carbamylated and/or acetylated antigens. These data are vital for the understanding of the breach of B-cell tolerance against PTM-antigens and the possible contribution of these antigens to RA-pathogenesis.

Is current smoking status and its relationship to anti-cyclic citrullinated peptide antibodies a predictor of worse response to biological therapies in rheumatoid arthritis patients?

OBJECTIVE: To assess the association between smoking, anti-cyclic citrullinated peptide (anti-CCP) antibody status, and clinical efficacy of biological therapies in rheumatoid arthritis (RA) patients. METHOD: This retrospective clinical practice setting study included 1349 RA patients from the METEOR database (aged >18 years). We collected data on sociodemographics, smoking status (smoker, <10, 10-19, and >20 cigarettes/day; ex-smoker; non-smoker), baseline disease activity parameters and anti-CCP, previous disease-modifying anti-rheumatic drugs (DMARDs), biological therapy, combined therapy (steroids and DMARDs), and follow-up disease activity. Clinical efficacy was assessed by European League Against Rheumatism (EULAR) good/moderate response rates for all aggregated biological therapies, based on both smoking and anti-CCP status. RESULTS: The non-smoking RA patients were more often female at biological therapy initiation than the ex-smokers and smokers (91.1% vs 60.4% and 67.9%, respectively, p < 0.001), and ex-smokers were older than non-smokers and smokers (mean ± sd 56.5 ± 11.1, 53.5 ± 13.3 and 51.3 ± 11.0 years old, respectively; p < 0.001). In total, 845 (62.6%) were non-smokers, 214 (15.9%) ex-smokers, and 290 (21.5%) smokers [daily cigarettes smoked: 148 (11%) <11; 61 (4.5%) 11-20; and 81 (6%) >20]. Anti CCP-antibody status was similar in both groups. Non-smokers showed higher baseline DAS28 than ex-smokers and smokers (5.0 ± 1.5 vs 4.7 ± 1.4 and 4.7 ± 1.4, respectively; p < 0.001) and used more baseline steroids and DMARDs. A higher EULAR response rate was observed in non-smokers than in ex-smokers and smokers (73% vs 65% and 64.1%, respectively; p = 0.004). Drug survival was higher in non-smokers compared to ex-smokers and smokers [57.7 months (46.4-53.8), 38.6 (30.3-46.8), and 50.1 (41.8-58.4); p < 0.001, respectively]. CONCLUSION: In daily clinical practice, non-smokers respond better than smokers to biological therapy, but this does not result in better drug survival.

Anti-cyclic citrullinated peptide antibodies, other common autoantibodies, and smoking as risk factors for lymphoma in patients with rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) are at increased risk of lymphoma. There is no biomarker to indicate future lymphoma risk in RA and it is not known whether factors associated with an increased risk of RA also confer an increased risk of lymphoma. We investigated whether anti-cyclic citrullinated peptide (CCP) antibodies, other autoantibodies, and smoking, are associated with lymphoma development in RA. METHOD: From two population-based case-control studies, the Scandinavian Lymphoma Etiology (SCALE) study and the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) I study, we identified lymphoma cases with a validated RA diagnosis (n = 50), to whom we matched study participants with RA but no lymphoma (n = 261), lymphoma but no RA (n = 257), and neither RA nor lymphoma (n = 233). Lymphomas were classified according to the WHO classification. Blood samples were analysed for immunoglobulin G (IgG), IgM, and IgA isotypes and IgG1-4 subclasses of anti-CCP antibodies and for 15 antinuclear antibody (ANA)-associated specific autoantibodies. Relative risks were estimated as crude and adjusted odds ratios (adjOR) with 95% confidence intervals (CIs) using logistic regression. RESULTS: We found no association between anti-CCP IgG ≥ 25 units/mL (adjOR 1.4, 95% CI 0.7-2.7), anti-CCP IgG ≥ 500 units/mL (adjOR 1.4, 95% CI 0.7-3.0), anti-CCP Ig of other isotypes, other autoantibodies (adjOR any vs none 0.6, 95% CI 0.3-1.2), or cigarette smoking (adjOR ever vs never 1.1, 95% CI 0.5-2.2) and lymphoma risk among patients with RA. CONCLUSION: In this study, neither anti-CCP antibodies (IgG, IgG1-4, IgM, or IgA), nor other common autoantibodies, nor smoking predicted lymphoma risk in RA.

Aesthetic dissatisfaction in patients with hand osteoarthritis and its impact on daily life.

OBJECTIVES: To evaluate the nature and extent of aesthetic dissatisfaction in patients with hand osteoarthritis (OA), and to investigate its impact on daily life and its determinants. METHOD: Patients with primary hand OA, consulting secondary care, underwent physical examination for the number of joints with bony joint enlargements, soft tissue swelling and deformities, and radiographs. Questionnaires were filled in to measure pain and function (Functional Index for Hand Osteoarthritis, FIHOA), dissatisfaction with the appearance of the hands and its impact (aesthetic scales from the Michigan Hand Outcomes Questionnaire, MHQ), anxiety and depression (the Hospital Anxiety and Depression Scale, HADS), and illness perceptions (the revised Illness Perception Questionnaire, IPQ-R). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using multivariate logistic regression as measures of relative risk for dissatisfaction with appearance or its impact, adjusted for age, sex, body mass index (BMI), and joint-specific abnormalities (bony joint enlargements, deformities, or radiographic severity), self-reported pain and function. RESULTS: Of 247 patients (mean age 61.6 years, 88% women), 63 (26%) were aesthetically dissatisfied and 33 (13%) reported impact on daily life due to dissatisfaction. Patients with joint-specific abnormalities were at higher risk for reporting dissatisfaction. Patients who reported impact also reported more depression and negative illness perceptions, independently from joint-specific abnormalities. CONCLUSIONS: Hand OA patients report aesthetic dissatisfaction with their hands regularly, especially in those with joint abnormalities. This dissatisfaction has a negative impact in a small group of patients who also reported more depression and negative illness perceptions. These results indicate the influence of psychosocial factors on outcome measures in patients with hand OA.

Effectiveness of four dynamic treatment strategies in patients with anticitrullinated protein antibody-negative rheumatoid arthritis: a randomised trial.

OBJECTIVE: To determine the most effective treatment strategy among anticitrullinated protein antibodies (ACPA)-negative patients with early rheumatoid arthritis. METHODS: In the BeSt study, 184 ACPA-negative patients were randomised to: (1) sequential monotherapy, (2) step-up therapy, (3) initial combination including prednisone, (4) initial combination including infliximab. Treatment was targeted at the disease activity score (DAS) ≤2.4. Early response and 10-year outcomes were compared between the four strategy-arms in ACPA-negative patients. RESULTS: ACPA-negative patients achieved more short-term functional improvement from initial combination therapy than when on monotherapy (at month 3, mean Health Assessment Questionnaire (HAQ) 0.71 vs 0.98, p=0.006; at month 6, 0.59 vs 0.87, p=0.004). Functional ability over time was comparable between the strategy-arms (p=0.551) with a mean HAQ of 0.6 at year 10 (p=0.580 for comparison across the strategy-arms). 10-year radiographic progression was negligible (median 0.5) and comparable between the 4 strategy-arms (p=0.082). At year 10, remission was achieved by 11/40 (28%), 9/45 (20%), 17/56 (30%) and 17/43 patients (40%) in strategy-arms 1-4, respectively (p=0.434). Over time, similar remission percentages were achieved in all strategy-arms (p=0.815). 18%, 16%, 20% and 21% in strategy-arms 1 to 4 (p=0.742) were in drug-free remission at year 10, with a median duration of 60 months across the arms. CONCLUSIONS: Initial combination therapy with methotrexate, sulfasalazine and prednisone, or methotrexate and infliximab, is the most effective treatment strategy for ACPA-negative patients, resulting in earlier functional improvement than when on initial methotrexate monotherapy. After 10 years of targeted treatment, in all strategy-arms favourable clinical outcomes were achieved and radiographic progression was limited. TRIAL REGISTRATION NUMBER: NTR262, NTR265.

Anti-NMDA receptor autoantibodies in patients with systemic lupus erythematosus and their first-degree relatives.

The objective of this study is to investigate the presence of autoantibodies cross-reacting with the NR2 subunit of the N-methyl-d-aspartate (NMDA) glutamate receptor in plasma samples of patients with systemic lupus erythematosus (SLE), in their healthy first-degree relatives and in healthy unrelated individuals and to determine whether these autoantibodies are specific for lupus patients in general or for the subgroup of SLE patients with neuropsychiatric (NP) manifestations. Plasma samples were collected from 51 lupus patients (19 with and 32 without NP manifestations), 161 first-degree relatives and 55 healthy unrelated controls. Antibodies to a linear peptide of the NR2 subunit of the NMDA receptor were determined by enzyme-linked immunosorbent assay. A significant difference in mean antibody reactivity between SLE patients and healthy unrelated controls (P < 0.01) and between firstdegree relatives and healthy unrelated controls (P < 0.001) was found. No difference was found between lupus patients and their first-degree relatives or between lupus patients with and without NP symptoms. In this study, anti-NMDA receptor autoantibodies show more specificity for lupus patients (but not for selected patients with NP symptoms) and their first-degree relatives than for healthy controls, indicating a familial basis to mount an immune response to this peptide.