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CoronaVac, an inactivated SARS-CoV-2 vaccine, has been approved for emergency use in several countries. However, its immunogenicity in immunocompromised individuals has not been well established. We initiated a prospective phase 4 controlled trial (no. NCT04754698, CoronavRheum) in 910 adults with autoimmune rheumatic diseases (ARD) and 182 age- and sex-frequency-matched healthy adults (control group, CG), who received two doses of CoronaVac. The primary outcomes were reduction of ≥15% in both anti-SARS-CoV-2 IgG seroconversion (SC) and neutralizing antibody (NAb) positivity 6 weeks (day 69 (D69)) after the second dose in the ARD group compared with that in the CG. Secondary outcomes were IgG SC and NAb positivity at D28, IgG titers and neutralizing activity at D28 and D69 and vaccine safety. Prespecified endpoints were met, with lower anti-SARS-Cov-2 IgG SC (70.4 versus 95.5%, P  < 0.001) and NAb positivity (56.3 versus 79.3%, P  < 0.001) at D69 in the ARD group than in the CG. Moreover, IgG titers (12.1 versus 29.7, P  < 0.001) and median neutralization activity (58.7 versus 64.5%, P  = 0.013) were also lower at D69 in patients with ARD. At D28, patients with ARD presented with lower IgG frequency (18.7 versus 34.6%, P  < 0.001) and NAb positivity (20.6 versus 36.3%, P  < 0.001) than that of the CG. There were no moderate/severe adverse events. These data support the use of CoronaVac in patients with ARD, suggesting reduced but acceptable short-term immunogenicity. The trial is still ongoing to evaluate the long-term effectiveness/immunogenicity. In a large prospective phase 4 trial, vaccination with CoronaVac, an inactivated SARS-CoV-2 vaccine, elicited significantly lower virus-specific IgG antibodies and neutralizing antibodies in patients with autoimmune rheumatic diseases than in age- and sex-matched healthy control trial participants.

In patients with autoimmune rheumatic disease, methotrexate therapy has been associated with poor immune response to vaccines, including those intended to provide protection against COVID-19. Emerging evidence supports the practice of temporarily discontinuing this treatment in order to improve immunogenicity.

Data on bone microarchitecture in premenopausal women with RA are scarce and have not been evaluated using histomorphometry. We assessed bone fragility in premenopausal RA women through static and dynamic histomorphometric parameters, compared to age- and sex-matched controls. Eighty patients were screened, and iliac crest biopsies were performed in those with fragility fractures or low BMD (Z-score ≤ −2.0). All analyses focus exclusively on the 12 women who underwent bone biopsy. Among these 12 premenopausal women with longstanding RA, mean age was 41.8 ± 6.6 yr and disease duration was 10.8 ± 5.8 yr. Bone volume (BV/TV) was numerically lower in RA patients compared with controls (p = .064). Thus, a reduction in bone volume cannot be excluded, given the limited statistical power. RA patients demonstrated reduced trabecular thickness, increased cortical porosity, and higher osteoclastic surface. Dynamic evaluation showed markedly lower mineralizing surface (MS/BS) and greater variability in mineralization lag time (Mlt). However, Mlt values remained within the physiological range and do not meet histological criteria for osteomalacia. Four patients (33%) showed absent tetracycline labeling. Osteoid indices correlated positively with disease activity, and MS/BS correlated inversely with glucocorticoid dose. In this selected group of premenopausal women with longstanding RA and osteoporosis by clinical criteria, bone fragility appears to result from a combination of trabecular thinning, cortical porosity, and disturbances in mineralization kinetics rather than from classic histomorphometric osteoporosis or osteomalacia.

ObjectivesTo evaluate long-term effects on gamma-globulins and autoantibodies of abatacept (ABA) versus tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA) patients.MethodEighteen RA patients undergoing abatacept (ABA-RA) and 18 age/sex-matched patients treated with TNFi (TNFi-RA) were compared regarding clinical data, total gamma-globulins (TGG), specific subtypes (IgG, IgM, IgA), free light chains (FLC), IgM/IgG rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP3), and anti-mutated citrullinated vimentin (anti-MCV), assessed before and every 6 months, up to 24 months. Exclusion criteria: previous abatacept/rituximab or low TGG (< 0.7 g/dL).ResultsAt baseline, female sex (78 vs. 78%), age (55 vs. 53 years), DAS28 (5.73 vs. 5.67), TGG (1.4 vs. 1.35 g/dL), IgG (1168 vs. 1079 mg/dL), IgM (107 vs. 113 mg/dL), IgA (333 vs. 322 mg/dL), kappa (342 vs. 249 mg/dL), lambda (170 vs. 150 mg/dL), IgM-RF (76 vs. 53 UI), IgG-RF (63 vs. 25 UI), anti-CCP3 (216 vs. 189 UI), and anti-MCV (202 vs. 102 UI) were comparable in ABA-RA and TNFi-RA (p > 0.05). Similar disease activity improvement was observed in both groups. In ABA-RA, significant decreases (p < 0.05) were observed in TGG (1.4 vs. 1.05 g/dL), IgG (1168 vs. 997), IgA (333 vs. 278 mg/dL), kappa (342 vs. 257 mg/dL), lambda (170 vs. 144 mg/dL), IgM-RF (76 vs. 37 UI), IgG-RF (65 vs. 24 UI), anti-CCP3 (216 vs. 183 UI), and anti-MCV (202 vs. 60 UI) at 6 months, without further decreases. In contrast, TNFi-RA showed no decrease in any of such parameters. ABA-RA also had more often transient IgG levels under the lower limit of normality (66.7% vs. 33.3%, p = 0.046). No severe infection occurred. DAS28, ESR, and CRP correlated significantly to gamma-globulins and FLC at baseline (p < 0.05), but these correlations were longitudinally lost in ABA-RA, but not in TNFi-RA.ConclusionABA, but not TNFi, induces a safe, persistent, long-term, and non-progressive reduction in gamma-globulins and autoantibodies, including anti-MCV. This pattern is dissociated from disease activity control.Key Points• ABA induces a long-term and non-progressive reduction in gamma-globulins and FLC, which occurs regardless of disease activity control.• ABA-induced reduction in gamma-globulins and FLC promotes a dissociation of such parameters and disease activity.• The same pattern of reduction is observed in autoantibodies: IgM-RF, IgG-RF, anti-CCP3, and anti-MCV.• Low transient IgG can be observed in RA patients treated with ABA, but does not correlate to infection.

The determination of durability and vaccine-associated protection is essential for booster doses strategies, however data on the stability of SARS-CoV-2 immunity are scarce. Here we assess anti-SARS-CoV-2 immunogenicity decay and incident cases six months after the 2 nd dose of Sinovac-CoronaVac inactivated vaccine (D210) in 828 autoimmune rheumatic diseases patients compared with 207 age/sex-balanced control individuals. The primary outcome is the presence of anti-S1/S2 SARS-CoV-2 IgG at 6 months compared to 6 weeks after 2nd vaccine dose for decay evaluation. Secondary outcomes are presence of neutralizing antibodies, percent inhibition by neutralizing, geometric mean titers and cumulative incident cases at 6 months after 2nd dose. Anti-S1/S2 IgG positivity and titers reduce to 23.8% and 38% in patients ( p  < 0.001) during the six-month follow up and 20% and 51% in controls ( p  < 0.001), respectively. Neutralizing antibodies positivity and percent inhibition declines 41% and 54% in patients ( p  < 0.001) and 39.7% and 47% in controls (p < 0.001). Multivariate logistic regression analysis show males (OR = 0.56;95% CI0.40-0.79), prednisone (OR = 0.56; 95% CI0.41-0.76), anti-TNF (OR = 0.66;95% CI0.45-0.96), abatacept (OR = 0.29; 95% CI0.15-0.56) and rituximab (OR = 0.32;95% CI0.11-0.90) associate with a substantial reduction in IgG response at day 210 in patients. Although cellular immunity was not assessed, a decrease of COVID-19 cases (from 27.5 to 8.1/100 person-years; p  < 0.001) is observed despite the concomitant emergence and spread of the Delta variant. Altogether we show a reduction in immunity 6-months of Sinovac-CoronaVac 2nd dose, particularly in males and those under immunosuppressives therapies, without a concomitant rise in COVID-19 cases. (CoronavRheum clinicaltrials.gov:NCT04754698). Characterising the response to SARS-CoV-2 post vaccination is critical in the appraisement of the induced immune response, performance and protective potential. Here the authors present data from a phase 4 clinical trial in autoimmune rheumatic disease patients 6 months post second dose of Sinovac-CoronaVac inactivated vaccine that show a marked reduction in antibody particularly in males or those under treatment with immune targeting therapies but saw no rise in COVID-19 disease.

This study aimed to investigate whether a single bout of exercise prior to the homologous booster dose of a SARS-CoV-2 inactivated vaccine (Sinovac-CoronaVac) could enhance immunogenicity in patients with dysfunctional immune system. This was a randomized controlled trial (1:1) within a single-arm, phase 4 vaccination trial, conducted in São Paulo, Brazil. Patients with spondyloarthritis assigned to the intervention group performed an exercise bout comprising three unilateral strength exercises involving eccentric and concentric contractions. After exercising, patients remained at rest for 1 h prior to vaccination, which was applied to the exercised arm. The control group remained at rest before vaccination. Immunogenicity was assessed before (Pre) and one month after (Post) the booster dose using seropositivity rates of total anti-SARS-CoV-2 S1/S2 IgG, geometric mean titers of anti-S1/S2 IgG (GMT), frequency of NAb positivity, and NAb activity. Before the booster dose, 16 patients from the exercise group and 16 patients from the control group exhibited seropositivity for IgG (59% vs. 57.1%), one month after the booster dose, seropositivity occurred in 96% vs. 100% of the cases (p = 0.84, group by time interaction). Only 10 patients from the exercise group and 12 patients from the control group showed positive NAb serology at Pre (37% vs. 42.8%). One month following the booster, NAb positivity was 96% vs. 93% (p = 0.41, group-by-time interaction). GMT was comparable between groups at Pre (p > 0.05). At Post, GMT increased similarly in both groups (exercise: 56.9%; control: 57.9%), with no group-by-time interaction (p = 0.82; estimated mean difference between groups at Post [EMD]: -40.4 UA/mL, 95%CI: -327, 246 UA/mL). Likewise, NAb activity was similar between groups at Pre and increased similarly in both of them as a result of the booster (47.5% vs. 39.9%), with no group-by-time interaction (p = 0.99; EMD: -6.19%, 95%CI: -17; 4.6%). In conclusion, a single bout of exercise did not enhance immunogenicity to a homologous booster dose of an inactivated SARS-CoV-2 vaccine among patients with spondyloarthritis. Studies assessing exercise as an adjuvant to first or second doses remain necessary.

ObjectiveTo evaluate the effect on immunogenicity and safety of 2-week methotrexate (MTX) discontinuation after each dose of the Sinovac-CoronaVac vaccine versus MTX maintenance in patients with rheumatoid arthritis (RA).MethodsThis was a single-centre, prospective, randomised, investigator-blinded, intervention study (NCT04754698, CoronavRheum) including adult patients with RA (stable Clinical Disease Activity Index (CDAI) ≤10, prednisone ≤7.5 mg/day) randomised (1:1) to withdraw MTX (MTX-hold) for 2 weeks after each vaccine dose or maintain MTX (MTX-maintain), evaluated at day 0 (D0), D28 and D69. Coprimary outcomes were anti-SARS-CoV-2 S1/S2 IgG seroconversion (SC) and neutralising antibody (NAb) positivity at D69. Secondary outcomes were geometric mean titres (GMT) and flare rates. For immunogenicity analyses, we excluded patients with baseline positive IgG/NAb, and for safety reasons those who flared at D28 (CDAI >10) and did not withdraw MTX twice.ResultsRandomisation included 138 patients with 9 exclusions (5 COVID-19, 4 protocol violations). Safety evaluation included 60 patients in the MTX-hold and 69 patients in the MTX-maintain group. Further exclusions included 27 patients (13 (21.7%) vs 14 (20.3%), p=0.848) with positive baseline IgG/NAb and 10 patients (21.3%) in MTX-hold with CDAI >10 at D28. At D69, the MTX-hold group (n=37) had a higher rate of SC than the MTX-maintain group (n=55) (29 (78.4%) vs 30 (54.5%), p=0.019), with parallel augmentation in GMT (34.2 (25.2–46.4) vs 16.8 (11.9–23.6), p=0.006). No differences were observed for NAb positivity (23 (62.2%) vs 27 (49.1%), p=0.217). At D28 flare, the rates were comparable in both groups (CDAI, p=0.122; Disease Activity Score in 28 joints with C reactive protein, p=0.576), whereas CDAI >10 was more frequent in MTX-hold at D69 (p=0.024).ConclusionWe provided novel data that 2-week MTX withdrawal after each dose of the Sinovac-CoronaVac vaccine improves anti-SARS-CoV-2 IgG response. The increased flare rates after the second MTX withdrawal may be attributed to the short-term interval between vaccine doses. This strategy requires close surveillance and shared decision making due to the possibility of flares.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by increased risk of cardiovascular disease and hypertension (HT). A single session of aerobic exercise may reduce blood pressure (BP) in different clinical groups; however, little is known about the acute effects of exercise on BP in RA patients. This is a randomized controlled crossover study that assessed the effects of a single session of aerobic exercise on resting BP, on BP responses to stressful stimuli, and on 24-h BP in women with RA and HT. Twenty women with RA and HT (53 ± 10 years) undertook sessions of 30-min treadmill exercise (50% VO 2max ) or control (no exercise) in a crossover fashion. Before and after the sessions, BP was measured at rest, and in response to the Stroop-Color Word Test (SCWT), the Cold Pressor Test (CPT), and an isometric handgrip test. After the sessions, participants were also fitted with an ambulatory BP monitor for the assessment of 24-h BP. A single session of exercise reduced resting systolic BP (SBP) (−5 ± 9 mmHg; p  < 0.05), and reduced SBP response to the SCWT (−7 ± 14 mmHg; p  < 0.05), and to the CPT (−5 ± 11 mmHg; p  < 0.05). Exercise did not reduce resting diastolic BP (DBP), BP responses to the isometric handgrip test or 24-h BP. In conclusion, a single session of aerobic exercise reduced SBP at rest and in response to stressful stimuli in hypertensive women with RA. These results support the use of exercise as a strategy for controlling HT and, hence, reducing cardiovascular risk in women with RA. Clinical Trial Registration: This study registered at the Brazilian Clinical Trials ( https://ensaiosclinicos.gov.br/rg/RBR-867k9g ) at 12/13/2019.

Background Biologic drugs such as adalimumab, etanercept, and infliximab represent major first-line and second-line treatments for rheumatoid arthritis (RA) patients. However, their high cost poses a massive burden on healthcare systems worldwide. The expiration of patents for these biologics has driven the production of biosimilar drugs, which are potentially less costly and remarkably similar, albeit not identical to the reference molecules. This paper aims to outline the protocol of a systematic review that will investigate the efficacy and safety profile of biosimilars compared to biologics (objective 1) and the impact of switching between biosimilar drugs and reference biologics on the management of RA patients (objective 2). Methods We will investigate the effects of any biosimilars of adalimumab, etanercept, and infliximab on RA patients. We will include randomized controlled trials (RCTs) or quasi-RCTs to assess efficacy and safety outcomes and RCTs with two- or multiple-part designs to evaluate the consequences of switching from reference biologics to biosimilar drugs (and vice-versa). Electronic searches will be performed through MEDLINE (via PubMed), EMBASE, LILACS, and CENTRAL (from inception to April 2021). Two independent reviewers will screen studies, extract data, and evaluate the risk of bias. The latter will be carried out considering specific domains from equivalence trials and switching studies. Random-effects models will be fitted to obtain summary estimates using either relative risk or standardized mean difference as a metric. The primary outcome will be the rate of treatment success according to the American College of Rheumatology 20 (ACR20), and the co-primary outcome will be the Health Assessment Questionnaire—Disability Index (HAQ-DI). Conclusions will be based on equivalence hypothesis testing using predefined margins of equivalence elicited from a group of experienced rheumatologists and prior studies. The overall certainty of the evidence will be assessed based on the GRADE system. Discussion The present investigation proposes a comprehensive, clinician-oriented approach to assess the equivalence and the impact of switching between biosimilars and biologics on the management of patients with RA. Our results will elucidate the efficacy, safety, immunogenicity of biosimilars, and the clinical consequences of substituting biologics with biosimilars in the management of RA. Systematic review registration PROSPERO CRD42019137152 and CRD42019137155

► Pre- and post-vaccination disease and muscle parameters were comparable. ► The vaccine was well tolerated without any severe adverse effects during follow-up. ► Seroconversion, seroprotection rate, GMTs and FI in the GMTs were comparable. The goal of the present study was to evaluate the influence of the influenza A H1N1/2009 vaccine on dermatomyositis/polymyositis (DM/PM) disease parameters and the potential deleterious effect of therapy on immune response. Thirty-seven DM and 21 PM patients (Bohan and Peter's criteria) were gender- and age-matched to 116 healthy controls. Seroprotection, seroconversion, the geometric mean titers (GMTs) and the factor increase (FI) in the GMTs were calculated. Disease safety was determined from a muscle enzyme analysis and the DM/PM scores [patient's visual analog scale (VAS), physician's VAS, manual muscle strength (MMT-8)] evaluated pre- and post-vaccination. The mean age (43.1±9.9 vs. 43.8±8.4 years, p=0.607) and gender distribution (p=1.00) were comparable between the patients and controls. After 21 days, seroconversion (p=0.394), seroprotection (p=0.08), GMT (p=0.573) and the FI in the GMT (p=0.496) were similar in both groups. The disease and muscle parameters remained stable throughout the study, including the creatine kinase (p=0.20) and aldolase levels (p=0.98), the physicians’ VAS (p=1.00), the patients’ VAS (p=1.00) and the MMT-8 (p=1.00). Regarding the influence of treatment, the seroconversion rates were comparable between the controls and patients undergoing treatment with glucocorticoid (GC) (p=0.969), GC >0.5mg/kg/day (p=0.395) and GC+immunosuppressors (p=0.285). Vaccine-related adverse events were mild and similar in the DM/PM and control groups (p>0.05). Our data support the administration of the pandemic influenza A H1N1/2009 vaccination in DM/PM, as we found no short-term harmful effects related to the disease itself and adequate immunogenicity in spite of therapy. Further studies are necessary to identify any long-term adverse effects in patients with these diseases.