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Aims: To validate an SPE-ultra-HPLC-MS/MS method for thalidomide (THD) measurement in dried plasma spot (DPS). Methods: Extraction included acetonitrile/water clean-up and online SPE. The LOD, LLOQ, linearity, precision, accuracy, recovery, matrix effect, process efficiency, carryover, stability, drug interference and dilution integrity were assessed. Results: The method was linear from 50 to 2000 ng/ml with a LOD of 20 ng/ml and LLOQ of 50 ng/ml. The coefficient of variation for precision was 0.4–7.9% for intra-assay and 1.3–8.9% for interassay, and accuracy was 81.4–97.1%. Adequate matrix effect (100.6–107.0%), recovery (88.7–105.0%) and process efficiency (91.3–109.3%) were registered. DPS was stable for 14 days at room temperature and 45°C ,and for 4 months at -80°C. The method was applied to quantify THD in both wet plasma and DPS from patients with cutaneous lupus receiving THD treatment. The difference between THD wet plasma and DPS concentration was

Background: Data on post-acute COVID-19 in autoimmune rheumatic diseases (ARD) are scarce, focusing on a single disease, with variable definitions of this condition and time of vaccination. The aim of this study was to evaluate the frequency and pattern of post-acute COVID-19 in vaccinated patients with ARD using established diagnosis criteria. Methods: Retrospective evaluation of a prospective cohort of 108 ARD patients and 32 non-ARD controls, diagnosed with SARS-CoV-2 infection (RT-PCR/antigen test) after the third dose of the CoronaVac vaccine. Post-acute COVID-19 (≥4 weeks and >12 weeks of SARS-CoV-2 symptoms) were registered according to the established international criteria. Results: ARD patients and non-ARD controls, balanced for age and sex, had high and comparable frequencies of > 4 weeks post-acute COVID-19 (58.3% vs. 53.1%, p=0.6854) and > 12 weeks post-acute COVID-19 (39.8% vs. 46.9%, p=0.5419). Regarding > 4 weeks post-acute COVID-19, frequencies of ≥3 symptoms were similar in ARD and non-ARD controls (54% vs. 41.2%, p=0.7886), and this was also similar in > 12 weeks post-acute COVID-19 (68.3% vs. 88.2%, p=0.1322). Further analysis of the risk factors for > 4 weeks post-acute COVID-19 in ARD patients revealed that age, sex, clinical severity of COVID-19, reinfection, and autoimmune diseases were not associated with this condition (p>0.05). The clinical manifestations of post-acute COVID-19 were similar in both groups (p>0.05), with fatigue and memory loss being the most frequent manifestations. Conclusion: We provide novel data demonstrating that immune/inflammatory ARD disturbances after third dose vaccination do not seem to be a major determinant of post-acute COVID-19 since its pattern is very similar to that of the general population. Clinical Trials platform (NCT04754698).

ObjectiveTo determine the immunogenicity of the third dose of CoronaVac vaccine in a large population of patients with autoimmune rheumatic diseases (ARD) and the factors associated with impaired response.MethodsAdult patients with ARD and age-balanced/sex-balanced controls (control group, CG) previously vaccinated with two doses of CoronaVac received the third dose at D210 (6 months after the second dose). The presence of anti-SARS-CoV-2 S1/S2 IgG and neutralising antibodies (NAb) was evaluated previously to vaccination (D210) and 30 days later (D240). Patients with controlled disease suspended mycophenolate mofetil (MMF) for 7 days or methotrexate (MTX) for 2 weekly doses after vaccination.ResultsARD (n=597) and CG (n=199) had comparable age (p=0.943). Anti-S1/S2 IgG seropositivity rates significantly increased from D210 (60%) to D240 (93%) (pConclusionsWe provide novel data on a robust response to the third dose of CoronaVac in patients with ARD, even in those with prevaccination COVID-19 seronegative status. Drugs implicated in reducing immunogenicity after the regular two-dose regimen were associated with non-responsiveness after the third dose, except for MTX.Trial registration numberNCT04754698.

To date, the only study that has assessed the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 mRNA) vaccine in systemic lupus erythematosus (SLE) observed a moderate response, but the sample size precluded an accurate analysis of the effect of individual drugs. Therefore, we evaluated the immunogenicity of an inactivated SARS-CoV-2 vaccine (Sinovac-CoronaVac) and the influence of different medications in SLE. Safety was also assessed.We conducted a prospective controlled study of 232 SARS-CoV-2-naive SLE patients and 58 SARS-CoV-2-naive controls who were vaccinated with 2 doses of Sinovac-CoronaVac with a 28-day interval (day 0/day 28 [D0/D28]). Immunogenicity analysis at D0/D28 and D69 included anti-SARS-CoV-2 S1/S2 IgG seroconversion (SC) and neutralizing antibodies (NAb) positivity. The influence of individual drugs on immune response and safety was assessed.Patients and controls were well balanced for age (P = 0.771). At D69, SLE patients showed a moderate SC (70.2% versus 98.1%; P 0.001) and moderate frequency of NAb positivity (61.5% versus 84.6%; P = 0.002), although both frequencies were lower than in controls. Factors associated with lower SC in univariate analysis at D69 were prednisone use (odds ratio [OR] 0.215 [95% confidence interval (95% CI) 0.108-0.427], P 0.001) and mycophenolate mofetil (MMF) use (OR 0.201 [95% CI 0.107-0.378], P 0.001), whereas hydroxychloroquine (HCQ) use led to a 2.5 increase in SC (P = 0.011). SLE patients who were receiving HCQ monotherapy had similar SC to controls at D69 (100% versus 98.1%; P = 1.000). In multivariate analysis, prednisone and MMF use were independently associated with lower SC (P 0.001) and NAb positivity (P 0.001). Safety analysis revealed no moderate/severe adverse events.Sinovac-CoronaVac has a moderate immunogenicity in SARS-CoV-2-naive SLE patients with an excellent safety profile. We further demonstrate that HCQ may improve SC, whereas prednisone and MMF had a major deleterious effect in vaccine response, reinforcing the need to investigate the role of temporary MMF withdrawal or a vaccine-booster dose (ClinicalTrials.gov identifier: NCT04754698).

Background Few prospective studies in cutaneous and systemic lupus erythematosus (CLE/SLE) assessed thalidomide-induced peripheral neuropathy (TiPN) incidence/reversibility, and most have not excluded confounding causes neither monitored thalidomide plasma levels. Objectives To evaluate TiPN incidence/reversibility, coasting effect and its association with thalidomide plasma levels in CLE/SLE. Methods One-year prospective study of thalidomide in 20 CLE/SLE patients without pregnancy potential, with normal nerve conduction study (NCS), and excluded other PN causes. Thalidomide levels were determined by high-performance liquid chromatography/tandem mass spectrometry. Results Twelve patients (60%) developed TiPN: 33.3% were symptomatic and 66.6% asymptomatic. Half of this latter group developed coasting effect (TiPN symptoms 1-3 months after drug withdrawal). The main predictive factors for TiPN were treatment duration ≥6 months (p = 0.025) and cumulative dose (p = 0.023). No difference in plasma thalidomide levels between patients with/without TiPN was observed (p = 0.464). After drug withdrawal, 75% symptomatic TiPN patients improved their symptoms. Seven TiPN patients underwent an additional NCS after drug withdrawal: 42.8% worsened NCS, 14.2% was stable, and 42.8% had improved NCS. Conclusion Our data provides novel evidence of coasting effect in half of asymptomatic patients with TiPN. The irreversible nature of this lesion in 25% of TiPN patients reinforces the relevance of early NCS monitoring, and suggests thalidomide use solely as a bridge for other effective therapy for refractory cutaneous lupus patients.

Objectives It is unknown if hydroxychloroquine blood level dynamics impact flare rates in lupus nephritis patients. We prospectively evaluated hydroxychloroquine levels to determine which blood-based patterns are more associated with disease activity. Methods In total, 82 lupus nephritis patients under a prescribed hydroxychloroquine dose of 4–5.5 mg/kg actual body weight (maximum 400 mg/day) for ≥3 months were evaluated at baseline and 7 months. Hydroxychloroquine blood levels were determined by liquid chromatography-tandem mass spectrometry. Flare was defined as increase ≥3 in the Systemic Lupus Erythematosus Disease Activity Index 2000 score and/or a change or increase in therapy. Results Overall, 9/82(11%) patients had flares during follow-up and had lower baseline hydroxychloroquine blood levels than those without flares (220.4 (53.5–1471.1) vs. 1006.3 (53.5–2137.8) ng/ml, p = 0.013). The hydroxychloroquine blood level cut-off that best predicted flares was 613.5 ng/ml (odds ratio = 8.67, 95% confidence interval: 1.66–45.18, p = 0.006). For 77 (94%) patients, the 7-month hydroxychloroquine level dynamics was evaluated and revealed: 59/77 (77%) had a persistent pattern of adequate (41/77(53%)) or fluctuating (18/77 (23%)) levels, with a low and comparable risk of flares (2/41 (5%) vs. 1/18 (5%), p = 1.000). The remaining group had persistent low levels (18/77 (23%)) and their flare frequency was significantly higher than the adequate group (5/18 (28%) vs. 2/41 (5%), p = 0.023). The frequencies of adequate/inadequate hydroxychloroquine blood levels in patients were comparable at baseline and 7 months (McNemar’s test, p = 0.480). Conclusion We provide novel evidence that hydroxychloroquine blood-level patterns (persistently low, adequate, or intermittent) have distinct impacts on flare rates in lupus nephritis patients. These findings reinforce the need of routine hydroxychloroquine measurements to maintain the appropriate blood levels.

ObjectivesTo 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 rheumatoid arthritis(RA) patients.MethodsThis was a single-center, prospective, randomized, investigator-blinded, intervention study (#NCT04754698, CoronavRheum), including adult RA patients(stable CDAI10 at D28).ResultsRandomization included 138 patients with 9 exclusions(5 COVID-19, 4 protocol violations). Safety evaluation included 60(MTX-hold) and 69(MTX-maintain) patients. Further exclusions consisted of 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, a higher increase in SC[29(78.4%) vs 30(54.5%),p=0.019] was observed in MTX-hold(n=37) in comparison to MTX-maintain(n=55), 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]. Longitudinal variations in disease activity scores were alike in both groups(CDAI,p=0.144; DAS28-CRP,p=0.718).ConclusionWe provided novel data that 2-week MTX withdrawal after each vaccine dose improves anti-SARS-CoV-2 immunogenicity. The comparable longitudinal variations of disease activity in both groups suggest that discontinuation is a feasible and efficient strategy in well-controlled RA patients, and may be even safer for vaccines with longer interval between doses or single dose schedules.FundingFAPESP/CNPq/B3-Bolsa de Valores-Brasil.

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.

ObjectivesTo evaluate the distinct impact of disease modifying antirheumatic drugs (DMARD) combination and monotherapy in immune response to an inactivated SARS-CoV-2 vaccine in patients with rheumatoid arthritis (RA).MethodsThis phase 4 prospective study analysed seroconversion (SC) of anti-SARS-CoV-2 immunoglobulin G (IgG) and neutralising antibodies (NAb) induced by the inactivated vaccine (CoronaVac) in patients with RA in comparison to controls (CG). Disease activity and treatment were also assessed. Only participants with baseline negative IgG/NAb were included.ResultsPatients with RA (N=260) and CG (N=104) had comparable median ages (59 years (50–65 years) vs 58 years (49.8–64 years), p=0.483). Patients with RA had moderate but lower SC (61.8% vs 94.2%, p0.05). After multivariate analyses, factors independently related to reduced SC were: older age (OR=0.79 (0.70–0.89) for each 5-year interval, p7.5 mg/day (OR=0.38 (0.19–0.74), p=0.004) were negatively related to the presence of NAb. Further comparison of SC/NAb positivity among RA treatment subgroups and CG revealed that methotrexate/tofacitinib/abatacept/tocilizumab use, in monotherapy or in combination, resulted in lower responses (pConclusionsPatients with RA under DMARD have a moderate immunogenicity to CoronaVac. We identified that nearly all DMARD combinations have a deleterious effect in immunogenicity, whereas a more restricted number of drugs (methotrexate/tofacitinib/abatacept/tocilizumab) also hampered this response as monotherapy. These findings reinforce the need of a broader approach, not limited to specific drugs, to improve vaccine response for this population.Trial registration detailsNCT04754698.

Background: Coronavirus disease 19 (COVID-19) has an increased risk of coagulopathy with high frequency of antiphospholipid antibodies (aPL). The recent reports of thrombosis associated with the adenovirus-based vaccines raises concern that SARS-CoV-2 immunization in primary antiphospholipid syndrome (PAPS) patients may trigger a dysregulated immune response with possible clotting complications. Therefore, the objectives of this study were to assess immunogenicity, aPL production and safety of Sinovac-Coronavac in PAPS patients.Methods: This prospective controlled phase 4 study of SARS-CoV-2-naïve PAPS patients and a control group (CG) consisted of a two-dose Sinovac-CoronaVac (D0/D28) and blood collection before vaccination (D0), at D28 and 6 weeks after second dose (D69) for immunogenicity/aPL levels. Outcomes were seroconversion (SC) rates of anti-SARS-CoV-2 S1/S2 IgG and/or neutralizing antibodies (NAb) at D28/D69. Safety and aPL production were also assessed. Results: Forty-four PAPS patients and 132 CG had comparable age (p=0.982) and sex (p>0.999). At D69, both groups had high and comparable SC (83.9% vs. 93.5%, p=0.092) and GMT [50.2(95%CI 34.5-73.2) vs. 61.7 (95%CI 52.8-72.3), p=0.249] as well as NAb positivity (77.4% vs. 78.7%, p=0.440), and NAb-activity [64.3% (49.0-77.0) vs. 60.9% (45.6-81.3), p=0.689]. Of note, for D28, the antibody response was very low and also similar in both groups SC (25.8% vs. 30.6% p=0.609). Antiphospholipid levels remained stable throughout the study at D0 vs D28 vs D69 (IgG aCL, p=0.058; IgM aCL, p=0.091; IgG aβ2GPI, p=0.513 and IgM aβ2GPI, p=0.468). Thrombotic event up to 6 months or other moderate/severe side effects were not observed.Conclusions: We provide novel evidence that Sinovac-CoronaVac vaccine has a high immunogenicity and excellent safety profile in PAPS. We further demonstrated that this vaccine did not trigger thrombosis or induced changes in aPL-related antibodies production. Our findings strongly support the recommendation of SARS-CoV-2 vaccination for PAPS patients.Trial registration: ClinicalTrials.gov - Identifier: NCT04754698 first registered on February 8th, 2021.

Introduction Influenza A (H3N2) virus is the most important cause of seasonal influenza morbidity and mortality in the last 50 years, surpassing the impact of H1N1. Data assessing immunogenicity and safety of this virus component are lacking in systemic lupus erythematosus (SLE) and restricted to small reports with other H3N2 strains. Objective This study aims to evaluate short-term immunogenicity and safety of influenza A/Singapore (H3N2) vaccine in SLE. Methods 81 consecutive SLE patients and 81 age- and sex-matched healthy controls (HC) were vaccinated with the influenza A/Singapore/INFIMH-16-0019/2016(H3N2)-like virus. Seroprotection (SP) and seroconversion (SC) rates, geometric mean titers(GMT), and factor increase in GMT(FI-GMT) and adverse events were assessed before and 4 weeks post-vaccination. Disease activity and therapies were also evaluated. Results Before immunization, SLE and HC groups had high SP rates (89% vs 77%, p = 0.061) and elevated GMT titer with higher levels in SLE (129.1(104.1–154.1) vs 54.8(45.0–64.6), p < 0.001). Frequency of two previous years’ influenza vaccination was high and comparable in SLE and HC (89% vs 90%, p = 1.000). Four weeks post-vaccination, median GMT increased for both groups and remained higher in SLE compared to HC (239.9(189.5–290.4) vs 94.5(72.6–116.4), p < 0.0001) with a comparable FI-GMT (2.3(1.8–2.9) vs 1.9(1.5-2.3), p = 0.051). SC rates were low and comparable for both groups (16% vs 11%, respectively, p = 0.974). Disease activity scores remained stable throughout the study ( p = 1.000) and severe adverse events were not identified. Conclusion Influenza A/Singapore (H3N2) vaccine has an adequate safety profile. The distinct immunogenicity pattern from other influenza A components characterized by a remarkably high pre- and post-vaccination SP rate and high GMT levels may be associated with previous influenza A vaccination. ( www.clinicaltrials.gov , NCT03540823).

Objectives To evaluate immunogenicity and safety of an inactivated SARS-CoV-2 vaccine in systemic autoimmune myopathies (SAMs) and the possible influence of baseline disease parameters, comorbidities and therapy on immune response. Methods This prospective controlled study included 53 patients with SAMs and 106 non-immunocompromised control group (CTRL). All participants received two doses of the Sinovac-CoronaVac vaccine (28-day interval). Immunogenicity was assessed by anti-SARS-CoV-2 S1/S2 IgG seroconversion (SC), anti-S1/S2 IgG geometric mean titre (GMT), factor increase GMT (FI-GMT), neutralizing antibodies (NAb) positivity, and median neutralizing activity after each vaccine dose (D0 and D28) and six weeks after the second dose (D69). Participants with pre-vaccination positive IgG serology and/or NAb and those with RT-PCR confirmed COVID-19 during the protocol were excluded from immunogenicity analysis. Results Patients and CTRL had comparable sex (P>0.99) and age (P=0.90). Immunogenicity of 37 patients and 79 CTRL-naïve participants revealed at D69, a moderate but significantly lower SC (64.9% vs 91.1%, P0.05). Conclusion Sinovac-CoronaVac is safe and has a moderate short-term immunogenicity in SAMs, but reduced compared with CTRL. We further identified that immunosuppression is associated with diminished NAb positivity. Trial registration COVID-19 CoronaVac in Patients With Autoimmune Rheumatic Diseases and HIV/AIDS (CoronavRheum), http://clinicaltrials.gov/ct2/show/NCT04754698

Background Thalidomide has shown exceptional results in systemic/cutaneous lupus erythematosus(SLE/CLE). Recently, lenalidomide has been also prescribed for SLE/CLE treatment. Literature regarding efficacy/adverse events for these drugs is scarce with a single systematic review and meta-analysis focused solely on thalidomide for refractory cutaneous lupus subtypes. Objective We, therefore, addressed in this narrative review the efficacy/adverse effects of thalidomide and lenalidomide for SLE and CLE. In addition, we provide a specialist approach for clinical practice based on the available evidence. Results Efficacy of thalidomide for refractory cutaneous lupus treatment was demonstrated by several studies, mostly retrospective with small sample size(≤20). The frequency of peripheral polyneuropathy is controversial varying from 15-80% with no consistent data regarding cumulative dose and length of use. Drug withdrawn results in clinical partial/complete reversibility for most cases (70%). For lenalidomide, seven studies (small sample sizes) reported its efficacy for SLE/CLE with complete/partial response in all patients with a mean time to response of 3 months. Flare rate varied from 25-75% occurring 0.5-10 months after drug withdrawn. There were no reports of polyneuropathy/worsening of previous thalidomide-induced neuropathy, but most of them did not perform nerve conduction studies. Teratogenicity risk exist for both drugs and strict precautions are required. Conclusions Thalidomide is very efficacious as an induction therapy for patients with severe/refractory cutaneous lupus with high risk of scarring, but its longstanding use should be avoided due to neurotoxicity. Lenalidomide is a promising drug for skin lupus treatment, particularly regarding the apparent lower frequency of nerve side effects.

CoronaVac(SARS-CoV-2 inactivated vaccine) has been largely used as the main immunogen for COVID-19 in several countries. However, its immunogenicity in immunocompromised individuals has not been established. This was a prospective controlled study of 910 adult ARD patients and 182 age- and sex-matched control group(CG) who received two doses of CoronaVac in a 28-days interrval. Anti-SARS-Cov-2 IgG and neutralizing antibodies were assessed at each vaccine shot and 6 weeks after the 2nd dose. Vaccine adverse events(AE) were similar in both groups. We observed significant lower anti-SARS-Cov-2 IgG seroconversion(70.4% vs. 95.5%,p

Background: Limited information is available on response to Covid-19 vaccines in autoimmune rheumatic disease patients(ARD) previously exposed to the SARS-CoV-2. We compared the dynamics of vaccine induced antibody production after immunization with CoronaVac in SARS-CoV-2 - seropositive ARD patients(ARD+) with two age/sex balanced groups: SARS-CoV-2 naive ARD patients(NAIVE-ARD) and SARS-CoV-2-seropositive control group(CTRL+). Methods: Participants of this phase 4 prospective controlled study were vaccinated with two doses of CoronaVac(28-days interval). Primary objective was immunogenicity dynamics evaluated by median neutralizing activity(NAb-activity)/anti-SARS-Cov-2 ln(IgG) titers[ln(IgG)] from D0-D28 and from D28-D69. Secondary objectives included safety and other immunogenicity parameters. Findings: Disease and therapy were similar in ARD+ and NAIVE-ARD groups(p>0·05). A comparable dynamics was observed for ARD+ and CTRL+ with a plateau increase occurring from D0-D28[ARD+, NAb-activity:59·1% to 81·8%, mean difference -12·1%,p=0·002 and anti-S1/S2-GMT:52·3 to 128·9, ln(IgG) mean difference -0·9,p 0·999) and anti-S1/S2-GMT(p 0·999 and D69:-12·3%,p=0·167/0·32%,p=0·258 with minor difference at D28:-13·6%, p=0·067/-0·45,p=0·006. Interpretation: ARD+ patients mount a robust plateau response after a single dose of inactivated SARS-CoV-2 vaccine, independent of pre-existing ARD/therapy, whereas NAIVE-ARD patients require the second dose to ensure a moderate antibody production. Our findings raise the possibility of a single dose regimen in ARD patients previously exposed to SARS-CoV-2.[clinicaltrials.gov#NCT04754698] Funding: FAPESP/CNPq/B3-Bolsa de Valores-Brasil. Declaration of Interest: The authors declare no competing interests. Ethical Approval: The protocol was approved by the National and Institutional Ethical Committee (CAAE: 42566621.0.0000.0068)

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.

Background: People living with HIV (PLWH) may have a poor or delayed response to vaccines, mainly when CD4+ T cell counts are low. There are limited data concerning the safety and immunogenicity of COVID-19 vaccines in PLWH. Methods: This prospective controlled study evaluated the safety and immunogenicity of the SARS-CoV-2 inactivated vaccine CoronaVac in PLWH compared with controls with no known immunosuppression. Immunogenicity was assessed with SARS-CoV-2 IgG seroconversion (SC), neutralizing antibodies (NAb) activity, and factor increase in IgG geometric mean titers (FI-GMT). We also investigated if levels of CD4+ T cell counts (< or ≥500 cells/mm3) were associated with CoronaVac immunogenicity. Findings: 511 participants (215 PLWH and 296 controls) were eligible for the immunogenicity analysis. At vaccine completion (D69), although the percentage of participants with SC and NAb positivity was high for both PLWH and controls, it was somewhat lower in PLWH. CD4+ T cell was identified as a relevant factor for immunogenicity, with lower SC and NAb positivity in PLWH with CD4+ counts

Objectives To retrospectively evaluate the performance and distinctive pattern of latent tuberculosis (TB) infection (LTBI) screening and treatment in patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA) under anti-tumor necrosis factor (TNF) therapy and determine the relevance of re-exposure and other risk factors for TB development. Methods A total of 135 and 83 patients with AS and PsA, respectively, were evaluated for LTBI treatment before receiving anti-TNF drugs via the tuberculin skin test (TST), chest radiography, and TB exposure history assessment. All subjects were evaluated for TB infection at 3-month intervals. Results The patients with AS were more often treated for LTBI than were those with PsA (42% versus 30%, p=0.043). The former also presented a higher frequency of TST positivity (93% versus 64%, p=0.002), although they had a lower frequency of exposure history (18% versus 52%, p=0.027) and previous TB (0.7% versus 6%, p=0.03). During follow-up [median, 5.8 years; interquartile range (1QR), 2.2-9.0 years], 11/218 (5%) patients developed active TB (AS, n=7; PsA, n=4). TB re-exposure was the main cause in seven patients (64%) after 12 months of therapy (median, 21.9 months; IQR, 14.2-42.8 months) and five LTBI-negative patients. TB was identified within the first year in four patients (36.3%) (median, 5.3 months; IQR, 1.2-8.8 months), two of whom were LTBI-positive. There was no difference in the TB-free survival according to the anti-TNF drug type/class; neither synthetic drug nor prednisone use was related to TB occurrence (p>0.05). Conclusion Known re-exposure is the most critical factor for incident TB cases in spondyloarthritis. There are also some distinct features in AS and PsA LTBI screening, considering the higher frequency of LTBI and TST positivities in patients with AS. Annual risk reassessment taking into consideration these peculiar features and including the TST should be recommended for patients in endemic countries.

Background Brazil faced a yellow fever(YF) outbreak in 2016–2018 and vaccination was considered for autoimmune rheumatic disease patients(ARD) with low immunosuppression due to YF high mortality. Objective This study aimed to evaluate, prospectively for the first time, the short-term immunogenicity of the fractional YF vaccine(YFV) immunization in ARD patients with low immunossupression. Methods and Results A total of 318 participants(159 ARD and 159 age- and sex-matched healthy controls) were vaccinated with the fractional-dose(one fifth) of 17DD-YFV. All subjects were evaluated at entry(D0), D5, D10, and D30 post-vaccination for clinical/laboratory and disease activity parameters for ARD patients. Post-vaccination seroconversion rate(83.7%vs.96.6%, p = 0.0006) and geometric mean titers(GMT) of neutralizing antibodies[1143.7 (95%CI 1012.3–1292.2) vs.731 (95%CI 593.6–900.2), p0.05). Conclusion Fractional-dose 17DD-YF vaccine in ARD patients resulted in a high rate of seroconversion rate(>80%) but lower than controls, with a longer but less intense viremia. This vaccine was immunogenic, safe and did not induce flares in ARD under low immunosuppression and may be indicated in YF outbreak situations and for patients who live or travel to endemic areas. Trial registration This clinical trial was registered with Clinicaltrials.gov (#NCT03430388)., Author summary Yellow fever is a viral hemorragic fever with high mortality rate and the vaccine is a remarkably successful way of preventing it. As a live attenuated virus vaccine, it is not recommended for rheumatic and other immunossupressed patients in general. However, in an outbreak scenario, the risk of dying of the disease can be higher than the risk of a vaccine serious adverse event. In 2018, the fractional-dose yellow fever vaccine was offered to the hospital employees and to the rheumatic patients without or with low immunossupression therapy in Hospital das Clinicas of University of São Paulo, during the yellow fever outbreak in São Paulo, Brazil. In order to optimize the yellow fever vaccine (YFV) supply, the fractional-dose (corresponding to one fifth) was adopted in the public vaccine campaign. This is the first study evaluating the primary vaccination with fractional-dose YFV in autoimmune rheumatic diseases(ARD) patients (n = 159) under low immunosuppression. Most vaccinated participants were able to produce enough neutralizing antibodies to be protected against yellow fever (seroconversion rate of 84% versus 96% in healthy controls). Neither activity of the rheumatic disease or serious adverse event was identified during the 30 days of followup after the vaccination.

INTRODUÇÃO: A síndrome antifosfolípide (SAF) é uma trombofilia adquirida que afeta indivíduos jovens produtivos causando dano permanente e impacto negativo na qualidade de vida. Recentemente, foi desenvolvido um índice de dano específico para síndrome antifosfolípide trombótica (DIAPS). No entanto, não existem dados referentes à comparação do dano medido pelo DIAPS na síndrome antifosfolípide primária (SAFP) e na SAF secundária (SAFS). OBJETIVO: Comparar a cinética do dano medido pelo DIAPS em pacientes com essas condições. MÉTODOS: Trata-se de uma análise retrospectiva de uma coorte de centro terciário seguida por aproximadamente 9 anos, utilizando um banco de dados padronizado de prontuário eletrônico. Cinquenta pacientes com SAFP, pareados com cinquenta pacientes com SAF secundária ao lúpus eritematoso sistêmico (LES), foram selecionados consecutivamente para o estudo. O DIAPS foi calculado uma vez por ano durante o acompanhamento até a última avaliação. Dano durante o acompanhamento e sua cinética foram comparados em ambos os grupos. RESULTADOS: SAFP e SAFS apresentaram idade no momento do estudo (47,10 ± 12,4 vs. 44,04 ± 10,80 anos, p = 0,19), tempo de seguimento no serviço (9,40 ± 3,60 vs. 10,94 ± 4,50 anos, p = 0,06) e no estudo (8,46 ± 0,97 vs. 8,72 ± 0,75, p=0,13) comparáveis. No diagnóstico, o grupo SAFP apresentava DIAPS maior que o SAFS (1,72 ± 1,17 vs. 0,82 ± 0,96, p < 0,001). Ao final do acompanhamento, os dois grupos apresentaram escores médios comparáveis de dano (2,33 ± 1,77 vs. 1,96 ± 1,65, p = 0,34). O incremento de dano durante o período de observação para o SAFP foi de apenas 35%, enquanto para o SAFS foi gradual, persistente e atingiu 139% no final do acompanhamento, com um incremento total de dano para o SAFP menor que o grupo SAFS (0,5 ± 0,86 vs. 0,94 ± 1,37, p < 0,001). Ressalta-se que a frequência de indivíduos que adquiriram dano foi menor no grupo SAFP do que no grupo SAFS (32% vs. 72%, p < 0,001). CONCLUSÃO: Um padrão distinto de dano entre SAFP e secundária foi identificado. O dano na SAFP é um evento precoce, enquanto o SAFS está associado a um maior dano a longo prazo, com um importante incremento de dano ao longo do acompanhamento INTRODUCTION: Antiphospholipid syndrome (APS) is an acquired thrombophilia that affects young productive individuals with permanent damage and negative impact in quality of life. Recently a damage index specific for APS (DIAPS) was developed. There are, however, no data regarding the comparison of damage measured by DIAPS in primary antiphospholipid syndrome (PAPS) and secondary APS (SAPS). OBJECTIVE: The primary purpose of this study was, therefore, to compare damage kinetic measured by DIAPS in patients with these conditions. METHODS: This is a retrospective analysis of a single tertiary center cohort followed for approximately 9 years, using a standardized prospective electronic chart database. Fifty PAPS patients age matched with fifty APS related to systemic lupus erythematosus (SLE) patients were consecutively selected for the study and DIAPS was calculated once-a-year during follow-up until final evaluation. Damage during follow-up and its kinetic in both groups were compared. RESULTS: PAPS and SAPS had comparable age at study moment (47.10±12.4 vs. 44.04±10.80 years, p=0.19), follow-up time in the department (9.40±3.60 vs. 10.94±4.50 years, p=0.06) and time of study follow-up (8.46 ± 0.97 vs. 8.72 ± 0,75, p=0,13). At diagnosis, PAPS group had higher DIAPS than SAPS (1.72±1.17 vs. 0.82±0.96, p < 0.001). At the end of follow-up both groups presented comparable mean damage scores (2.33 ± 1.77 vs. 1.96 ± 1.65, p = 0.34). The damage increment throughout the observation period for PAPS was solely 35% whereas for SAPS it was gradual, persistent and reached 139% at the end of follow up with a total damage increment for PAPS lower than SAPS group (0.5 ± 0.86 vs. 0.94 ± 1.37, p < 0.001). Of note, the frequency of individuals that acquired damage was lower in PAPS than in SAPS group (32% vs. 72%, p < 0.001). CONCLUSION: A distinct pattern of damage in PAPS and SAPS was identified. Damage in PAPS is an early event, while SAPS is associated with higher long-term damage with a striking increment of damage along the follow-up