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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.

The American Academy of Ophthalmology (2016-AAO) recommended hydroxychloroquine (HCQ) dose not to exceed 5 mg/kg/day (real body weight). Recently, it was reported that prescribed 2016-AAO dose provided adequate HCQ levels for most lupus nephritis (LN) patients, with low flare risk. However, the minimum HCQ dose required to keep adequate levels is unknown. To evaluate if a further reduction in 2016-AAO dose (2–3 mg/kg/day) would sustain 12-month HCQ levels in LN patients with stable inactive disease. Seventy-three stable LN patients under prescribed full HCQ 2016-AAO dose for ≥6 months and adequate baseline HCQ levels (≥613.5 ng/mL) were divided in two groups: reduced 2016-AAO dose (2–3 mg/kg/day), n = 32, and full 2016-AAO dose (5 mg/kg/day), n = 41. All patients were assessed at baseline, 3, 6, and 12 months. HCQ levels were measured by liquid chromatography-tandem mass spectrometry. Flare was defined as augment ≥ 3 in SLE Disease Activity Index-2000 and/or change in treatment. Rigorous clinical/laboratorial surveillance was performed. Prospective evaluation revealed for reduced 2016-AAO dose group a decrease of HCQ levels from baseline to 3 months (1,404.9 ± 492.0 vs. 731.6 ± 385.0 ng/mL, p 0.05). Prescribed HCQ low-dose regimen (2–3 mg/kg/day) does not sustain, for most patients, 6- and 12-month adequate HCQ levels. Full 2016-AAO dose maintained HCQ levels way above this limit. ClinicalTrials.gov : NCT03122431, registered on April 20, 2017

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.

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.

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

Introduction In 2016 the American Academy of Ophthalmology(2016-AAO) recommended a maximum daily HCQ use of 5.0 mg/kg real body weight(RBW) taking into consideration minimizing eye toxicity. Retinopathy in systemic lupus erythematosus(SLE) patients was recently associated with obesity and this condition is progressively more common in these patients. However, the impact of obesity in HCQ blood levels remains controversial. Objective To determine if the 2016-AAO recommendation based on RBW with and without maximum daily dose restriction results in adequate and safe blood levels in obese lupus nephritis(LN) patients. Methods A cross-sectional study was performed with 108 LN patients under the prescribed 2016-AAO dose for at least 3 months. LN patients were assessed for demographic characteristics, body mass index(BMI), disease parameters, HCQ dose, concomitant treatment and HCQ blood levels measured by liquid chromatography-tandem mass spectrometry. Obesity was defined as BMI ≥30kg/m2. Results Obesity was identified in 35/108(32%) LN patients. The calculation of HCQ daily dosage revealed that obese patients were under a lower prescribed daily dose according to the real body weight (RBW) [4.4(2.9-5.4) vs. 4.9(4-5.5)mg/Kg/day, p Conclusion Obese patients under the 2016-AAO prescribed dose of HCQ based on RBW with and without maximum daily dose restriction have a very high HCQ blood levels compared to non-obese patients, with a potential increased risk of ocular toxicity. The use of 2016-AAO dose of HCQ according to the ideal body weight for this group of patients should be considered.Clinicaltrials.gov #NCT0312243.

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)

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The genesis of rheumatoid arthritis (RA) is complex and dependent on genetic background and exposure to environmental xenobiotic. Indeed, smoking is associated to developing and worsening pre-existing RA. Nevertheless, the mechanisms and cigarette compounds involved in the harmful processes have not been elucidated. Here, we investigated if the exposure to hydroquinone (HQ), an abundant pro-oxidative compound of cigarette and benzene metabolite, could worsen the ongoing RA. Hence, collagen-induced arthritis (CIA) was induced in male Wistar rats by s.c. injection of 400 μg (200 μL) of bovine collagen type II emulsified in complete Freund's adjuvant on day 1, and a booster injection was performed on day 7. Exposures to nebulized HQ (25 ppm), saline solution or HQ vehicle solution (5% ethanol in saline) were carried out for 1 h, once a day, on days 21–27 after CIA induction. On day 27, animals were euthanized and samples were collected for further analyses. Exposure to HQ caused loss of weight, intensified paw edema, enhanced levels of tumor necrosis factor-α (TNF-α) and anti-citrullinated protein antibody (ACPA) in the serum; augmented synoviocyte proliferation and influx of aril hydrocarbon receptor (AhR) positive cells into the synovial membrane, altered collagen fibre rearrangement in the synovia, and synoviocytes isolated from HQ exposed rats secreted higher levels of pro-inflammatory cytokines, TNF-α and interleukin-1β. Associated, we point out HQ as an environmental pollutant that aggravates RA, suggesting its participation on worsening RA in smoking patients.