Clinical, histologic, and immunologic signatures of Small Fiber Neuropathy in Systemic Lupus Erythematosus.

BACKGROUND AND OBJECTIVES: Systemic Lupus Erythematosus (SLE) often causes damage to small nerve fibers, leading to distressing painful and autonomic symptoms. Despite this, Small Fiber Neuropathy (SFN) remains an underrecognized complication for SLE patients. In this cross-sectional study, we aimed to assess SFN in patients with SLE and to explore its correlations with immunologic disease features and clinical manifestations. METHODS: We recruited 50 SLE patients (1 male to 12.5 females, aged 20-80 years) reporting painful disturbances. We conducted a comprehensive clinical and neurophysiological evaluation, using Nerve Conduction Studies and Quantitative Sensory Testing. Additionally, we carried out an extensive laboratory assessment of disease-related serological parameters. We also performed a thorough skin biopsy analysis, investigating somatic and autonomic innervation while detecting complement and inflammatory cell infiltrates within the skin. RESULTS: Out of 50 patients, 19 were diagnosed with SFN, primarily characterized by a non-length-dependent distribution; 7 had a mixed neuropathy, with both large and small fiber involvement. Patients with SFN were younger than patients with a mixed neuropathy (p = .0143); furthermore, they were more likely to have a history of hypocomplementemia (p = .0058) and to be treated with cyclosporine A (p = .0053) compared to patients without neuropathy. However, there were no significant differences in painful and autonomic symptoms between patients with and without SFN. DISCUSSION: This study highlights the relevant frequency of SFN with a non-length-dependent distribution among SLE patients experiencing painful symptoms. Indeed, SFN emerges as an early manifestation of SLE-related neuropathy and is closely associated with hypocomplementemia, suggesting a potential pathogenic role of the complement system. Moreover, SFN may be influenced by disease-modifying therapies. However, the precise role of SFN in shaping painful and autonomic symptoms in patients with SLE remains to be fully elucidated.

Autoimmunity to stromal-derived autoantigens in rheumatoid ectopic germinal centers exacerbates arthritis and affects clinical response.

Ectopic lymphoid structures (ELSs) in the rheumatoid synovial joints sustain autoreactivity against locally expressed autoantigens. We recently identified recombinant monoclonal antibodies (RA-rmAbs) derived from single, locally differentiated rheumatoid arthritis (RA) synovial B cells, which specifically recognize fibroblast-like synoviocytes (FLSs). Here, we aimed to identify the specificity of FLS-derived autoantigens fueling local autoimmunity and the functional role of anti-FLS antibodies in promoting chronic inflammation. A subset of anti-FLS RA-rmAbs reacting with a 60 kDa band from FLS extracts demonstrated specificity for HSP60 and partial cross-reactivity to other stromal autoantigens (i.e., calreticulin/vimentin) but not to citrullinated fibrinogen. Anti-FLS RA-rmAbs, but not anti-neutrophil extracellular traps rmAbs, exhibited pathogenic properties in a mouse model of collagen-induced arthritis. In patients, anti-HSP60 antibodies were preferentially detected in RA versus osteoarthritis (OA) synovial fluid. Synovial HSPD1 and CALR gene expression analyzed using bulk RNA-Seq and GeoMx-DSP closely correlated with the lympho-myeloid RA pathotype, and HSP60 protein expression was predominantly observed around ELS. Moreover, we observed a significant reduction in synovial HSP60 gene expression followed B cell depletion with rituximab that was strongly associated with the treatment response. Overall, we report that synovial stromal-derived autoantigens are targeted by pathogenic autoantibodies and are associated with specific RA pathotypes, with potential value for patient stratification and as predictors of the response to B cell-depleting therapies.

Application of SLE-DAS to assess subcutaneous belimumab efficacy in a cohort of systemic lupus erythematosus patients.

OBJECTIVES: To assess the efficacy of subcutaneous (sc) belimumab (BLM) by the application of SLE-DAS in a monocentric SLE cohort. METHODS: We evaluated SLE patients treated with sc BLM from March 2019. Disease activity has been assessed by SLEDAI-2k, SLE-DAS and PGA (Physician Global Assessment) in all the established time-points [baseline (T0), after 1 (T1), 3 (T3), 6 (T6) and 12 (T12) months]. Furthermore, we applied and compared the achievement of remission according to SLE-DAS values (SLEDAS ≤2.08 + PDN ≤5mg/daily) and DORIS definition (clinical SLEDAI- 2k=0 + PGA<0.5 + antimalarial treatment, PDN≤5mg/daily, stable immunosuppressive treatment). RESULTS: We enrolled 86 patients [M/F 5/81, median age 48 years (IQR 17.5), median disease duration 166 months (IQR 216)]. At baseline, median values of SLEDA-2k and SLE-DAS were 6 (IQR 4) and 5.77 (IQR 4.33), respectively, and they significantly correlated (r=0.719, CI 95% 0.586-0.815, p<0.0001). Median duration of treatment was 14 months (IQR 20). We found a significant reduction of SLEDAI-2k and SLE-DAS already at T1, maintained in the subsequent time-points (p<0.0001). At T12, a remission state was achieved by 60.4% of patients according to SLE-DAS definition and by 62.3% according to the DORIS definition. Both definitions of remission have demonstrated an agreement of 84%, with a Cohen's kappa equal to 0.6. CONCLUSIONS: In this study we applied SLE-DAS to assess the efficacy of sc BLM, by analysing its over-time changes and by comparing its performance with SLEDAI-2k. Indeed, our results suggest the usefulness of this new activity index in a real-life setting.

Fever and dyspnea after anti-Covid-19 vaccination: a challenging diagnosis.

There is still little information regarding the long-term safety of the vaccines. We report a case of new-onset adult-onset Still's disease (AOSD) that occurred following Covid-19 vaccination. This patient went to the emergency room with dyspnea from the last two weeks and bilateral swellings that occurred several weeks after the first vaccination. Based on the symptoms and laboratory results, we suspected AOSD. Considering the time relationship between Covid-19 vaccination and AOSD onset in our patient, and possible mechanisms linking vaccination with the onset of autoimmune disorders, physicians should consider adverse events from Covid-19 vaccination and assess the benefits and risks of vaccination for each patient.

KLRG1 is reduced on NK cells in SLE patients, inversely correlates with disease activity and is modulated by hydroxychloroquine in vitro.

OBJECTIVES: Killer cell lectin-like receptor G 1 (KLRG1), a transmembrane receptor with inhibitory capacity expressed in human immune cells, emerged as a novel susceptibility gene for systemic lupus erythematosus (SLE). The aim of this study was to investigate the expression of KLRG1 in SLE patients compared to healthy controls (HC) on both NK and T cells and to evaluate its possible involvement in SLE pathogenesis. METHODS: Eighteen SLE patients and twelve healthy controls were enrolled. Peripheral blood mononuclear cells (PBMCs) from these patients were phenotypically characterized by immunofluorescence and flow cytometry. The effect of the hydroxychloroquine (HCQ) in vitro on KLRG1 expression and its signaling mediated functions in NK cells were analyzed. RESULTS: KLRG1 expression was significantly reduced on the analyzed immune cell populations in SLE patients compared to HC, especially on total NK cells. Moreover, expression of KLRG1 on total NK cells inversely correlated with the SLEDAI-2K. A direct association between KLRG1 expression on NK cells and patients' treatment with HCQ was observed. In vitro treatment with HCQ increased KLRG1 expression on NK cells. In HC, KLRG1+ NK cells showed reduced degranulation and IFNγ production, while in SLE patient, this inhibition occurred only for the IFNγ production. CONCLUSION: With this study we revealed a reduced expression and an impaired function of KLRG1 on NK cells in SLE patients. These results suggest a possible role of KLRG1 in the pathogenesis of SLE and as a novel biomarker of this disease.

Application of Machine Learning Models in Systemic Lupus Erythematosus.

Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease and is extremely heterogeneous in terms of immunological features and clinical manifestations. This complexity could result in a delay in the diagnosis and treatment introduction, with impacts on long-term outcomes. In this view, the application of innovative tools, such as machine learning models (MLMs), could be useful. Thus, the purpose of the present review is to provide the reader with information about the possible application of artificial intelligence in SLE patients from a medical perspective. To summarize, several studies have applied MLMs in large cohorts in different disease-related fields. In particular, the majority of studies focused on diagnosis and pathogenesis, disease-related manifestations, in particular Lupus Nephritis, outcomes and treatment. Nonetheless, some studies focused on peculiar features, such as pregnancy and quality of life. The review of published data demonstrated the proposal of several models with good performance, suggesting the possible application of MLMs in the SLE scenario.

Effectiveness of non-medical switch from adalimumab bio-originator to SB5 biosimilar and from ABP501 adalimumab biosimilar to SB5 biosimilar in patients with chronic inflammatory arthropathies: a monocentric observational study.

OBJECTIVES: The use of biosimilars is constantly growing, prompting healthcare payers to encourage the switch to these drugs which are less expensive than the reference bio-originator. While switching from a bio-originator to a biosimilar is supported by increasing evidence, data on the switch between different biosimilars of the same reference product are scant. Our study aimed to evaluate the effectiveness of the non-medical switch both between adalimumab (ADA) bio-originator and SB5 biosimilar and between two different ADA biosimilars in patients with inflammatory chronic arthritis. METHODS: We observed adult patients with a diagnosis of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) treated with ADA bio-originator or ABP501 ADA biosimilar (Amgevita) who switched to SB5 ADA biosimilar (Imraldi) for administrative/economic reasons. Patients were followed up for 4 months. RESULTS: One hundred and ten patients [33 RA, 40 PsA, 37 axSpA; F:M= 49:61; median age 56 years (25th-75th percentile 48-66)] switched from ADA bio-originator to SB5. After 4 months (T4), we observed a significant reduction of patients in remission/low disease activity (baseline 92.7% vs. T4 80.9%; p=0.009), with a risk of moderate-high disease activity significantly higher after the switch [RR 2.6 (95% IC 1.2 to 5.7), p=0.01]. However, no differences were found in DAS28-CRP, DAPSA, ASDAS-CRP, and BASDAI, while patients with RA and PsA experienced a worsening in the patient global assessment-VAS (p=0.04 and p=0.02, respectively), and in patients with PsA a worsening in HAQ was also observed (p=0.03). Forty patients switched from ABP501 biosimilar to SB5 [12 with RA, 25 with PsA, and 3 with axSpA; F:M=24:16; median age 56 years (25th-75th percentile 44-66)]. After 4 months, no differences in DAS28-CRP and DAPSA nor in the percentage of patients in remission/low disease activity were found compared to baseline. Likewise, no differences were found in patient-reported outcomes (PROs). CONCLUSIONS: Our results provide a reassuring profile of effectiveness when switching from ADA originator to one of its biosimilars and between two different biosimilars. However, the worse outcome in PROs in patients initially treated with the bio-originator addresses the attention to a possible nocebo response, which should encourage comprehensive communication with patients.

Citrullinated and carbamylated proteins in extracellular microvesicles from plasma of patients with rheumatoid arthritis.

OBJECTIVES: To investigate the expression of citrullinated and carbamylated proteins in extracellular microvesicles (EMVs) from RA patients. METHODS: We enrolled 24 RA naïve for biological therapy and 20 healthy donors (HD), matched for age and sex. For each patient, laboratory and clinical data were recorded and clinical indexes were measured (Clinical Disease Activity Index, Simplified Disease Activity Index, DAS28). EMVs in RA patients and HD were purified from plasma and measured by nanoparticle tracking analysis (NanoSight). Further, EMVs were incubated with anti-citrullinated/carbamylated proteins antibodies and processed by flow cytometry and western blot to evaluate the expression of citrullinated/carbamylated antigens. RESULTS: NanoSight revealed a significant increase of EMVs in RA compared with HD. Moreover, cytofluorimetric analysis showed a significative higher expression of citrullinated antigens on EMVs' surface in RA than donors, while no substantial difference was found in the expression of carbamylated antigens. These data were confirmed by western blot which identified vimentin, glycolytic enzyme alpha-enolase 1 and collagen type II as the main citrullinated and carbamylated proteins carried by EMVs. Finally, a relevant correlation between the expression of citrullinated antigens and disease activity was found. CONCLUSIONS: The results of this study suggest an involvement of EMVs in the pathogenesis of RA by inducing autoimmunity.

Hepatitis B and C virus infection in patients with Systemic and Cutaneous Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a multifactorial etiology. The primary aim of this study was to estimate HCV and HBV infection prevalence in a cohort of SLE and Cutaneous Lupus Erythematosus (CLE). We assessed the frequency of these infections in our cohort and the possible associations with disease clinical/laboratory features and disease activity status. The prevalence of chronic HBV infection was 2.2% in the CLE group, while no HBsAg positive patients were identified in the SLE group. Conversely, the prevalence of anti-HCV positive was 2.2% in the SLE group while no anti-HCV positive patients were identified in the CLE group. We found no significant association between anti-HBc positive status and clinical manifestations or disease activity status in either group of patients. Hemodialysis resulted significantly associated with anti-HBc positivity in SLE. In the present study, we found HBsAg positivity in CLE patients but not in the Systemic form (SLE); conversely, a similar prevalence of anti-HBc antibodies in both groups was observed. A possible protective role exerted by SLE in HBV infection may be hypothesized. A higher frequency of HCV infection in SLE compared to CLE suggests a possible involvement of HCV in some SLE-related clinical and immunological features.

Erosive arthritis in systemic lupus erythematosus: application of cluster analysis.

OBJECTIVES: In the present study, we applied cluster analysis (CA) in SLE patients with joint involvement to identify which disease subset most commonly develops erosive damage. METHODS: We collected clinical and laboratory data of SLE patients with a clinical history of joint involvement (arthritis/arthralgia). Ultrasonographic assessment was performed at level of MCPs and PIPs joints, to identify erosive arthritis, defined as the presence of erosions in at least one joint. Moreover, we detected RF, ACPA anti-CarP, and Dkk1 serum levels. We applied an unsupervised hierarchical CA to identify the aggregation of patients into different subgroups sharing common characteristics in terms of clinical and laboratory phenotypes. RESULTS: CA included 112 SLE patients (M/F 6/106; median age 45 years, IQR 17; median disease duration 96 months, IQR 165). Arthritis was observed in 82 patients (73.2%) and inflammatory arthralgia in 30 (26.8%). US-detected erosive arthritis was observed in 29 patients (25.9%). CA on clinical and laboratory features allowed the identification of four main clusters: in particular erosive arthritis was located in a cluster including renal and neuropsychiatric involvement, serositis, positivity for ACPA, anti-Carp, anti-Sm, anti-RNP, detectable levels of Dkk1. CONCLUSIONS: The application of CA made it possible to better characterise SLE phenotype including erosive arthritis. In particular, feature-driven CA leads to the identification of a more aggressive disease, due to a common pathogenic mechanism.

Are interferon-gamma release assays reliable to detect tuberculosis infection in patients with rheumatoid arthritis treated with Janus kinase inhibitors?

BACKGROUND: Screening for latent tuberculosis infection is recommended in patients with rheumatoid arthritis (RA) starting Janus kinase inhibitors (Jaki). Interferon (IFN)-gamma release assays (IGRAs) are increasingly used for this purpose. Jaki tend to decrease the levels of IFNs, questioning the reliability of IGRAs during treatment with these drugs. OBJECTIVES: To compare the performance of QuantiFERON-TB Gold Plus (QFT-P) and QFT Gold In-tube (QFT-GIT) in RA patients treated with Jaki. METHODS: RA patients underwent QFT-P and QFT-GIT at baseline (T0), and after 3 (T3) and 12 months (T12) of treatment with Jaki. The agreement between the two tests was calculated. The agreement between IGRAs and tuberculin skin test (TST) or chest radiography at baseline was also determined. The variability of QTF-P results was longitudinally assessed. RESULTS: Twenty-nine RA patients (F/M 23/6; median age/IQR 63/15.5 years; median disease duration/IQR 174/216 months) were enrolled. A perfect agreement was found between QFT-P and QFT-GIT at all times (κ = 1). At T0, no agreement was recorded between IGRAs and TST (κ = -0.08) and between TST and chest radiography (κ = -0.07), a low agreement was found between QFT-P and chest radiography (κ = 0.17). A variation of 33.3% in the results of QFT-P was recorded at T3 vs T0, of 29.4% at T12 vs T0, and of 11.8% at T12 vs T3. The median levels of IFN-γ produced by lymphocytes in response to the mitogen of QFT-P decreased after 3 months followed by an increase after 12 months (not significant). No change in the median number of circulating lymphocytes was documented. Glucocorticoids intake was associated with a higher probability of negative or indeterminate IGRA results at T0 (p<0.0001). CONCLUSION: A response to IGRAs is detectable during treatment with Jaki. However, fluctuations in the results of IGRAs have been observed in the absence of correlation with clinical outcomes, thus challenging their interpretation.

Development of Systemic Autoimmune Diseases in Healthy Subjects Persistently Positive for Antiphospholipid Antibodies: Long-Term Follow-Up Study.

We longitudinally followed a single-center cohort of anti-phospholipid (aPL) positive healthy subjects to evaluate the evolution to systemic autoimmune diseases (sAD) and to describe clinical and serological associated features. Since 2010, we have consecutively screened healthy subjects who were positive, in at least two consecutive determinations, for one or more aPL [anti-Cardiolipin (aCL) IgM/IgG, anti-Beta2Glycoprotein I (aB2GPI) IgM/IgG, Lupus Anticoagulant (LA)]. All subjects were evaluated every six months, or in accordance with the patient's clinical course, in order to record the development of clinical and laboratory features suggestive for sAD. Ninety-five subjects [M/F 20/75, median age at first determination 46 years, Interquartile Range (IQR) 19] were enrolled. Thirty-three subjects (34.7%) were positive for only one aPL [15 (15.8%) for aCL, 15 (15.8%) for LA, and 5 (5.3%) for aB2GPI]; 37 (38.9%) had double positivity [32 (33.6%) for aCL and aB2GPI; 5 (5.3%) for aCL and LA], 23 (24.2%) had triple positivity. We prospectively followed up our cohort for a median period of 72 months (IQR 84). During a total follow-up of 7692 person-months, we found an absolute risk for sAD development equal to 1.8%. Specifically, 14 (14.7%) patients developed a sAD: in four patients (4.2%), after developing a thrombotic event, an antiphospholipid syndrome was diagnosed, 7 (7.4%) patients developed an Undifferentiated Connective Tissue Disease after a median period of 76 months (IQR 75.5), and lastly, three (3.1%) patients could be classified as affected by Systemic Lupus Erythematosus according to the ACR/EULAR 2019 criteria. The presence of triple positivity status resulted in being significantly associated with the progression to sAD (p-value = 0.03). In conclusion, we observed the development of sAD in almost 15% of aPL positive subjects. Triple positivity was significantly associated with this progression, suggesting a possible role as biomarker for this condition. Thus, our results could suggest the need for periodic follow-up for such patients to assess early diagnosis and treatment.

Relationship Between Gender Differences and Clinical Outcome in Patients With the Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS), characterized by artherial and/or venous thrombosis, pregnancy morbidity and "antiphospholipid" antibodies (aPLs), is more common in women than in men, with a female to male ratio of about 3.5:1. Only few studies have investigated the clinical differences between male and female patients with APS. Therefore, this study was aimed to analyze the differences of clinical manifestations and laboratory tests, at diagnosis, between female and male APS patients and the clinical outcome. We enrolled 191 consecutive APS patients (125 with primary APS, PAPS, and 66 with secondary APS, SAPS) with a female predominant ratio of approximately 3:1 (142 vs 49). The prevalence of PAPS was higher in males than females (p<0.001). The analysis of aPL profile revealed that high IgM anti-cardiolipin (aCL) and high-medium IgG aCL titers were more frequent in males. In thrombotic APS peripheral arterial thrombosis was more common in male than female patients (p=0.049), as well as myocardial infarction (p=0.031). Multivariate analysis to correct for cardiovascular risk factors, high titer of aPLs and triple positivity for aPLs, revealed that the odds ratio for myocardial infarction in male was 3.77. Thus, APS may be considered as a disease in which serological (IgM titer) and clinical profiles are influenced by gender.

The Impacts of the Clinical and Genetic Factors on Chronic Damage in Caucasian Systemic Lupus Erythematosus Patients.

Objective: The purpose of this study was to determine the distribution of organ damage in a cohort of systemic lupus erythematosus (SLE) patients and to evaluate the roles of clinical and genetic factors in determining the development of chronic damage. Methods: Organ damage was assessed by the SLICC Damage Index (SDI). We analyzed a panel of 17 single-nucleotide polymorphism (SNPs) of genes already associated with SLE, and we performed a phenotype−genotype correlation analysis by evaluating specific domains of the SDI. Results: Among 175 Caucasian SLE patients, 105 (60%) exhibited damage (SDI ≥1), with a median value of 1.0 (IQR 3.0). The musculoskeletal (26.2%), neuropsychiatric (24.6%) and ocular domains (20.6%) were involved most frequently. The presence of damage was associated with higher age, longer disease duration, neuropsychiatric (NP) manifestations, anti-phospholipid syndrome and the positivity of anti-dsDNA. Concerning therapies, cyclophosphamide, mycophenolate mofetil and glucocorticoids were associated with the development of damage. The genotype−phenotype correlation analysis showed an association between renal damage, identified in 6.9% of patients, and rs2205960 of TNFSF4 (p = 0.001; OR 17.0). This SNP was significantly associated with end-stage renal disease (p = 0.018, OR 9.68) and estimated GFR < 50% (p = 0.025, OR 1.06). The rs1463335 of MIR1279 gene was associated with the development of NP damage (p = 0.029; OR 2.783). The multivariate logistic regression analysis confirmed the associations between TNFSF4 rs2205960 SNP and renal damage (p = 0.027, B = 2.47) and between NP damage and rs1463335 of MIR1279 gene (p = 0.014, B = 1.29). Conclusions: Our study could provide new insights into the role of genetic background in the development of renal and NP damage.

Autophagy Hijacking in PBMC From COVID-19 Patients Results in Lymphopenia.

Autophagy is a homeostatic process responsible for the self-digestion of intracellular components and antimicrobial defense by inducing the degradation of pathogens into autophagolysosomes. Recent findings suggest an involvement of this process in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the role of autophagy in the immunological mechanisms of coronavirus disease 2019 (COVID-19) pathogenesis remains largely unexplored. This study reveals the presence of autophagy defects in peripheral immune cells from COVID-19 patients. The impairment of the autophagy process resulted in a higher percentage of lymphocytes undergoing apoptosis in COVID-19 patients. Moreover, the inverse correlation between autophagy markers levels and peripheral lymphocyte counts in COVID-19 patients confirms how a defect in autophagy might contribute to lymphopenia, causing a reduction in the activation of viral defense. These results provided intriguing data that could help in understanding the cellular underlying mechanisms in COVID-19 infection, especially in severe forms.

Lack of cross-reactivity between rheumatoid factor IgM and anti-S1 receptor binding domain of SARS-CoV-2 IgM: a case-control study.

OBJECTIVES: Since the onset of the COVID-19 outbreak, concern has been raised about reliability of SARS-CoV-2 serological tests in people with serum positivity for rheumatoid factor (RF), due to its ability to interfere during tests carried out with immunoassay techniques, leading to false positive results. The aim of this study was to analyse, on sera from RF seropositive rheumatoid arthritis (RA) patients, the interference between RF IgM and anti-S1 RBD IgM. METHODS: The study was conducted on consecutive patients affected by RF seropositive RA and, as control group, COVID-19 patients with SARS-CoV-2 pneumonia hospitalised at Sapienza University of Rome from April 2020 and April 2021. Serum samples from COVID-19 patients during their hospitalisation were collected, while RA subjects' samples were harvested prior to the onset of the COVID-19 pandemic. All samples were tested for RF IgM using nephelometry and ELIA, and for anti-S1 RBD IgM by ELISA. RESULTS: Forty RF seropositive RA and 42 COVID-19 patients were enrolled. In all RA patients, both nephelometric assay and ELIA showed RF IgM positivity, while only one patient of the control group tested positive for RF IgM by nephelometric assay and ELIA. IgM directed to S1 RBD were not detected in sera of RA patients, while all COVID-19 patients presented anti-S1 RBD IgM (median anti-S1 RBD IgM COVID-19 vs. RA: 368.5 IU/mL, IQR 654 IU/mL vs. 18.45 IU/mL, IQR 20 IU/mL; p<0.0001). CONCLUSIONS: This study confirmed the lack of cross-reactivity between RF and anti-S1 RBD IgM, offering to clinicians a valuable tool for a better management of RA patients undergoing SARSCoV-2 serological tests.

Porphyromonas gingivalis amount in the tongue biofilm is associated with erosive arthritis in systemic lupus erythematosus.

BACKGROUND: Several data have demonstrated the occurrence of erosive arthritis in Systemic Lupus Erythematosus (SLE) patients. However, a few studies have focused on the pathogenic mechanisms involved in this feature. The implication of oral pathogens has been proved in Rheumatoid Arthritis: in particular, Porphyromonas gingivalis (Pg), by inducing citrullination, could trigger autoimmune response. Here, we evaluated amount of Pg on the tongue in a cohort of SLE patients with arthritis, focusing on the association with the erosive phenotype. METHODS: SLE patients with arthritis were enrolled. DAS28 was applied to assess activity. Erosive damage was evaluated by ultrasound at level of MCP (metacarpophalangeal) and PIP (proximal interphalangeals) joints. All subjects underwent a tongue cytologic swab in order to quantify the amount of Pg (real-time PCR). The bacterium expression was obtained from the ratio between the patient's DNA amount and that obtained from healthy subjects. RESULTS: 33 patients were enrolled (M/F 3/30; median age 47 years, IQR 17; median disease duration 216 months, IQR 180): 12 of them (36.4%) showed erosive damage, significantly associated with ACPA positivity (p = 0.03) and higher values of DAS28 (p = 0.01). A mean ratio of 19.7 ± 31.1 was found for Pg amount. Therefore, we used Pg mean values as threshold, identifying two groups of patients, namely, highPg and lowPg. Erosive damage was significantly more frequent in highPg patients in comparison with lowPg (60.0% vs 26.0%, p = 0.001). Furthermore, highPg patients showed higher prevalence of skin manifestations, serositis, and neurological involvement (p = 0.005, p = 0.03, p = 0.0001, respectively). CONCLUSION: The possible contribution of oral microbiota in SLE erosive arthritis was here evaluated for the first time, finding a significant association between erosive damage and higher expression of Pg at tongue level.

Autophagy in Rheumatic Diseases: Role in the Pathogenesis and Therapeutic Approaches.

Autophagy is a lysosomal pathway for the degradation of damaged proteins and intracellular components that promotes cell survival under specific conditions. Apoptosis is, in contrast, a critical programmed cell death mechanism, and the relationship between these two processes influences cell fate. Recent evidence suggests that autophagy and apoptosis are involved in the self-tolerance promotion and in the regulatory mechanisms contributing to disease susceptibility and immune regulation in rheumatic diseases. The aim of this review is to discuss how the balance between autophagy and apoptosis may be dysregulated in multiple rheumatic diseases and to dissect the role of autophagy in the pathogenesis of rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome. Furthermore, to discuss the potential capacity of currently used disease-modifying antirheumatic drugs (DMARDs) to target and modulate autophagic processes.

Fever in systemic lupus erythematosus: associated clinical features and genetic factors.

OBJECTIVES: Fever has been recently included in the new 2019 EULAR/ACR classification criteria for systemic lupus erythematosus (SLE). Thus, we investigated the possible association of fever with other clinical disease manifestations. Then, we analysed a panel of 30 SNPs to verify their possible contribution to the pathogenesis of this constitutional symptom. METHODS: In this retrospective study we collected clinical/laboratory features in a SLE cohort, including the occurrence of fever (body temperature >37.5°C, excluding infective aetiology). A phenotype-genotype correlation analysis was carried out. RESULTS: We evaluated 167 patients (M/F 12/155, median age at the disease diagnosis 30 years, IQR 17; median disease duration 240 months, IQR 156). Seventy patients (41.9%) reported fever, significantly associated with: serositis and haematological manifestations (p=0.02 and p=0.00001, respectively). A significant association between fever and leukopenia (p=0.003), haemolytic anaemia (p=0.04), and thrombocytopenia (p=0.04) was observed. In addition, significantly higher median SLICC Damage Index (SDI) values were observed in patients with fever in comparison with those without [2 (IQR 3) vs. 1 (IQR 2); p=0.005]. The genotype/phenotype analysis showed an association between fever and the rs13361189 of Immunity Related GTPase M (IRGM) gene (p=0.003; OR 3.89, CI 1.16-13.03), confirmed also in multivariate logistic regression analysis (p=0.028, B=1.39). CONCLUSIONS: The association between IRGM rs13361189 polymorphism and the occurrence of inflammatory fever, could provide new insights into the role of genetic background in the pathogenesis of this SLE-related feature.

Clinical Delphi on aPL Negativization: Report from the APS Study Group of the Italian Society for Rheumatology (SIR-APS).

BACKGROUND: The rate of antiphospholipid antibody (aPL) negativization in antiphospholipid syndrome (APS) patients is uncertain, but it is estimated to be as high as 8%. Currently, a consensus definition of aPL negativization is lacking, as well as international recommendations on how to approach treatment in patients with a persistent aPL-negative seroconversion. AIM: The aim of the Delphi survey was to evaluate the clinical approach and level of consensus among experts from the APS Study Group of the Italian Society for Rheumatology (SIR-APS) in different clinical scenarios. METHODS: Experts of SIR-APS were contacted using a survey methodology. RESULTS: A structured survey was circulated among 30 experts. Up to 90% of the interviewed experts agreed on defining aPL negativization as the presence of two negative determinations, 1 year apart (90%). Almost full consensus exists among experts in some clinical settings, including: (1) the role of aPL negativization in the management of a thrombotic event determined by concomitant presence of cardiovascular risk factors, both modifiable and not modifiable (90%); (2) approach to young patients with triple aPL positivity who experienced pulmonary arterial thrombotic events and tested negative for aPL detection after 5 years of vitamin K antagonist (VKA) treatment (90%); (3) the use of "extra criteria" aPL antibody testing before pondering VKA suspension (93%). CONCLUSION: A substantial agreement exists among experts on how to define aPL negativization. VKA suspension should be embraced with extreme caution, particularly in case of previous thrombotic events and/or triple aPL positivity. Nevertheless, VKA cessation might be considered when risk factors are carefully monitored/treated and the presence of "extra criteria" aPL is ruled out.