Abstract Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory, multi-factorial disease sustained by environmental and genetic factors. These seem to be necessary but not sufficient in the ...disease development, nonetheless they can be responsible of different clinical pictures and response to therapy, and they can represent potential therapeutic targets. Several genes have been indicated so far in the pathogenesis of RA. The most important region is the Human Leukocyte Antigen (HLA) that contributes to approximately half of the genetic susceptibility for RA. The association seems to be stronger or specific for anti-citrullinated protein antibodies positive disease. Several alleles in the epitope-recognition part of the HLA molecule that show the highest association with RA susceptibility, also share a common string of amminoacid residues (the so-called shared-epitope hypothesis). Other variants in potentially pathogenic genes located in non-MHC regions have been implicated by recently performed genome wide analysis studies. These genes include PTPN22, TRAF1-C5, PADI4, STAT4. Other polymorphisms seem to be responsible for more aggressive disease phenotype such as those located at TNF, IL-1, IL-6, IL-4, IL-5, OPN, PRF1. However, still nowadays, the genetic background of RA remains to be clearly depicted, and the efforts in the post-genomic era can bring to an estimation of the real likelihood of the genetic effect on RA. Finally, the discovery of new genes associated with the disease can be relevant in finding potential biomarkers, potentially useful in disease diagnosis and treatment.
Abstract
Although the rapid onset of effect of glucocorticoids (GCs) allows rapid control of rheumatoid arthritis (RA) symptoms, their chronic use may be associated with several adverse events. The ...2022 update of EUALR recommendations for the management of patients with RA suggests to reduce and discontinue oral GCs as quickly as possible. Considering GCs as a "bridging therapy" to promptly reduce symptoms and control inflammation, fast-acting drugs such as tofacitinib could allow faster and safer tapering of GCs. The purpose of this pilot study was to evaluate the steroid-sparing effect of adding tofacitinib in patients with RA inadequately responsive to methotrexate taking concomitant GCs. In this open-label pilot study, we enrolled patients with moderate to severe RA on a stable dose of prednisone (5–12.5 mg/day) who started treatment with tofacitinib. After 1 month, in patients who achieved at least a moderate EULAR response (decrease of > 1.2 in DAS28_CRP), GCs was tapered according to a predetermined schedule until complete discontinuation at week 12. Disease activity was assessed after 4, 12, 24 and 48 weeks of treatment. The primary endpoint was the percentage of patients discontinuing GCs after 12 weeks of tofacitinib treatment. We enrolled 30 patients (26 F: 4 M, mean age 60 ± 13 years, mean disease duration 13.2 ± 7.8 years). The primary endpoint was achieved: 9 patients (30%) discontinued GCs at week-12. At week-24, other 12 patients (46%) withdrew GCs. The median prednisone dose decreased from 5 mg/day (interquartile range 5–10 mg) to 2.5 (0–5) mg/day at week 12 and 48 (p < 0.00001 vs baseline). At week 48, 12 out of 30 patients (40%) had discontinued prednisone. The percentage of patients achieving remission or low disease activity increased throughout the follow-up without any difference between patients who discontinued or not the GC. In this cohort of long-standing RA patients treated with tofacitinib, the discontinuation of glucocorticoids was achievable in up to 30% of patients. These results should encourage rheumatologists to consider GCs tapering and discontinuation of GCs, as suggested by the 2022 EULAR recommendations, an achievable goal.
Systemic lupus erythematosus (SLE)–related arthritis has been traditionally defined as non-erosive and is therefore considered a minor manifestation requiring a mild treatment. However, the concept ...of non-erosive arthritis in SLE has been challenged with the advent of sensitive imaging techniques, such as high-resolution ultrasound with power Doppler or magnetic resonance. The application of these new imaging tools has demonstrated that up to 40% of SLE patients with joint involvement can develop erosive damage. Thus, this more aggressive phenotype can be identified not only in patients overlapping with rheumatoid arthritis (RA). This issue has been considered for the first time in the classification criteria proposed by Systemic Lupus International Collaborating Clinics in 2012, in which the old definition of “non-erosive arthritis” was replaced with either synovitis or tenderness in two or more joints with morning stiffness, suggesting the possible presence of an erosive phenotype. Accordingly, the 2019 EULAR/ACR’s SLE recommendations advise treatment with immunosuppressant or biological drugs for patients with RA-like moderate arthritis. As a result, several studies have investigated the presence of biomarkers associated with SLE erosive damage. A relevant role seems to be played by the autoantibodies directed against post-translational modified proteins: above all, a significant association has been observed with antibodies directed against citrullinated and carbamylated proteins. Conversely, the rheumatoid factor was not associated with this more aggressive SLE-related arthritis. Nonetheless, some pro-inflammatory factors have been associated with erosive damage in SLE patients. These results suggest new pathogenic mechanisms underlining erosive arthritis, only partially shared with RA. Hence, in the present narrative review, we summarized available data about erosive arthritis in SLE patients, in the light of its impact on therapeutic decisions.
The strict link between periodontitis (PD) and rheumatoid arthritis (RA) has been widely demonstrated by several studies. PD is significantly more frequent in RA patients in comparison with healthy ...subjects: this prevalence is higher in individuals at the earliest stages of disease and in seropositive patients. This is probably related to the role of P. gingivalis in inducing citrullination and leading to the development of the new antigens. Despite the many studies conducted on this topic, there is very little data available concerning the possibility to use the same biomarkers to evaluate both RA and PD patients. The aim of the review is to summarize this issue. Starting from genetic factors, data from literature demonstrated the association between HLA-DRB1 alleles and PD susceptibility, similar to RA patients; moreover, SE-positive patients showed simultaneously structural damage to the wrist and periodontal sites. Contrasting results are available concerning other genetic polymorphisms. Moreover, the possible role of proinflammatory cytokines, such as TNF and IL6 and autoantibodies, specifically anticyclic citrullinated peptide antibodies, has been examined, suggesting the need to perform further studies to better define this issue.
To explore the pathogenic association between periodontal disease and rheumatoid arthritis focusing on the role of Porphyromonas gingivalis.
In the last decades our knowledge about the pathogenesis ...of rheumatoid arthritis substantially changed. Several evidences demonstrated that the initial production of autoantibodies is not localized in the joint, rather in other immunological-active sites. A central role seems to be played by periodontal disease, in particular because of the ability of P. gingivalis to induce citrullination, the posttranslational modification leading to the production of anticitrullinated protein/peptide antibodies, the most sensitive and specific rheumatoid arthritis biomarker.
The pathogenic role of P. gingivalis has been demonstrated in mouse models in which arthritis was either triggered or worsened in infected animals. P. gingivalis showed its detrimental role not only by inducing citrullination but also by means of other key mechanisms including induction of NETosis, osteoclastogenesis, and Th17 proinflammatory response leading to bone damage and systemic inflammation.
Objective
Osteoporosis (OP) and fragility fractures (FF) are common comorbidities in patients with systemic lupus erythematosus (SLE). This study aimed to (1) assess the prevalence of these ...conditions in a cohort of SLE patients (2) evaluate the risk factors associated with FF, and (3) compare the accuracy of four different FF risk assessment algorithms to determine which performs better in this specific rheumatologic population.
Materials and Methods
We conducted a cross-sectional study with SLE women who underwent bone mineral density assessment by dual-energy X-ray absorptiometry (DEXA) within 3 months of their last visit. Conventional radiology methods were used to evaluate the presence of FF. The 10-year risk of osteoporotic fractures was estimated using four tools: DeFRA, FRAX (adjusted for GC dosage), GARVAN, and QFracture. The comparison of these computational tools was analyzed by the area under the receiver operating characteristic (ROC) curves.
Results
We analyzed 86 SLE patients with a median age of 56 years (IQR 12.1) and a median age at diagnosis of 34 years (IQR 17.2). The median T-score values at the femoral neck and lumbar spine were −1.6 (IQR 0.9) and −1.7 (IQR 1.1), respectively. Of the patients, 33 (38.4%) had OP, with 13 patients (15.1%) experiencing FF. Univariate analysis showed that the presence of FF was associated with thrombocytopenia (p = .01), hemolytic anemia (p = .0001), and the intake of cyclosporine A (p = .002), cyclophosphamide (p = .006), and rituximab (p = .001). The median 10-year risk of major FF for the four calculation tools were as follows: DeFRA 9.85 (IQR 8.6); FRAX GC 8.8 (IQR11.7); GARVAN 12 (IQR 8.2); QFracture 4.1 (IQR 5.8). We observed a significant correlation among all instruments evaluated (p < .0001); in particular, the best correlation was recorded between the FRAX GC and the DeFRA (r = 0.85). DeFRA was the best tool for this population with an AUC of 0.94 (p < .0001, CI 0.88–1).
Conclusions
OP is a common comorbidity in SLE patients, even in younger patients. FF appears to be more frequent in patients with hematologic involvement. The comparison of the four algorithms shows that DeFRA is the most accurate tool and should be applied to SLE patients.
Autophagy is a degradation mechanism by which cells recycle cytoplasmic components to generate energy. By influencing lymphocyte development, survival, and proliferation, autophagy regulates the ...immune responses against self and non-self antigens. Deregulation of autophagic pathway has recently been implicated in the pathogenesis of several autoimmune diseases, including rheumatoid arthritis (RA). Indeed, autophagy seems to be involved in the generation of citrullinated peptides, and also in apoptosis resistance in RA. In this review, we summarize the current knowledge on the role of autophagy in RA and discuss the possibility of a clinical application of autophagy modulation in this disease.
Objectives
To evaluate humoral and cell-mediated response after three doses of BNT162b2 SARS-CoV-2 vaccine in patients with systemic lupus erythematosus (SLE) treated with Belimumab (BLM).
Methods
...SLE patients were vaccinated with three doses of BNT162b2-mRNA vaccine (two-dose primary vaccination, third booster dose after 6 months). The humoral immune response was assessed one and 6 months after the second dose (T1, T2), and 6 months after the booster dose (T3). Serological assay was performed (The Liaison® SARS-CoV-2 TrimericS IgG chemiluminescent). Spike-specific T-cell response was monitored 6 months after the second vaccine dose and the percentage of cytokines producing T cells was assessed by flow cytometry.
Results
Twelve patients 12F; median age 46 years (IQR 8.25); median disease duration 156 months (IQR 188) were enrolled. At T1, all patients showed seroconversion (median anti-Spike IgG levels 1610 BAU/mL, IQR 1390). At T2––day of the third dose––a significant reduction of median anti-Spike IgG antibodies levels was observed 214 BAU/mL (IQR 94); p = 0.0009. Anti-Spike IgG were significantly increased at T3, reaching a median value of 1440 BAU/mL (IQR 1316; p = 0.005). Despite declining humoral immunity, almost 60% of patients mounted a virus-specific CD4 + T-cell response 6 months after primary vaccination.
Conclusions
BLM does not impair humoral response to primary BNT162b2 SARS-CoV-2 vaccination. During the follow-up, a decline in antibody levels is evident and the third dose is crucial to increase the specific immune response. Finally, we observed a recall T-cell response to the Spike antigen 6 months after the first vaccination cycle.
Scientific literature demonstrated the impairment in cognitive/executive functions and pragmatic language in SLE patients, potentially involving also asymptomatic subjects. The present study focuses ...on the assessment in an SLE cohort of emotional intelligence, which is an ability regulated by the network of the executive functions, cognitive abilities involved in the initiation, planning, organization, and regulation of achievement-oriented behaviors: with emotional. Thus, emotional intelligence, defined as the ability to reason with emotions, was evaluated in a SLE cohort diagnosed according to the 1997 American College of Rheumatology criteria. As control healthy subjects were enrolled. The Mayer–Salovey–Caruso Emotional Intelligence Test (MSCEIT), a skill-scale that measures the ability to perform tasks and solve emotional problems, was administered to patients and controls. Second, a group of SLE patients underwent the Visual Thinking Strategies (VTS) method in order to assess the potential impact of art in cognitive skills like critical thinking, problem solving, and emotional intelligence quotient. The protocol also included the evaluation of the improvement of some skills using a validated VTS skill grid. Self-reported scales for anxiety and depression were performed to rule out the influence of mood disorders on emotional intelligence. The present study demonstrated similar quotient scores of emotional intelligence in SLE patients and healthy controls. Furthermore, VTS method could help in improving this cognitive ability in patients, by implementing critical thinking and problem solving, promoting empathy, and improving tolerance to ambiguity and relational capacity.
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