The association between sonographic enthesitis with sonographic synovitis and tenosynovitis in psoriatic arthritis patients.

OBJECTIVES: To examine the association between sonographic enthesitis with sonographic synovitis and tenosynovitis in PsA patients, and the association between sonographic enthesitis and clinical characteristics. METHODS: Consecutive PsA patients that fulfilled the ClASsification criteria for Psoriatic ARthritis (CASPAR) were prospectively recruited. Each patient was evaluated by comprehensive clinical and sonographic assessment (greyscale and Doppler), the latter including 52 joints, 40 tendons and 14 entheses [according to MAdrid Sonography Enthesitis Index (MASEI) plus lateral epicondyles] performed by an experienced sonographer blinded to the clinical data. The US enthesitis score was further categorized to inflammatory (hypoechogenicity, thickening, bursitis and Doppler) and structural (enthesophytes/calcifications and erosions) subcategories. Multivariate linear regression models assessed the association between enthesitis and the selected variables. RESULTS: A total of 158 PsA patients [mean (s.d.) age 52.3 (13) years, 88 (55.7%) females] were analysed. Multivariate linear regression analyses showed a significant association between sonographic enthesitis and sonographic synovitis (ß = 0.18, P = 0.008) and between sonographic enthesitis and sonographic tenosynovitis (ß = 0.06, P = 0.02). These associations were derived from the enthesitis inflammatory subcategory of the MASEI (P < 0.05). Associations between enthesitis and synovitis were also demonstrated on the level of the elbow, knee and ankle joints (P < 0.05). In addition, sonographic enthesitis was significantly associated with older age, male sex, swollen joint count, CRP level and physical occupation. CONCLUSIONS: Sonographic enthesitis is associated with sonographic synovitis and tenosynovitis. The severity of sonographic enthesitis may represent a marker for inflammatory activity in other musculoskeletal domains.

Effect of Secukinumab and Tumor Necrosis Factor Inhibitors on Humoral Response to BNT162b2 mRNA Vaccine in Patients With Spondyloarthritis Compared to Immunocompetent Controls.

OBJECTIVE: To assess the humoral response to the BNT162b2 mRNA vaccine among patients with spondyloarthritis (SpA) receiving secukinumab (SEC) compared to those receiving tumor necrosis factor inhibitors (TNFi) and immunocompetent controls. METHODS: Consecutive patients with psoriatic arthritis or axial SpA receiving SEC (n = 37) or TNFi (monotherapy, n = 109; + methotrexate [MTX], n = 16), immunocompetent controls (n = 122), and patients with rheumatoid arthritis (RA) receiving TNFi therapy (controls, n = 50) were vaccinated with 2 or 3 doses of the BNT162b2 vaccine. We evaluated humoral response, adverse events, and disease activity, and monitored for breakthrough coronavirus disease 2019 (COVID-19) postvaccination. RESULTS: The 2-dose vaccine regimen induced a comparable seropositive response in all study groups. S1/S2 antibody titers (in binding antibody units/mL; mean [SD]) were higher in the SEC group vs the TNFi + MTX-SpA and TNFi-RA groups (192.5 [68.4] vs 104.6 [46.9], P < 0.001, and 143.1 [81.9], P = 0.004). After 6 months, 96.3%, 96.6%, and 80.9% of the SEC, immunocompetent, and TNFi monotherapy-SpA groups (P = 0.10), respectively; 66.7% of the TNFi + MTX-SpA group (P = 0.03); and 63% of the TNFi-RA group (P = 0.004) remained seropositive. S1/S2 antibody titer decline was steeper in the TNFi groups than the SEC group. After the third dose, 100% of the SpA and immunocompetent and 88.9% of the TNFi-RA (P = 0.25) groups were seropositive. Rate of breakthrough COVID-19 infection was higher in the TNFi groups than in the SEC group (36-37.5% vs 10.8%). No significant between-group differences were observed for postvaccination disease activity and adverse events. CONCLUSION: SEC did not interfere with the immunogenic response to BNT162b2 vaccine in patients with SpA; however, TNFi therapy was associated with lower S1/S2-antibody titers, faster decline, and higher rate of breakthrough infections.

Synovial monocytes from psoriatic and rheumatoid arthritis patients are modulated differently by TNF inhibitors and glucocorticoids: an ex-vivo study.

OBJECTIVES: Synovial monocytes (expressing CD14+CD16+) affect pro-inflammatory responses in the synovium microenvironment of psoriatic arthritis (PsA) and rheumatoid arthritis (RA). The effect of various drugs on those cells was evaluated. METHODS: Synovial fluid mononuclear cells (SFMCs) from PsA (n=29) and RA (n=11) patients were cultured with biologics or glucocorticoids (GCs). CD14+CD16+ cells were analysed by flow cytometry. TNF secretion was assessed by ELISA and changes in cytokine and matrix metalloproteinase-9 (MMP-9) mRNA by qPCR. RESULTS: TNF inhibitors (i) [adalimumab (ADA) and infliximab (IFX)] significantly reduced the %CD14+CD16+ cells (p<0.04 and p<0.02, respectively) compared to IL-17Ai, IL-12/23i, and GCs in PsA patients' SFMCs. Similarly, those TNFi reduced the %CD14+CD16+ cells (p<0.05 and p<0.02, respectively) compared to IL-6Ri, CD20i and GCs in RA patients' SFMCs. TNFi (ADA p<0.01, IFX p=0.0003), and GCs (p<0.05) reduced TNF levels in PsA patients SFMCs supernatants. IFX down-regulated IL-1ß mRNA (p<0.005) while GCs betamethasone (BET) (p<0.01) and methylprednisolone acetate (MPA) (p<0.005) led to IL-1ß up-regulation. IFX down-regulated IL-8 and MMP-9 (p<0.01) and up-regulated IL-10 (p<0.005), and GCs did so to a greater extent (for IL-8, BET p<0.0001 and MPA p<0.005, for MMP-9, BET and MPA p<0.0001 and for IL-10, BET and MPA p<0.0001). CONCLUSIONS: TNFi but not GCs reduced the inflammatory monocytes. Both TNFi and GCs inhibited TNF secretion but differently modulated IL-1ß, IL-8, MMP-9 and IL-10 gene expression. Our data point to TNFi as a modulator of synovial monocytes.

Immunogenicity induced by two and three doses of the BNT162b2 mRNA vaccine in patients with autoimmune inflammatory rheumatic diseases and immunocompetent controls: a longitudinal multicentre study.

OBJECTIVES: To evaluate long-term kinetics of the BNT162b2 mRNA vaccine-induced immune response in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) and immunocompetent controls. METHODS: A prospective multicentre study investigated serum anti-SARS-CoV-2 S1/S2 IgG titre at 2-6 weeks (AIIRD n=720, controls n=122) and 6 months (AIIRD n=628, controls n=116) after the second vaccine, and 2-6 weeks after the third vaccine dose (AIIRD n=169, controls n=45). T-cell immune response to the third vaccine was evaluated in a small sample. RESULTS: The two-dose vaccine regimen induced a higher humoral response in controls compared with patients, postvaccination seropositivity rates of 100% versus 84.72%, p<0.0001, and 96.55% versus 74.26%, p<0.0001 at 2-6 weeks and at 6 months, respectively. The third vaccine dose restored the seropositive response in all controls and 80.47% of patients with AIIRD, p=0.0028. All patients treated with methotrexate monotherapy, anticytokine biologics, abatacept and janus kinase (JAK) inhibitors regained the humoral response after the third vaccine, compared with only a third of patients treated with rituximab, entailing a 16.1-fold risk for a negative humoral response, p≤0.0001. Cellular immune response in rituximab-treated patients was preserved before and after the third vaccine and was similar to controls. Breakthrough COVID-19 rate during the Delta surge was similar in patients and controls, 1.83% versus 1.43%, p=1. CONCLUSIONS: The two-dose BNTb262 regimen was associated with similar clinical efficacy and similar waning of the humoral response over 6 months among patients with AIIRD and controls. The third vaccine dose restored the humoral response in all of the controls and the majority of patients.

Ultrasound, magnetic resonance imaging and radiography of the finger joints in psoriatic arthritis patients.

OBJECTIVES: To report the discrepancies and agreements between US, MRI and radiography of the hand in PsA, and to compare the sensitivity and specificity of US and radiography to MRI as the gold standard imaging study in PsA. METHODS: All of the 100 prospectively recruited consecutive PsA patients underwent clinical assessment and concomitant radiographic, US and MRI studies of the MCP, PIP and DIP joints of one hand. Synovitis, flexor tenosynovitis, extensor paratenonitis, erosions and bone proliferations were identified and scored. All readers were blinded to clinical data, and agreement was calculated based on prevalence-adjusted bias-adjusted kappa (PABAK). RESULTS: The prevalence of synovitis, flexor tenosynovitis, extensor paratenonitis and erosions was similar for US and MRI, while that of bone proliferation was significantly increased in US and radiography compared with MRI (P < 0.001). The absolute agreement between US and MRI was good-to-very good for synovitis (85-96%, PABAK = 0.70-0.92), flexor tenosynovitis (93-98%, PABAK = 0.87-0.96) and extensor paratenonitis (95-98%, PABAK = 0.90-0.97). Agreement between US, MRI and radiography was 96-98% (PABAK = 0.92-0.97) for erosions and 71-93% (PABAK = 0.47-0.87) for bone proliferations. Sensitivity of US with MRI as gold standard was higher for synovitis (0.5-0.86) and extensor paratenonitis (0.63-0.85) than for flexor tenosynovitis (0.1-0.75), while the specificity was high for each pathology (0.89-0.98). CONCLUSION: There is very good agreement between US and MRI for the detection of inflammatory changes in finger joints in PsA. US, radiography and MRI have a good-to-very good agreement for destructive changes.

T cell functions of psoriatic arthritis patients are regulated differently by TNF, IL-17A and IL-6 receptor blockades in vitro.

OBJECTIVES: The impact of biologics used in PsA management on T cells is unknown. This study evaluated the effect of tumour necrosis factor-alpha (TNFα), interleukin-17A (IL-17A), and IL-6 receptor (IL-6R) blockers on T cell function in PsA patients and healthy controls peripheral blood mononuclear cells (PBMCs). METHODS: A total of 111 PsA patients and 32 healthy controls were recruited. PBMCs were co-cultured in presence of the biologics. T cell activation and proliferation were analysed by flow cytometry and cytokines in supernatants were measured by ELISA. The effect of biologics on lymphocyte proliferation was determined in response to phytohemagglutinin (PHA). RESULTS: Activated CD4+CD25+ T cells were significantly reduced by adalimumab (ADA) in PsA patients as compared to medium, ixekizumab (IXE), and tocilizumab (TCZ), while in healthy controls, ADA reduced the activated CD4+CD25+ T cells non-significantly. Elevated TNFα and IL-1ß levels were produced in supernatants of PsA patients as compared to healthy controls. TNFα, IL-17A, IL-1ß, and MMP-3 levels were reduced by ADA compared to medium (p<0.0001, p<0.0004, p<0.04, p<0.04, respectively). IXE reduced IL-17A (p<0.0001) but not the other cytokines. ADA had higher susceptibility to inhibit PHA-induced proliferation in both PsA patients and healthy controls (p<0.03) as compared to IXE and TCZ. CONCLUSIONS: Both TNF and IL-17A blockers are suitable for PsA treatment, but exhibit different activity on T cells. Moreover, the study reveals part of the mechanism exerted by ADA and provides a possible explanation for TCZ inefficacy in PsA.

Seroprevalence of SARS-CoV-2 antibodies in patients with autoimmune inflammatory rheumatic diseases.

OBJECTIVES: To assess the prevalence of anti-SARS-CoV-2 antibodies in autoimmune inflammatory rheumatic disease (AIIRD) patients, and to define clinical factors associated with seropositivity. METHODS: A cross sectional study was conducted at a tertiary rheumatology department in Israel. Consecutive patients completed a questionnaire and were tested for SARS-CoV-2 anti-nucleoprotein IgG (N-IgG). If this was positive, an anti-S1/S2 spike IgG (S-IgG) test was done. If both were positive, the patient was considered seropositive. Seropositive patients were retested after 3 months. RESULTS: The study included 572 AIIRD patients. Thirty patients were found seropositive, for a seroprevalence of 5.24%. The seropositive rate was significantly lower for patients treated with immunosuppressive medications (3.55%, p≤0.01), and specifically for patients treated with biologic disease-modifying anti-rheumatic drugs (bDMARDs) (2.7%, p≤0.05). These associations remained significant in the multivariate regressions adjusting for age, sex and exposure to a known COVID-19 patient. A second serology test 3 months later was collected in 21 of the 30 seropositive patients. In a mean±standard deviation (SD) of 166.63±40.76 days between PCR and second serology, 85% were still positive for N-IgG, and 100% were still positive for S-IgG, with a higher mean±SD titre compared to the first S-IgG (166.77±108.77 vs. 132.44±91.18, respectively, p≤0.05). CONCLUSIONS: Humoral response to SARS-CoV-2 in AIIRD patients may be affected be immunosuppressive treatment, especially bDMARDs. In patients with AIIRD, titres of SARS-CoV-2 IgG antibodies, especially N-IgG antibodies, fade with time, while S-IgG antibodies persist.

Role of ultrasound for assessment of psoriatic arthritis patients with fibromyalgia.

OBJECTIVE: To investigate whether ultrasonography (US), as an objective imaging modality, can optimise the evaluation of disease activity in psoriatic arthritis (PsA) patients with concomitant fibromyalgia syndrome (FMS). METHODS: The study population included 156 consecutive PsA patients who were recruited prospectively and fulfilled the ClASsification criteria for Psoriatic ARthritis criteria. The patients underwent complete clinical evaluation including assessment of fulfilment of the 2016 fibromyalgia classification criteria. All of the patients underwent US evaluation including 52 joints, 40 tendons and 14 entheses. The US score was based on the summation of a semiquantitative score (including synovitis, tenosynovitis and enthesitis). Scoring was performed by a sonographer blinded to the clinical data. Spearman's correlation coefficient and multivariate linear regression models were used to examine the association of FMS with clinical and the US scores. RESULTS: Forty-two patients (26.9%) with coexisting PsA and FMS were compared with 114 (73.1%) PsA patients without FMS. Patients with PsA and FMS had significantly increased scores for clinical composite indices, including non-Minimal Disease Activity, Composite Psoriatic Disease Activity Index (CPDAI), Disease Activity for Psoriatic Arthritis (DAPSA) and Psoriatic Arthritis Disease Activity Score (PASDAS) (p<0.001). In contrast, the total US score and its subcategories were similar for those with and without FMS. The total US score significantly correlated with CPDAI, DAPSA and PASDAS (p<0.001) in the PsA without FMS but not in the PsA with FMS group. FMS was significantly associated with higher clinical scores (p<0.001) but not with the US score (multivariable linear regression models). CONCLUSIONS: US has significantly greater value than composite clinical scores in the assessment of disease activity in PsA patients with FMS.

Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in adult patients with autoimmune inflammatory rheumatic diseases and in the general population: a multicentre study.

INTRODUCTION: Vaccination represents a cornerstone in mastering the COVID-19 pandemic. Data on immunogenicity and safety of messenger RNA (mRNA) vaccines in patients with autoimmune inflammatory rheumatic diseases (AIIRD) are limited. METHODS: A multicentre observational study evaluated the immunogenicity and safety of the two-dose regimen BNT162b2 mRNA vaccine in adult patients with AIIRD (n=686) compared with the general population (n=121). Serum IgG antibody levels against SARS-CoV-2 spike S1/S2 proteins were measured 2-6 weeks after the second vaccine dose. Seropositivity was defined as IgG ≥15 binding antibody units (BAU)/mL. Vaccination efficacy, safety, and disease activity were assessed within 6 weeks after the second vaccine dose. RESULTS: Following vaccination, the seropositivity rate and S1/S2 IgG levels were significantly lower among patients with AIIRD versus controls (86% (n=590) vs 100%, p<0.0001 and 132.9±91.7 vs 218.6±82.06 BAU/mL, p<0.0001, respectively). Risk factors for reduced immunogenicity included older age and treatment with glucocorticoids, rituximab, mycophenolate mofetil (MMF), and abatacept. Rituximab was the main cause of a seronegative response (39% seropositivity). There were no postvaccination symptomatic cases of COVID-19 among patients with AIIRD and one mild case in the control group. Major adverse events in patients with AIIRD included death (n=2) several weeks after the second vaccine dose, non-disseminated herpes zoster (n=6), uveitis (n=2), and pericarditis (n=1). Postvaccination disease activity remained stable in the majority of patients. CONCLUSION: mRNA BNTb262 vaccine was immunogenic in the majority of patients with AIIRD, with an acceptable safety profile. Treatment with glucocorticoids, rituximab, MMF, and abatacept was associated with a significantly reduced BNT162b2-induced immunogenicity.

Rituximab for refractory manifestations of the antiphospholipid syndrome: a multicentre Israeli experience.

OBJECTIVES: The clinical manifestations of the antiphospholipid syndrome (APS) are heterogeneous and related to anti-phospholipid antibodies (aPL). There is some evidence that B cells are involved in the pathogenesis of this condition. Thus the ability of rituximab (RTX) to deplete B cells makes it an appealing potential therapy for refractory antiphospholipid syndrome (APS). Real world data on RTX treatment of APS are still lacking. This study was conducted to report outcomes of RTX administration in the treatment of different aspects of APS. METHODS: This is a retrospective case series study on APS patients from 3 medical centres in Israel who were treated with RTX during 2010-2019 for refractory manifestations of APS including diffuse alveolar haemorrhage, recurrent thrombosis, cytopenia, neurological and skin manifestations. Medical records were reviewed regarding the clinical indication for RTX treatment, concomitant medications, RTX protocol, aPL status and response to treatment. Outcomes were defined as complete response if full resolution of the "indicated manifestation" was achieved and maintained for at least 12 months, partial response or no response. RESULTS: We identified 40 APS patients who were treated with RTX for refractory manifestations of this condition, of whom, 24 patients (60%) were female with a mean age of 40 years, and 31 patients (78%) were diagnosed with primary APS. A favourable response to RTX was documented in 32 patients (80%) including a complete response in 22 patients (55%). Response to RTX treatment was associated with a rituximab protocol of 375mg/m2 x 4 compared to a fixed dose of 1000 mg x2 (100% vs. 65%; p=0.01). Complete response was associated with a decrease in aPL titres within 4-6 months post treatment, whereas no significant change in aPL titres was observed in patients with partial or no response. CONCLUSIONS: Consistent with previous small case series, we report a good therapeutic response to RTX in patients with difficult to treat manifestations of APS. In this cohort, treatment protocols were associated with outcomes. Although further studies are required to verify our observations, our data support a plausible role for B cell depletion in refractory APS.

Soluble ST2 and CXCL-10 may serve as biomarkers of subclinical diastolic dysfunction in SLE and correlate with disease activity and damage.

OBJECTIVE: Subclinical myocardial dysfunction has been reported to occur early in systemic lupus erythematous (SLE). The study aim was to search for biomarkers of subclinical myocardial dysfunction which may correlate with disease activity in SLE patients. METHODS: This is a prospective, controlled, cross-sectional study of 57 consecutive patients with SLE and 18 controls. Serum samples were obtained to determine serum soluble ST2 (sST2), CXCL-10 and high-sensitivity troponin (hs-troponin) levels. All participants underwent an echocardiographic tissue Doppler study. RESULTS: sST2, CXCL-10 and hs-troponin levels were higher in patients with higher SLE disease activity (SLEDAI). sST2 and CXCL-10 levels were higher in patients with more disease damage as measured by the SLE damage index. Measures of diastolic dysfunction, as assessed by echocardiographic tissue Doppler negatively correlated with log CXCL-10: including E/A; E/e'lateral and E/e'septal, while E/e' positively correlated with CXCL-10. Diastolic dysfunction parameters also correlated with log sST2 levels, a negative correlation was seen with E/e'lateral and a positive correlation was seen with E/e'. Systolic dysfunction parameters positively correlated with hs-troponin: LVED, LVES, IVS, LVMASS and LVMASS index. In a multivariate analysis, sST2 and CXCL-10 were found to be significantly different in SLE vs. healthy controls, independent of each other and independent of cardiovascular risk factors. CONCLUSIONS: Soluble ST2 and CXCL-10 are markers of disease activity and accrued damage in SLE and may serve as sensitive biomarkers for detection of subclinical diastolic dysfunction, independent of traditional cardiovascular risk factors.

Prevalence of high-sensitivity cardiac troponin T in real-life cohorts of psoriatic arthritis and general population: a cross-sectional study.

Patients with psoriatic arthritis (PsA) are at increased risk of cardiovascular disease (CVD). High-sensitivity cardiac troponin T (hs-cTnT) is a novel biomarker of CVD. The objective of this study is to determine the prevalence of circulating hs-cTnT in patients with PsA compared to the general population and to characterize a PsA subset with detectable hs-cTnT. A cross-sectional analysis of serum hs-cTnT levels was performed in 116 consecutive patients with PsA and the Tel-Aviv Medical Center Inflammatory Survey cohort of the general population (n = 6052) as a control group. The level and prevalence of hs-cTnT (ng/L) were similar in the entire study population: 4.94 ± 4.4, 30.2% in PsA, 5.17 ± 6.7, 34.2% and 5.38 ± 4.3, 37.9% in unmatched and matched control groups according to age, gender and cardiovascular risk factors, respectively. Factors associated with detectable hs-cTnT in PsA included male gender (p = 0.002), age (p = 0.007), hypertension (p < 0.001), diabetes mellitus (p < 0.001), and smoking (p = 0.001). Axial disease, present in 25% of patients with PsA, was significantly associated with detectable hs-cTnT (p = 0.004). This association remained significant after adjusting for age, gender and traditional cardiovascular risk factors. No correlation between hs-cTnT levels and disease characteristics, PsA activity indices, C-reactive protein levels, or treatments for PsA was found. In summary, serum hs-cTnT was detectable in about the third of the PsA and control cohorts. In PsA, axial disease was significantly associated with detectable hs-TnT, warranting a particular attention to cardiovascular risk assessment in this sub-group. The role of hs-cTnT as a biomarker for CVD in PsA should be further investigated in prospective studies.

[RITUXIMAB IN RHEUMATOID ARTHRITIS - THERAPEUTIC ASPECTS BASED ON 18 YEARS OF GLOBAL EXPERIENCE].

INTRODUCTION: Rituximab, a monoclonal antibody against CD20 positive B cell, depletes these cells peripherally, and is a successful treatment in rheumatoid arthritis (RA). It is the second efficacious biologic to be established in the treatment of RA after TNFα blockers. Eighteen years of global experience from diverse clinical trials and from "real world" data, have demonstrated clinical efficacy in various disease scenarios and patient populations - short and long disease duration, methotrexate naïve patients and those with incomplete response to methotrexate, biologic naïve patients and those with incomplete response to previous biologics. Moreover, it has demonstrated the inhibition of radiographic progression. It seems to be most efficacious in seropositive patients. Despite vast experience, the need for concomitant traditional disease-modifying anti rheumatic drugs (DMARD), the optimal retreatment dose, and the favored retreatment interval remain somewhat uncertain. The recommended dosage is 1000 mg, administered twice, with a 2 weeks interval, although in some cases, a reduced dosage of 500 mg, administered twice may be considered. The safety profile of rituximab includes mainly infusion-related reactions, which are usually mild. A small risk of major infections has remained stable over time and repeated courses. Opportunistic infections are infrequent. Nevertheless, reactivation of hepatitis B is still a concern. Tuberculosis, malignancies, cardiovascular events and deterioration of interstitial lung disease do not appear to be increased. Since rituximab severely impairs the humoral response to vaccinations, they should be administered prior to treatment whenever possible. Rituximab has been a powerful addition to the large armamentarium for the treatment of RA. Rituximab is indicated in Israel as a second line biologic treatment for active RA.

Effect of Tocilizumab on Fatigue and Bone Mineral Density in Patients with Rheumatoid Arthritis.

BACKGROUND: Chronic fatigue is common among patients with rheumatoid arthritis (RA), affecting quality of life. Osteoporosis is a prevalent co-morbidity in RA patients. OBJECTIVES: To assess the effect of long-term treatment with tocilizumab on fatigue and bone mineral density (BMD) in RA patients with inadequate response to synthetic or biologic disease-modifying anti-rheumatic drugs. METHODS: In this multicenter, open-label, non-controlled, single-arm study, patients ≥ 18 years of age received intravenous tocilizumab 8 mg/kg every 4 weeks for 96 weeks. The primary outcome was the change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score from baseline to weeks 24, 48, 72, and 96. BMD was assessed before and 96 weeks after treatment. RESULTS: The study comprised 145 patients (mean age 53.4 ± 13.4 years, 83.4% women). Of these, 88 (60.7%) completed the 2 year treatment period. The mean FACIT-Fatigue score improved consistently starting from week 4 and showed a statistically significant increase of 5.0 ± 9.7, 6.8 ± 10.5, 7.3 ± 10.9, and 7.3 ± 10.4 from baseline to weeks 24, 48, 72, and 96, respectively (P < 0.0001). Mean BMD of femoral neck and total spine remained stable. Disease activity, acute phase reactants, and composite efficacy measures decreased during the study, while hemoglobin levels increased. Adverse events and serious adverse events were as expected for the known and previously described data. CONCLUSIONS: Tocilizumab therapy for 2 years significantly and clinically decreased fatigue. BMD remained stable and no new safety issue was reported.

Sputum Anticitrullinated Protein Antibodies in Patients With Long-standing Rheumatoid Arthritis.

OBJECTIVE: The aim of this study was to evaluate the presence of autoantibodies to cyclic citrullinated synthetic peptides (ACPAs) in the sputum of patients with long-standing rheumatoid arthritis (RA). METHODS: Nineteen consecutive RA patients and 16 age- and sex-matched control subjects participated in this cross-sectional study. All underwent complete lung function tests and provided induced sputum. Antibodies to citrullinated (CitP) and the corresponding norleucine-containing (NorP) peptides in the sputum of the RA patients and control subjects, as well as in the serum of the RA patients, were determined by enzyme-linked immunosorbent assay. RESULTS: Patients with RA had the following characteristics: mean disease duration of 12 years, Disease Activity Score for 28 joints of 3.44, and Sharp-van der Heijde score of 57.5. Ten of the 19 RA patients showed high titers of ACPAs in their sera. Four of the seropositive (40%), none of the seronegative RA patients, and only 1 of the control subjects showed detectable levels of ACPAs in their sputum. The ratio between the reactivity with CitP and NorP peptides in the sputum was significantly higher in RA sputum than in control sputum (1.33 ± 1.2 vs. 0.64 ± 0.14, P = 0.02). A positive correlation was found between sputum ACPAs and age, serum ACPAs, sputum anti-NorP, serum anti-CitP/NorP reactivity ratio, and the proportion of neutrophils and lymphocytes in the sputum. No significant correlation was found between sputum ACPAs and disease severity, history of smoking, lung function tests, or treatment for RA. CONCLUSIONS: Anticitrullinated protein/peptide antibodies can be detected in the sputum of RA patients and are correlated with the presence in the serum.

Immunogenicity and safety of vaccination against seasonal 2012 influenza virus among patients with psoriatic arthritis and psoriasis.

OBJECTIVES: We aimed to assess the immunogenicity and safety of vaccination against seasonal influenza in psoriatic arthritis (PsA) and psoriasis (Pso) patients. METHODS: Patients with PsA or Pso and healthy controls were vaccinated with the Sanofi Pasteur vaccine recommended by the WHO in 2012. Clinical and laboratory assessments were performed on the day of the vaccination and 4-6 weeks later. The immunogenicity of the vaccine was evaluated by haemagglutination inhibition assay. RESULTS: The study included 63 consecutive PsA patients and 4 Pso patients (mean age 50.1, 37 females, 30 males, 55.2% treated with tumour necrosis factor alpha blockers [TNF-α], 31.3% on disease-modifying anti-rheumatic drugs [DMARDs]) and 30 healthy controls. The geometric mean titers increased significantly in all participants for each of the subtypes tested. A substantial and similar proportion of patients in both groups responded to the vaccine. The response rate was not affected by parameters such as age, gender, disease activity or the use of TNF-α blockers or DMARDs. There were no significant changes in the patients' 68 tender and 66 swollen joint counts, dactylitis, PASI, global evaluation of the patient and physician and ESR, while there was a rise in CRP levels. CONCLUSIONS: Vaccination against seasonal influenza is safe and induces an appropriate response in patients with PsA, similar to healthy controls.

Is B Cell-Targeted Therapy Effective in Systemic Lupus Erythematosus?

In the past decade we have witnessed a dramatic change in the management of autoimmune diseases, such as rheumatoid arthritis, due to the development of new biologic drugs designed to target key mediators in the autoimmune process. However, the development of similar target-specific drugs for the management of SLE has not been as successful. The B cell has long been considered central to the pathogenesis of SLE and has been regarded as an important target for biologic drugs. Several B cell-targeted drugs have been developed and although the mechanisms seem promising, most of the studies published to date have failed to achieve their primary endpoints, leading to an ongoing debate regarding the role of B cell therapy in SLE. The present report discusses the pros and cons of B cell-targeted therapy in SLE, reviews the clinical studies, and offers possible explanations forthe discrepancies between randomized control studies and real-life experience.

Learning and memory-related brain activity dynamics are altered in systemic lupus erythematosus: a functional magnetic resonance imaging study.

BACKGROUND: Memory impairment is prevalent in systemic lupus erythematosus (SLE); however, the pathogenesis is unknown. METHODS: We studied 12 patients with SLE without clinically overt neuropsychiatric manifestations and 11 matched healthy controls, aiming to characterize neural correlates of memory impairment, using structural and functional magnetic resonance imaging (MRI). The paradigm consisted of three encoding and free-recall cycles, allowing characterization of dynamics along consecutive retrieval attempts. RESULTS: During learning, patients with SLE and healthy controls showed brain activity changes in two principal networks, the default mode network (DMN) and the task-positive network (TPN). Patients with SLE demonstrated significantly less deactivation in the DMN and greater activation in the TPN, reflecting greater recruitment of both networks. The anterior medial prefrontal cortex (amPFC) of the DMN emerged as the only region where brain activity dynamics were altered both over the learning process (p < 0.006), and within free-recall period attempts (p < 0.034). Patients showed significant positive correlations between learning efficiency and hippocampal activity, and greater hippocampal functional connectivity, with pronounced connectivity to DMN structures. CONCLUSIONS: Increased brain activation in patients with SLE during learning may reflect compensatory mechanisms to overcome memory impairment. Our findings localize this impairment to the amPFC, consistent with the behavioral pattern seen in SLE. Altered networking of the hippocampal subsystem of the DMN is consistent with hippocampal neuronal damage seen in SLE, and may reflect compensatory cortical reorganization to cope with dysfunction in these regions pivotal to mnemonic functions.

Sex-Based Differences in Sonographic and Clinical Findings Among Patients With Psoriatic Arthritis.

OBJECTIVE: To investigate sex-based sonographic differences in patients with psoriatic arthritis (PsA). METHODS: The study population included consecutive prospectively recruited patients with PsA, as determined by the CASPAR (Classification for Psoriatic Arthritis) criteria, who underwent clinical and physical examinations, followed by a detailed ultrasound (US) evaluation (greyscale and Doppler). US evaluation included 52 joints, 40 tendons, and 14 points of entheses (Modified Madrid Sonographic Enthesis Index [MASEI] plus lateral epicondyles) performed by an experienced sonographer blinded to the clinical data. The US score was based on the summation of a semiquantitative score for synovitis, tenosynovitis, and enthesitis. The US enthesitis score was categorized into inflammatory lesions (ie, hypoechogenicity, thickening, bursitis, and Doppler) and structural lesions (ie, enthesophytes/calcifications and erosions). RESULTS: The study population of 158 patients included 70 males and 88 females. The males had higher rates of employment (P = 0.01), Psoriasis Area and Severity Index scores (P = 0.04), and mean swollen joint counts (P = 0.04). The total US score and its subcategory scores-the synovitis and tenosynovitis scores-were similar for both sexes, whereas the total enthesitis score and its subcategory score-the inflammatory enthesitis score-were significantly higher for the males compared to the females (P = 0.01 and P = 0.005, respectively). Hypoechogenicity, thickening, and enthesophytes were more prevalent in males compared to females (P < 0.05). Multivariate ordinal logistic regression models showed that male sex was associated with a higher US inflammatory enthesitis score compared to female sex (odds ratio 1.96, P = 0.02). CONCLUSION: Sonographic enthesitis was more prevalent in males compared to females with PsA. These differences were not reflected by enthesitis disease activity scores derived from clinical assessment.

Heart Valve Surgery in Antiphospholipid Syndrome Patients-Morbidity and Mortality.

OBJECTIVES: To assess valve surgery outcomes in antiphospholipid syndrome (APS). METHODS: A retrospective study assessing complications and mortality rate and possible factors associated with adverse outcomes of APS patients undergoing valve surgery in two tertiary medical centers. RESULTS: Twenty-six APS patients (median age at surgery 47.5 years) who underwent valve surgery were detected, of whom 11 (42.3%) had secondary APS. The mitral valve was most commonly involved (n = 15, 57.7%). A valve replacement was performed in 24 operations (92.3%), 16 of which (66.7%) were mechanical valves. Fourteen (53.8%) patients sustained severe complications, and four of them died. The presence of mitral regurgitation (MR) was associated with severe complications and mortality (odds ratio (95% confidence interval) 12.5 (1.85-84.442), p = 0.008, for complications. All deceased patients had MR (p = 0.033). The presence of Libman-Sacks endocarditis (LSE) (7.333 (1.272-42.294), p = 0.045), low C3 (6.667 (1.047-42.431), p = 0.05) and higher perioperative prednisone doses (15 ± 21.89 vs. 1.36 ± 3.23 mg/day, p = 0.046) were also associated with complications. A lower glomerular filtration rate (GFR) was associated with mortality (30.75 ± 19.47 vs. 70.68 ± 34.44 mL/min, p = 0.038). CONCLUSIONS: Significant morbidity and mortality were observed among APS patients undergoing valve surgery. MR was associated with mortality and complications. LSE, low complement and higher doses of corticosteroids were associated with complications, while a low GFR was associated with mortality.