Older Age, a High Titre of Neutralising Antibodies and Therapy with Conventional DMARDs Are Associated with Protection from Breakthrough Infection in Rheumatoid Arthritis Patients after the Booster Dose of Anti-SARS-CoV-2 Vaccine.

Objectives: We aimed to analyse the incidence and severity of breakthrough infections (BIs) in rheumatoid arthritis (RA) patients after a COronaVIrus Disease 2019 (COVID-19) vaccination booster dose. Methods: We enrolled 194 RA patients and 1002 healthcare workers (HCWs) as controls. Clinical, lifestyle and demographic factors were collected at the time of the third dose, and immunogenicity analyses were carried out in a subgroup of patients at 4-6 weeks after the third dose. Results: BIs were experienced by 42% patients (82/194) with a median time since the last vaccination of 176 days. Older age (>50 years; aHR 0.38, 95% CI: 0.20-0.74), receiving conventional synthetic disease modifying antirheumatic drugs (csDMARDs) (aHR 0.52, 95%CI: 0.30-0.90) and having a titre of neutralising antibodies >20 (aHR 0.36, 95% CI: 0.12-1.07) were identified as protective factors. Conversely, anti-IL6R treatment and anti-CD20 therapy increased BI probability. BIs were mostly pauci-symptomatic, but the hospitalisation incidence was significantly higher than in HCWs (8.5% vs. 0.19%); the main risk factor was anti-CD20 therapy. Conclusions: Being older than 50 years and receiving csDMARDs were shown to be protective factors for BI, whereas anti-IL6R or anti-CD20 therapy increased the risk. Higher neutralising antibody titres were associated with a lower probability of BI. If confirmed in a larger population, the identification of a protective cut-off would allow a personalised risk-benefit therapeutic management of RA patients.

The Third Dose of BNT162b2 COVID-19 Vaccine Does Not "Boost" Disease Flares and Adverse Events in Patients with Rheumatoid Arthritis.

Data on the risk of adverse events (AEs) and disease flares in autoimmune rheumatic diseases (ARDs) after the third dose of COVID-19 vaccine are scarce. The aim of this multicenter, prospective study is to analyze the clinical and immunological safety of BNT162b2 vaccine in a cohort of rheumatoid arthritis (RA) patients followed-up from the first vaccine cycle to the third dose. The vaccine showed an overall good safety profile with no patient reporting serious AEs, and a low percentage of total AEs at both doses (40/78 (51.3%) and 13/47 (27.7%) patients after the second and third dose, respectively (p < 0.002). Flares were observed in 10.3% of patients after the end of the vaccination cycle and 12.8% after the third dose. Being vaccinated for influenza was inversely associated with the onset of AEs after the second dose, at both univariable (p = 0.013) and multivariable analysis (p = 0.027). This result could allow identification of a predictive factor of vaccine tolerance, if confirmed in larger patient populations. A higher disease activity at baseline was not associated with a higher incidence of AEs or disease flares. Effectiveness was excellent after the second dose, with only 1/78 (1.3%) mild breakthrough infection (BI) and worsened after the third dose, with 9/47 (19.2%) BI (p < 0.002), as a probable expression of the higher capacity of the Omicron variants to escape vaccine recognition.

Booster dose of SARS-CoV-2 messenger RNA vaccines strengthens the specific immune response of patients with rheumatoid arthritis: A prospective multicenter longitudinal study.

OBJECTIVES: To characterize the kinetics of humoral and T-cell responses in rheumatoid arthritis (RA)-patients followed up to 4-6 weeks (T3) after the SARS-CoV-2 vaccine booster dose. METHODS: Health care workers (HCWs, n = 38) and patients with RA (n = 52) completing the messenger RNA vaccination schedule were enrolled at T3. In each cohort, 25 subjects were sampled after 5 weeks (T1) and 6 months (T2) from the first vaccine dose. The humoral response was assessed by measuring anti-receptor-binding domain (RBD) and neutralizing antibodies, the T-cell response by interferon-γ-release assay (IGRA), T cell cytokine production, and B cell phenotype at T3 by flow cytometry. RESULTS: Patients with RA showed a significant reduction of antibody titers from T1 to T2 and a significant increase at T3. T-cell response by IGRA persisted over time in patients with RA, whereas it increased in HCWs. Most patients with RA scored positive for anti-RBD, neutralizing antibody and T-cell responses, although the magnitude was lower than HCWs. The spike-specific-cytokine response was mainly clusters of differentiation (CD)4+ T cells restricted in both cohorts and significantly lower with reduced interleukin-2 response and CD4-antigen-responding naïve T cells in patients with RA. Unswitched memory B cells were reduced in patients with RA compared with HCWs independently of vaccination. CONCLUSION: COVID-19 vaccine booster strengthens the humoral immunity in patients with RA even with a reduced cytokine response.

Kinetics of the B- and T-Cell Immune Responses After 6 Months From SARS-CoV-2 mRNA Vaccination in Patients With Rheumatoid Arthritis.

Objective: To assess the kinetics of the humoral and cell-mediated responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in rheumatoid arthritis (RA) patients treated with different immunosuppressive therapies. Methods: Following vaccine completed schedule, health care workers (HCWs, n = 49) and RA patients (n = 35) were enrolled at 5 weeks (T1) and 6 months (T6) after the first dose of BNT162b2-mRNA vaccination. Serological response was assessed by quantifying anti-receptor-binding domain (RBD)-specific immunoglobulin G (IgG) and SARS-CoV-2 neutralizing antibodies, while cell-mediated response was assessed by a whole-blood test quantifying the interferon (IFN)-γ response to spike peptides. B-cell phenotype and IFN-γ-specific T-cell responses were evaluated by flow cytometry. Results: After 6 months, anti-RBD antibodies were still detectable in 91.4% of RA patients, although we observed a significant reduction of the titer in patients under Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4)-Ig [median: 16.4 binding antibody units (BAU)/ml, interquartile range (IQR): 11.3-44.3, p < 0.0001] or tumor necrosis factor (TNF)-α inhibitors (median: 26.5 BAU/ml, IQR: 14.9-108.8, p = 0.0034) compared to controls (median: 152.7 BAU/ml, IQR: 89.3-260.3). All peripheral memory B-cell (MBC) subpopulations, in particular, the switched IgG+ MBCs (CD19+CD27+IgD-IgM-IgG+), were significantly reduced in RA subjects under CTLA-4-Ig compared to those in HCWs (p = 0.0012). In RA patients, a significantly reduced anti-RBD IgG titer was observed at T6 vs. T1, mainly in those treated with CTLA-4-Ig (p = 0.002), interleukin (IL)-6 inhibitors (p = 0.015), and disease-modifying antirheumatic drugs (DMARDs) ± corticosteroids (CCSs) (p = 0.015). In contrast, a weak nonsignificant reduction of the T-cell response was reported at T6 vs. T1. T-cell response was found in 65.7% of the RA patients at T6, with lower significant magnitude in patients under CTLA-4-Ig compared to HCWs (p < 0.0001). The SARS-CoV-2 IFN-γ-S-specific T-cell response was mainly detected in the CD4+ T-cell compartment. Conclusions: In this study, in RA patients after 6 months from COVID-19 vaccination, we show the kinetics, waning, and impairment of the humoral and, to a less extent, of the T-cell response. Similarly, a reduction of the specific response was also observed in the controls. Therefore, based on these results, a booster dose of the vaccine is crucial to increase the specific immune response regardless of the immunosuppressive therapy.

ImmunosuppressiveTherapies Differently Modulate Humoral- and T-Cell-Specific Responses to COVID-19 mRNA Vaccine in Rheumatoid Arthritis Patients.

Objective: To assess in rheumatoid arthritis (RA) patients, treated with different immunosuppressive therapies, the induction of SARS-CoV-2-specific immune response after vaccination in terms of anti-region-binding-domain (RBD)-antibody- and T-cell-specific responses against spike, and the vaccine safety in terms of clinical impact on disease activity. Methods: Health care workers (HCWs) and RA patients, having completed the BNT162b2-mRNA vaccination in the last 2 weeks, were enrolled. Serological response was evaluated by quantifying anti-RBD antibodies, while the cell-mediated response was evaluated by a whole-blood test quantifying the interferon (IFN)-γ-response to spike peptides. FACS analysis was performed to identify the cells responding to spike stimulation. RA disease activity was evaluated by clinical examination through the DAS28crp, and local and/or systemic clinical adverse events were registered. In RA patients, the ongoing therapeutic regimen was modified during the vaccination period according to the American College of Rheumatology indications. Results: We prospectively enrolled 167 HCWs and 35 RA patients. Anti-RBD-antibodies were detected in almost all patients (34/35, 97%), although the titer was significantly reduced in patients under CTLA-4-inhibitors (median: 465 BAU/mL, IQR: 103-1189, p<0.001) or IL-6-inhibitors (median: 492 BAU/mL, IQR: 161-1007, p<0.001) compared to HCWs (median: 2351 BAU/mL, IQR: 1389-3748). T-cell-specific response scored positive in most of RA patients [24/35, (69%)] with significantly lower IFN-γ levels in patients under biological therapy such as IL-6-inhibitors (median: 33.2 pg/mL, IQR: 6.1-73.9, p<0.001), CTLA-4-inhibitors (median: 10.9 pg/mL, IQR: 3.7-36.7, p<0.001), and TNF-α-inhibitors (median: 89.6 pg/mL, IQR: 17.8-224, p=0.002) compared to HCWs (median: 343 pg/mL, IQR: 188-756). A significant correlation between the anti-RBD-antibody titer and spike-IFN-γ-specific T-cell response was found in RA patients (rho=0.432, p=0.009). IFN-γ T-cell response was mediated by CD4+ and CD8+ T cells. Finally, no significant increase in disease activity was found in RA patients following vaccination. Conclusion: This study showed for the first time that antibody-specific and whole-blood spike-specific T-cell responses induced by the COVID-19 mRNA-vaccine were present in the majority of RA patients, who underwent a strategy of temporary suspension of immunosuppressive treatment during vaccine administration. However, the magnitude of specific responses was dependent on the immunosuppressive therapy administered. In RA patients, BNT162b2 vaccine was safe and disease activity remained stable.

May Bacterial Infections Trigger Bullous Pemphigoid? Case Report and Review of Literature.

Bullous pemphigoid (BP) is an autoimmune blistering skin disease, mainly observed in the elderly. Infections have been suggested as possible disease triggers. However, infections may even heavily influence the disease clinical course and mortality. A 75-year-old woman was admitted to hospital for severe erythematosus blistering disease, accompanied by hyper-eosinophilia and hyper-IgE. The culture of bullous fluid was positive for Enterococcus faecalis, the blood culture was positive for Staphylococcus aureus, and the urine culture was positive for Proteus mirabilis and Escherichia coli. Moreover, circulating anti-BP180 IgG was present and the histopathological/ultrastructural examination of a lesional skin biopsy was compatible with BP. High eosinophil levels (up to 3170/µL) were found throughout the clinical course, while values below 1000/µL were associated with clinical improvement. The total IgE was 1273 IU/mL, and specific anti-G/V-penicillin/ampicillin IgE antibodies were positive. The patient had a complete clinical recovery in two months with methyl-prednisolone (40 then 20 mg/day) and low-dose azathioprine (50 mg/day) as a steroid-sparing agent. The steroid treatment was tapered until interruption during a one-year period and intravenous immunoglobulins have been administered for three years in order for azathioprine to also be interrupted. The patient stopped any treatment five years ago and, in this period, has always been in good health. In this case, the contemporaneous onset of different bacterial infections and BP is suggestive of bacterial infections acting as BP trigger(s), with allergic and autoimmune pathways contributing to the disease pathogenesis.

The Role of Lung Colonization in Connective Tissue Disease-Associated Interstitial Lung Disease.

Connective tissue diseases (CTDs) may frequently manifest with interstitial lung disease (ILD), which may severely impair quality and expectation of life. CTD-ILD generally has a chronic clinical course, with possible acute exacerbations. Although several lines of evidence indicate a relevant role of infections in the acute exacerbations of CTD-ILD, little information is available regarding the prevalence of infections in chronic CTD-ILD and their possible role in the clinical course. The aim of the present retrospective study was the identification of lung microbial colonization in broncho-alveolar lavage from patients affected by stable CTD-ILD with radiologically defined lung involvement. We demonstrated that 22.7% of patients with CTD-ILD display microbial colonization by Pseudomonas aeruginosa, Haemophilus influenzae, and non-tuberculous mycobacteria. Moreover, these patients display a major radiologic lung involvement, with higher impairment in lung function tests confirmed in a multivariate logistic regression analysis. Overall, the present study provides new information on lung colonization during CTD-ILD and its possible relationship with lung disease progression and severity.

Immunogenicity of Viral Vaccines in the Italian Military.

Military personnel of all armed forces receive multiple vaccinations and have been doing so since long ago, but relatively few studies have investigated the possible negative or positive interference of simultaneous vaccinations. As a contribution to fill this gap, we analyzed the response to the live trivalent measles/mumps/rubella (MMR), the inactivated hepatitis A virus (HAV), the inactivated trivalent polio, and the trivalent subunits influenza vaccines in two cohorts of Italian military personnel. The first cohort was represented by 108 students from military schools and the second by 72 soldiers engaged in a nine-month mission abroad. MMR and HAV vaccines had never been administered before, whereas inactivated polio was administered to adults primed at infancy with a live trivalent oral polio vaccine. Accordingly, nearly all subjects had baseline antibodies to polio types 1 and 3, but unexpectedly, anti-measles/-mumps/-rubella antibodies were present in 82%, 82%, and 73.5% of subjects, respectively (43% for all of the antigens). Finally, anti-HAV antibodies were detectable in 14% and anti-influenza (H1/H3/B) in 18% of the study population. At mine months post-vaccination, 92% of subjects had protective antibody levels for all MMR antigens, 96% for HAV, 69% for the three influenza antigens, and 100% for polio types 1 and 3. An inverse relationship between baseline and post-vaccination antibody levels was noticed with all the vaccines. An excellent vaccine immunogenicity, a calculated long antibody persistence, and apparent lack of vaccine interference were observed.

Safety of Multiple Vaccinations and Durability of Vaccine-Induced Antibodies in an Italian Military Cohort 5 Years after Immunization.

We previously examined the safety and immunogenicity of multiple vaccines administered to a military cohort, divided into two groups, the first composed of students at military schools, thus operating inside the national borders for at least 3 years, and the other formed of soldiers periodically engaged in a 9-month-long mission abroad (Lebanon). In the current study, we analyzed 112 individuals of this cohort, 50 pertaining to the first group and 62 to the second group, in order to examine the possible late appearance of side effects and to calculate the half-life of the induced antibodies. Moreover, the possible involvement of B-cell polyclonal activation as a pathogenetic mechanism for long term antibody persistence has even been explored. No late side effects, as far as autoimmunity and/or lymphoproliferation appearance, have been noticed. The long duration of the vaccine induced anti-HAV antibodies has been confirmed, whereas the antibodies induced by tetravalent meningococcal polysaccharide vaccine have been found to persist above the threshold for putative protection for a longer time, and anti-tetanus, diphtheria, and polio 1 and 3 for a shorter time than previously estimated. No signs of polyclonal B-cell activation have been found, as a possible mechanism to understand the long antibody persistence.

Impact of Mediterranean Diet on Disease Activity and Gut Microbiota Composition of Rheumatoid Arthritis Patients.

Rheumatoid arthritis (RA) is an autoimmune disorder in which gut and oral microbiota play a crucial role. Diet is a modifiable factor that can influence both microbiota composition and arthritis outcome; previous studies have suggested associations between dietary habits and RA, with contrasting results. We investigate the protective effect of the Mediterranean diet (MD) on disease activity and the gut microbiota profile in RA patients. Sixty consecutive RA patients were enrolled upon filling a validated 14-item questionnaire for the assessment of adherence to the Mediterranean diet (Prevention with Mediterranean Diet-PREDIMED). Then, 16S analysis was employed to explore the gut microbiota within the two cohorts of patients. Patients with high adherence to MD (20) had a significantly lower C-reactive protein (p < 0.037) and disease activity (p < 0.034) than the 40 patients with low/moderate adherence to MD. An inverse association between MD and disease activity was confirmed by multivariate analysis after adjustments for all the different demographic, clinical and serologic variables. A healthier gut microbiota composition was observed in the high adherence group, with a significant decrease in Lactobacillaceae and an almost complete absence of Prevotella copri with respect to the low/moderate adherence group. In conclusion, our findings support the protective role of MD on disease activity and microbiota composition in RA patients, and suggest the feasibility of shifting the habitual diet to modulate the gut microbiota and promote the benefits associated with MD.

Prevalence of Hepatitis B Virus Markers in Patients with Autoimmune Inflammatory Rheumatic Diseases in Italy.

Chronic hepatitis B virus (HBV) infection may be reactivated by immunosuppressive drugs in patients with autoimmune inflammatory rheumatic diseases. This study evaluates HBV serum markers' prevalence in rheumatic outpatients belonging to Spondyloarthritis, Chronic Arthritis and Connective Tissue Disease diagnostic groups in Italy. The study enrolled 302 subjects, sex ratio (M/F) 0.6, mean age ± standard deviation 57 ± 15 years, 167 (55%) of whom were candidates for immunosuppressive therapy. The Spondyloarthritis group included 146 subjects, Chronic Arthritis 75 and Connective Tissue Disease 83 (two patients had two rheumatic diseases; thus, the sum is 304 instead of 302). Ten subjects (3%) reported previous anti-HBV vaccination and tested positive for anti-HBs alone with a titer still protective (>10 IU/mL). Among the remaining 292 subjects, the prevalence of positivity for HBsAg, isolated anti-HBc, anti-HBc/anti-HBs, and any HBV marker was 2%, 4%, 18%, and 24%, respectively. A total of 26/302 (9%) patients with γ-globulin levels ≤0.7 g/dL were more frequently (p = 0.03455) prescribed immunosuppressive therapy, suggesting a more severe rheumatic disease. A not negligible percentage of rheumatic patients in Italy are at potential risk of HBV reactivation related to immunosuppressive therapy. Before starting treatment, subjects should be tested for HBV markers. Those resulting positive should receive treatment or prophylaxis with Nucleos (t) ides analogue (NUCs) at high barrier of resistance, or pre-emptive therapy, according to the pattern of positive markers. HB vaccination is recommended for those who were never exposed to the virus.

Psychological Distress in Patients with Autoimmune Arthritis during the COVID-19 Induced Lockdown in Italy.

Lockdowns imposed by governments worldwide as a way to limit the spread of severe atypical respiratory syndrome-coronavirus-2 (SARS-CoV2) have had heavy psychological and economic consequences. Arthritis patients are a vulnerable population at an increased risk of peritraumatic stress. This could be due to several reasons, including the fear of shortage of medicine and difficulty receiving periodical medical checks. In the present case-control study, psychological distress in patients with autoimmune arthritis during the coronavirus disease 2019 (COVID-19) pandemic were investigated. An electronic survey was conducted to gather information on the perceived change in the emotional state, general health (GH), fatigue, joint pain, and disease activity during the lockdown, in 100 patients with autoimmune arthritis and 100 controls. Mental health status was measured using the Depression, Anxiety and Stress Scale (DASS-21). The COVID-19 Peritraumatic Distress Index (CPDI) was used to assess the frequency of peritraumatic stress disorders related to COVID-19. Patients reported a significant worsening of perceived GH (36% vs. 7%; p < 0.001), a significantly higher mean CPDI score (p < 0.001) than controls. Using multivariate analysis, arthritis patients had significantly higher CPDI scores (+3.67 points; p = 0.019), independent of depression, anxiety, and stress symptoms, comorbidities, and sociodemographic and lifestyle characteristics. Logistic regression analysis showed that the risk of reporting worsened GH was 9-fold higher in patients than controls (p < 0.001). Patients with autoimmune arthritis are at higher risk of psychological distress related to COVID-19 pandemic; thus targeted intervention should be designed to strengthen coping capacity in this vulnerable population.

One-year effectiveness, retention rate, and safety of secukinumab in ankylosing spondylitis and psoriatic arthritis: a real-life multicenter study.

BACKGROUND: Secukinumab (SEC) is effective for ankylosing spondylitis (AS) and psoriatic arthritis (PsA) in randomized trials, but real-life data are lacking. RESEARCH DESIGN AND METHODS: Real-life, prospective observational study on 169 consecutive outpatients at baseline (T0) and at 6 (T6) and 12 months (T12) after starting SEC (39 AS, 23%; 130 PsA, 77%). RESULTS: Significant improvement was seen at T6 and T12 for all clinical variables, including TJC, SJC, ESR, CRP, DAPSA, ASDAS-CRP, and BASDAI, as well as in patient-reported outcomes like VAS-pain. By multivariable regression analysis, in AS patients high BASDAI at T0 correlated with diagnostic delay (R2 = 0.4; p = 0.009) and peripheral joint involvement (R2 = 0.4; p = 0.04). During follow-up, reduction of BASDAI positively correlated with high ESR (R2 = 0.65; p = 0.04). ASDAS-CRP at T0 positively correlated with high ESR (R2 = 0.34; p = 0.004). Reduction of ASDAS-CRP from T0 to T6 correlated with current smoking status (R2 = 0.42; p = 0.003). In PsA patients, reduction of DAPSA score from T0 to T12 is negatively correlated with the presence of metabolic syndrome (R2 = 0.41; p = 0.0025). SEC was well tolerated; 10 patients discontinued treatment for non-severe adverse events. CONCLUSIONS: Secukinumab is effective and safe in patients with AS and PsA in a real-life setting.

Using INTERCheck® to Evaluate the Incidence of Adverse Events and Drug-Drug Interactions in Out- and Inpatients Exposed to Polypharmacy.

BACKGROUND: Polypharmacy exposes patients with comorbidities (particularly elderly patients) to an increased risk of drug-specific adverse events and drug-drug interactions. These adverse events could be avoided with the use of a computerized prescription support system in the primary care setting. The INTERCheck® software is a prescription support system developed with the aim of balancing the risks and benefits of polytherapy and examining drug-drug interactions. OBJECTIVES: This observational study used the INTERCheck® software to evaluate the incidence of adverse events and of drug-drug interactions in outpatients and inpatients receiving multiple medications. METHODS: Patients were randomly enrolled from the outpatient department (n = 98) and internal medicine ward (n = 46) of S. Andrea Hospital of Rome. Polypharmacological treatment was analyzed using INTERCheck® software, and the prevalence of risk indicators and adverse events was compared between the two groups. RESULTS: Polypharmacy (use of five or more drugs) applied to all except three cases among outpatients and one case among inpatients. A significant positive correlation was found between the number of medications and the INTERCheck® score (ρ = 0.67; p < 0.000001), and a significant negative correlation was found between the drug-related anticholinergic burden and cognitive impairment (r = - 0.30 p = 0.01). Based on the INTERCheck® analysis, inpatients had a higher score for class D (contraindicated drug combination should be avoided) than did outpatients (p = 0.01). The potential class D drug-drug interactions were associated with adverse events that caused hospitalization (χ2 = 7.428, p = 0.01). CONCLUSIONS: INTERCheck® analysis indicated that inpatients had a high risk of drug-drug interactions and a high percentage of related adverse drug events. Further prospective studies are necessary to evaluate whether the INTERCheck® software may help reduce polypharmacy-related adverse events when used in a primary care setting and thus potentially avoid related hospitalization and severe complications such as physical and cognitive decline.

Tetanus-diphtheria vaccination in adults: the long-term persistence of antibodies is not dependent on polyclonal B-cell activation and the defective response to diphtheria toxoid re-vaccination is associated to HLADRB1∗01.

Cellular and humoral immune responses to tetanus-diphtheria vaccine (Td) were assessed in human leukocyte antigen (HLA)-typed Italian military personnel who received multiple concomitant vaccines. Td-specific antibodies and T-lymphocytes were measured in individuals with one (group-1) and more than one (group-2) Td boosters. A third group (group-3), who received several vaccines, but not Td, was studied to verify the hypothesis of the polyclonal B-cell activation as mechanism for antibody persistence. The antibody response to Td toxoids was higher in group-1, who showed lower baseline antibody levels, than in group-2 subjects. The antibody response to tetanus was higher than to diphtheria toxoid in both groups. No correlation between antibody and cellular response, and no interference in the response to Td by co-administration of different vaccines were observed. HLA-DRB1∗01 allele was detected at significant higher frequency in subjects unable to double the baseline anti-diphtheria antibody levels after the vaccination. Anti-tetanus and diphtheria antibodies half-lives were assessed and the long-lasting persistence above the threshold for protection (0.1 IU/ml) was estimated in over 65 and 20 years, respectively. No significant increase of anti-diphtheria antibodies was observed in consequence of polyclonal B-cell activation. This study emphasizes the duration of Td vaccination-induced seroprotection, suggesting that re-vaccination should probably be performed at intervals longer than 10 years. No reciprocal interference by concomitantly administered vaccines has been observed. HLA-DRB1∗01 allele was significantly associated with anti-diphtheria defective response. Finally, this study does not confirm that anti-diphtheria antibody levels are maintained by polyclonal B-cell activation. Clinical trial registry: The study was registered with NCT01807780.

Analysis of Gut Microbiota in Rheumatoid Arthritis Patients: Disease-Related Dysbiosis and Modifications Induced by Etanercept.

A certain number of studies were carried out to address the question of how dysbiosis could affect the onset and development of rheumatoid arthritis (RA), but little is known about the reciprocal influence between microbiota composition and immunosuppressive drugs, and how this interaction may have an impact on the clinical outcome. The aim of this study was to characterize the intestinal microbiota in a groups of RA patients treatment-naïve, under methotrexate, and/or etanercept (ETN). Correlations between the gut microbiota composition and validated immunological and clinical parameters of disease activity were also evaluated. In the current study, a 16S analysis was employed to explore the gut microbiota of 42 patients affected by RA and 10 healthy controls. Disease activity score on 28 joints (DAS-28), erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, anti-cyclic citrullinated peptides, and dietary and smoking habits were assessed. The composition of the gut microbiota in RA patients free of therapy is characterized by several abnormalities compared to healthy controls. Gut dysbiosis in RA patients is associated with different serological and clinical parameters; in particular, the phylum of Euryarchaeota was directly correlated to DAS and emerged as an independent risk factor. Patients under treatment with ETN present a partial restoration of a beneficial microbiota. The results of our study confirm that gut dysbiosis is a hallmark of the disease, and shows, for the first time, that the anti-tumor necrosis factor alpha (TNF-α) ETN is able to modify microbial communities, at least partially restoring a beneficial microbiota.

Anti-polysaccharide and anti-diphtheria protective antibodies after 13-valent pneumococcal conjugate vaccination in rheumatoid arthritis patients under immunosuppressive therapy.

Immunogenicity of 13-valent pneumococcal polysaccharide (PnPS) conjugate vaccine (PCV13) was evaluated in 38 rheumatoid arthritis patients under immunosuppressive treatment and 20 healthy controls (HC). Antibodies to all PnPS and diphtheria-toxin analogue conjugate protein were measured pre- (T0), 1 (T1), 6 (T2), 12 (T3) months post-immunization. Patients and HC had similar response to individual PnPS. Mean antibody levels to all PnPS but one doubled at T1 compared with T0, with T3 persistence for only 8-7/13 PnPS. Baseline antibody levels was inversely associated with the rate of responders at T1 (T1/T0≥2) to 11/13 PnPS. Few subjects reached protective IgG levels against some serotypes frequently isolated in Italian patients with invasive pneumococcal disease. Antibody response was not influenced by therapy, except the one to PS7F, which was reduced by tumor necrosis factor-α-inhibitors. Vaccination increased also anti-diphtheria IgG. Despite this study substantially confirmed the PCV13 immunogenicity in immunocompromised patients, it also revealed some limitations.

Lack of evidence for post-vaccine onset of autoimmune/lymphoproliferative disorders, during a nine-month follow-up in multiply vaccinated Italian military personnel.

Anecdotal case reports, amplified by mass media and internet-based opinion groups, have recently indicated vaccinations as possibly responsible for autoimmunity/lymphoproliferation development. Multiply vaccinated Italian military personnel (group 1, operating in Italy, group 2, operating in Lebanon) were followed-up for nine months to monitor possible post-vaccine autoimmunity/lymphoproliferation onset. No serious adverse event was noticed in both groups. Multivariate analysis of intergroup differences only showed a significant association between lymphocyte increase and tetanus/diphtheria vaccine administration. A significant post-vaccine decrease in autoantibody positivity was observed. Autoantibodies were also studied by microarray analysis of self-proteins in subjects exposed to ≥4 concurrent vaccinations, without observing significant difference among baseline and one and nine months post-vaccine. Moreover, HLA-A2 subjects have been analyzed for the possible CD8T-cell response to apoptotic self-epitopes, without observing significant difference between baseline and one month post-vaccine. Multiple vaccinations in young adults are safe and not associated to autoimmunity/lymphoproliferation onset during a nine-month-long follow-up.

TCD4pos lymphocytosis in rheumatoid and psoriatic arthritis patients following TNFα blocking agents.

BACKGROUND: Lymphocyte expansion and true lymphocytosis are commonly observed in the everyday clinical practice. The meaning of such phenomenon is often poorly understood so that discrimination between benign and malignant lymphocytosis remains difficult to establish. This is mainly true when lymphocytosis rises in patients affected by immune-mediated chronic inflammatory diseases under immunosuppressive treatment, conditions potentially associated with lymphomagenesis. In this brief report the development of mild T CD4pos lymphocytosis in a group of patients with chronic arthritis under anti-TNF-α treatment is described. METHODS: Two hundred eight rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients have been evaluated longitudinally for at least 1-year before and 2-years after anti-TNF-α therapy introduction for the possible appearance of a lymphocyte expansion. In patients who developed lymphocyte expansion, T, B and NK cells were analysed. RESULTS: Twenty-five out of 208 (12%) subjects developed a mild T CD4pos lymphocytosis, during anti-TNF-α therapy, which reverted after its interruption. Higher lymphocyte count, more frequent use of steroids and shorter disease duration, before biological therapy start, have emerged as risk factors for lymphocytosis development. CONCLUSIONS: This is the first longitudinal cohort study evaluating the onset of lymphocytosis in RA and PsA patients under anti-TNF-α treatment and its possible clinical relevance. A mild T CD4pos lymphocytosis has been observed in 12% of RA and PsA patients probably related to anti-TNF-α treatment as previously reported by anecdotal cases. Patients with higher baseline lymphocyte count, use of steroids and shorter disease duration before the introduction of biologic therapy, seem to be prone to develop this laboratory reversible abnormality.

Anti-Infectious Human Vaccination in Historical Perspective.

A brief history of vaccination is presented since the Jenner's observation, through the first golden age of vaccinology (from Pasteur's era to 1938), the second golden age (from 1940 to 1970), until the current period. In the first golden age, live, such as Bacille Calmette Guérin (BCG), and yellow fever, inactivated, such as typhoid, cholera, plague, and influenza, and subunit vaccines, such as tetanus and diphtheria toxoids, have been developed. In the second golden age, the cell culture technology enabled polio, measles, mumps, and rubella vaccines be developed. In the era of modern vaccines, in addition to the conjugate polysaccharide, hepatitis A, oral typhoid, and varicella vaccines, the advent of molecular biology enabled to develop hepatitis B, acellular pertussis, papillomavirus, and rotavirus recombinant vaccines. Great successes have been achieved in the fight against infectious diseases, including the smallpox global eradication, the nearly disappearance of polio, the control of tetanus, diphtheria, measles, rubella, yellow fever, and rabies. However, much work should still be done for improving old vaccines, such as BCG, anthrax, smallpox, plague, or for developing effective vaccines against old or emerging infectious threats, such as human-immunodeficiency-virus, malaria, hepatitis C, dengue, respiratory-syncytial-virus, cytomegalovirus, multiresistant bacteria, Clostridium difficile, Ebola virus. In addition to search for innovative and effective vaccines and global infant coverage, even risk categories should adequately be protected. Despite patients under immunosuppressive therapy are globally increasing, their vaccine coverage is lower than recommended, even in developed and affluent countries.