Management of psoriatic arthritis: a consensus opinion by expert rheumatologists.

Background: Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease involving several articular and extra-articular structures. Despite the important progresses recently made in all of the aspects of this disease, its management is still burdened by unresolved issues. The aim of this exercise was to provide a set of statements that may be helpful for the management of PsA. Methods: A group of 38 Italian rheumatologists with recognized expertise in PsA selected and addressed the following four topics: "early PsA," "axial-PsA," "extra-articular manifestations and comorbidities," "therapeutic goals." Relevant articles from the literature (2016-2022) were selected by the experts based on a PubMed search. A number of statements for each topic were elaborated. Results: Ninety-four articles were selected and evaluated, 68 out of the 1,114 yielded by the literature search and 26 added by the Authors. Each of the four topic was subdivided in themes as follows: transition from psoriasis to PsA, imaging vs. CASPAR criteria in early diagnosis, early treatment for "early PsA"; axial-PsA vs. axialspondyloarthritis, diagnosis, clinical evaluation, treatment, standard radiography vs. magnetic resonance imaging for "axial PsA"; influence of inflammatory bowel disease on the therapeutic choice, cardiovascular comorbidity, bone damage, risk of infection for "comorbidities and extra-articular manifestations"; target and tools, treat-to-target strategy, role of imaging for "therapeutic goals." The final document consisted of 49 statements. Discussion: The final product of this exercise is a set of statements concerning the main issues of PsA management offering an expert opinion for some unmet needs of this complex disease.

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.

Humoral and cellular responses to spike of δ SARS-CoV-2 variant in vaccinated patients with immune-mediated inflammatory diseases.

OBJECTIVES: We assessed vaccination-induced antibody and cellular responses against spike from the ancestral strain and from the delta (δ) SARS-CoV-2 variant in patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive therapy in comparison with immunocompetent subjects. METHODS: We enrolled patients with IMID and immunocompetent subjects who completed the vaccination schedule within 4-6 months from the first dose. The interferon (IFN)-γ-response to spike peptides that were derived from the ancestral and the δ SARS-CoV-2 were measured by ELISA. Anti-Receptor Binding Domain IgG antibodies were also evaluated. RESULTS: We enrolled 43 patients with IMID and nine immunocompetent subjects. No significant differences were found after comparing the specific immune response (IFN-γ) between patients with IMID and immunocompetent subjects to the ancestral (p = 0.36) or δ peptide pool (p = 0.51). Nevertheless, IFN-γ-specific responses to the ancestral or to the δ pools were reduced in subjects taking CTLA4-IgG or TNF-α inhibitors compared with subjects treated with IL-6 inhibitors or Disease Modifying Anti-Rheumatic Drugs. Regarding the antibody response, no significant differences were observed between patients with IMID and immunocompetent individuals. CONCLUSIONS: Cellular responses to δ SARS-CoV-2 variant remain largely intact in patients with IMID. However, the magnitude of these responses is dependent on the specific IMID immunosuppressive regimen. Serological response was also similar between the IMID and control groups.

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.

Uptake pattern of [68Ga]Ga-DOTA-NOC in tissues: implications for inflammatory diseases.

BACKGROUND: [68Ga]Ga-DOTA-NOC binds to somatostatin receptor (SSTR) subtypes 2 and 5, also expressed on lymphocytes and macrophages, but no information is available about uptake in tissues that might be affected by a chronic inflammatory process. Our aim was to obtain normal reference values for: [68Ga]Ga-DOTA-NOC uptake in tissues prone to chronic inflammation. METHODS: Retrospective study in 81 patients who performed the scan for a suspicion of neuroendocrine tumor (NET). We analyzed major joints, salivary glands, thyroid, aortic wall from images acquired after injection of 173.9±1 Mbq of: [68Ga]Ga-DOTA-NOC. We calculated the SUVmax and SUVtarget/SUVgluteus ratio or SUVtarget/SUVaorta ratio. Data are reported as mean±2 or ±3 standard deviations (SD). RESULTS: SUVmax values appeared more reliable than other ratios. In thyroid we found a mean SUVmax of 1.36±0.45, with no values >3SD; in parotid glands 0.98±0.40, with 2 values >3SD; in submandibular glands 0.99±0.37, with 2 values >3SD; in aortic arch 1.71±0.50, with 1 value >3SD; in thoracic aorta 2.03±0.52, with 1 value >3SD; in abdominal aorta 2.19±0.49, with no value >3SD; in shoulders 0.92±0.31 and in hips 0.87±0.34, with 2 and 4 values >3SD, respectively. These 12 values with SUVmax >3SD, belong to 5 patients, 3 of which had signs of xerostomia and/or arthritis. A statistically significant correlation was observed between SUVmax and age in all examined tissues but in the aorta. CONCLUSIONS: Tissues in which lymphocytic infiltration may occur show that SUVmax is tissue-dependent. Within tissue variability, an SUVmax greater than the mean +3SD is rarely found amongst patients without a symptomatic chronic inflammatory process but, when found, may highlight a chronic inflammatory condition.

Duration of clinical remission and low disease activity impacts on quality of life and its domains in psoriatic arthritis patients: results from an Italian multicentre study.

OBJECTIVES: Long-term quality of life (QoL) is significantly compromised in patients with psoriatic arthritis (PsA) and only partially improves achieving remission or low disease activity. The main aim of this study is to evaluate the QoL in PsA patients and to investigate their possible relationship with clinical remission and low disease activity, and with its duration over time. METHODS: A multicentre cross-sectional observational study has been performed. QoL domains considered were analysed through PROs. Chi2 test was used for analysis of contingency tables, while Mann-Whitney test and Kruskal-Wallis test with Holm's pairwise comparison corrections were used to compare ranks. To evaluate variables associated to the different QoL domains, univariate and multiple linear regressions were used. RESULTS: 143 participants were included in this study. The physical component of the Short Form-36 or Functional Assessment of Chronic Illness Therapy-Fatigue tends to improve with short duration of low or minimal disease activity. However, this is not confirmed for the mental component of SF-36 (MCS), which improved only with longer duration of low/minimal disease activity. CONCLUSIONS: This study proves the existence of an inverse relation between disease activity and QoL domains. Apart from low or minimal disease activity, also its persistence over time has a great influence on the patient's perception of their clinical condition; therefore, persistence over time of clinical remission/low disease activity should be added to the latest definition of treat-to-target in PsA.

Severe Acute Respiratory Syndrome Coronavirus-2 Infection and Autoimmunity 1 Year Later: The Era of Vaccines.

Impressive efforts have been made by researchers worldwide in the development of target vaccines against the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and in improving the management of immunomodulating agents. Currently, different vaccine formulations, such as viral vector, mRNA, and protein-based, almost all directed toward the spike protein that includes the domain for receptor binding, have been approved. Although data are not conclusive, patients affected by autoimmune rheumatic diseases (ARDs) seem to have a slightly higher disease prevalence, risk of hospitalization, and death from coronavirus disease-2019 (COVID-19) than the general population. Therefore, ARD patients, under immunosuppressive agents, have been included among the priority target groups for vaccine administration. However, specific cautions are needed to optimize vaccine safety and effectiveness in these patients, such as modification in some of the ongoing immunosuppressive therapies and the preferential use of mRNA other than vector-based vaccines. Immunomodulating agents can be a therapeutic opportunity for the management of COVID-19 patients; however, their clinical impact depends on how they are handled. To place in therapy immunomodulating agents in the correct window of opportunity throughout the identification of surrogate markers of disease progression and host immune response is mandatory to optimize patient's outcome.

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.

Anti-COVID-19 Vaccination in Patients with Autoimmune-Autoinflammatory Disorders and Primary/Secondary Immunodeficiencies: The Position of the Task Force on Behalf of the Italian Immunological Societies.

The Coronavirus disease 2019 (COVID-19) pandemic has represented an unprecedented challenge for humankind from health, economic, and social viewpoints. In February 2020, Italy was the first western country to be deeply hit by the pandemic and suffered the highest case/fatality rate among western countries. Brand new anti-COVID-19 vaccines have been developed and made available in <1-year from the viral sequence publication. Patients with compromised immune systems, such as autoimmune-autoinflammatory disorders (AIAIDs), primary (PIDs) and secondary (SIDs) immunodeficiencies, have received careful attention for a long time regarding their capacity to safely respond to traditional vaccines. The Italian Immunological Societies, therefore, have promptly faced the issues of safety, immunogenicity, and efficacy/effectiveness of the innovative COVID-19 vaccines, as well as priority to vaccine access, in patients with AIADs, PIDs, and SIDs, by organizing an ad-hoc Task Force. Patients with AIADs, PIDs, and SIDs: (1) Do not present contraindications to COVID-19 vaccines if a mRNA vaccine is used and administered in a stabilized disease phase without active infection. (2) Should usually not discontinue immunosuppressive therapy, which may be modulated depending on the patient's clinical condition. (3) When eligible, should have a priority access to vaccination. In fact, immunizing these patients may have relevant social/health consequences, since these patients, if infected, may develop chronic infection, which prolongs viral spread and facilitates the emergence of viral variants.

Hepatitis B (HBV) reactivation in patients receiving biologic therapy for chronic inflammatory diseases in clinical practice.

INTRODUCTION AND AIM: Biologic treatment - particularly with the anti-TNF molecules - is frequently used in clinical practice to treat the severe form for both chronic rheumatic diseases and inflammatory bowel diseases. The immunosuppression induced by biologic therapies increases the risk of infections, including tuberculosis, as well as hepatitis B virus (HBV) reactivation may occur in inactive carriers or occult HBV infection (OBI) subjects during biologic therapy. This study aimed to update data on HBV prevalence and reactivation in patients receiving biologic therapy for either chronic rheumatic diseases or IBD, and to describe their management in clinical practice. MATERIALS AND METHODS: This study was performed in 6 Italian centers (3 Rheumatology Units and 3 Gastroenterology Units). Clinical, biochemical and virological data, as well as follow up information, were recorded and analyzed. RESULTS: 984 patients were considered, including 817 with rheumatic disease and 167 with IBD. A total of 43 showed HBV infection (38 OBI and 5 carriers) accounting for a prevalence of 4%. Among OBI patients, 1 (2.6%) case of HBV reactivation occurred in a male patient with Crohn disease. Among the 5 HBV carriers, two patients (1 with spondyloarthritis and 1 with rheumatoid arthritis) did not received HBV antiviral therapy, and both experienced flare of hepatitis at 47 and 49 months following biologic therapy starting. DISCUSSION: Data of our study highlight that guidelines on management of HBV patients treated with biologic therapies should be still implemented in clinical practice when considering that, although infrequent, HBV reactivation could be potentially life-threatening.

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.

Inhibition of Phosphodiesterase-4 in Psoriatic Arthritis and Inflammatory Bowel Diseases.

Phosphodiesterases (PDEs) are a heterogeneous superfamily of enzymes which catalyze the degradation of the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Among PDEs, PDE4 is the most widely studied and characterized isoenzyme. PDE4 blocking can lead to increased levels of intracellular cAMP, which results in down-regulation of inflammatory responses by reducing the expression of tumor necrosis factor (TNF), interleukin (IL)-23, IL-17, interferon-γ, while increasing regulatory cytokines, such as IL-10. Therefore, PDE4 has been explored as a therapeutic target for the treatment of different chronic inflammatory conditions such as psoriatic arthritis (PsA) and inflammatory bowel disease (IBD). PsA shares clinical, genetic, and pathogenic features with IBD such as ulcerative colitis (UC) and Crohn's disease (CD), and enteropathic spondyloarthritis (eSpA) represent a frequent clinical evidence of the overlap between gut and joint diseases. Current therapeutic options in PsA patients and underlying UC are limited to synthetic immunosuppressants and anti-TNF. Apremilast is an oral PDE4 inhibitor approved for the treatment of active PsA patients with inadequate response to synthetic immunosuppressants. The efficacy and a good safety profile observed in randomized clinical trials with apremilast in PsA patients have been confirmed by few studies in a real-life scenario. In addition, apremilast led to significant improvement in clinical and endoscopic features in UC patients in a phase II RCT. By now there are no available data regarding its role in eSpA patients. In view of the above, the use of apremilast in eSpA patients is a route that deserves to be deepened.

Vitamin D Signaling in Gastro-Rheumatology: From Immuno-Modulation to Potential Clinical Applications.

In the last decades, the comprehension of the pathophysiology of bone metabolism and its interconnections with multiple homeostatic processes has been consistently expanded. The branch of osteoimmunology specifically investigating the link between bone and immune system has been developed. Among molecular mediators potentially relevant in this field, vitamin D has been recently pointed out, and abnormalities of the vitamin D axis have been described in both in vitro and in vivo models of inflammatory bowel diseases (IBD) and arthritis. Furthermore, vitamin D deficiency has been reported in patients affected by IBD and chronic inflammatory arthritis, thus suggesting the intriguing possibility of impacting the disease activity by the administration vitamin D supplements. In the present review, the complex interwoven link between vitamin D signaling, gut barrier integrity, microbiota composition, and the immune system was examined. Potential clinical application exploiting vitamin D pathway in the context of IBD and arthritis is presented and critically discussed. A more detailed comprehension of the vitamin D effects and interactions at molecular level would allow one to achieve a novel therapeutic approach in gastro-rheumatologic inflammatory diseases through the design of specific trials and the optimization of treatment protocols.

Facial Transplantation: Nonimmune-Related Hyperacute Graft Failure-The Role of Perfusion Injury: A Case Report.

BACKGROUND: The aim of this study was to report the first case of acute facial allograft transplantation (facial allograft transplantation) failure with allograft removal and autologous free-flap reconstruction. METHODS: A 49-year-old female patient affected by neurofibromatosis type 1 with a massive neurofibroma infiltrating the whole left hemiface was planned for FAT for the left hemiface including the auricle, all skin and soft tissues from the temporal region, periorbital and nasal region, and up to the perioral area. The maxillary process of the zygomatic bone, left hemimaxilla, and hemimandible from contralateral parasyphysis to the incisura mandibulae were also included. RESULTS: Total surgical time was 26 hours. There were 2 intraoperative arterial thromboses that were solved with new anastomoses and sufficient flap perfusion. On postoperative day 2, the allograft became pale with suspected arterial occlusion and the patient returned to the operative room for exploration no flow into the FAT was found. The allograft was removed and the recipient site reconstructed with a skin-grafted composite left latissimus dorsi-serratus anterior flap. CONCLUSIONS: Hyperacute loss of FAT is a very dramatic event, and the activation of a backup surgical plan is crucial to save patient's life, give a reasonable temporary reconstruction, and return on the waiting-list for a second face transplantation.

Multicenter Validation of the DETAIL Questionnaire for the Screening of Spondyloarthritis in Patients With Inflammatory Bowel Diseases.

OBJECTIVE: Spondyloarthritis (SpA) is among the most frequent extraintestinal manifestations of inflammatory bowel diseases (IBD). In this study, we aimed to validate the DETection of Arthritis in Inflammatory boweL diseases (DETAIL) questionnaire in a multicenter cohort of patients with IBD enrolled at 11 gastroenterology units. METHODS: From October 2018 to March 2019, consecutive adult patients with IBD, either Crohn disease or ulcerative colitis, independently filled out the DETAIL questionnaire in the outpatient waiting room. Within 2 weeks a blinded rheumatologist assessed all the patients, irrespective of the DETAIL results, and classified them to be affected or not by SpA. The performance of the questions was evaluated through Bayesian analysis. RESULTS: Overall, 418 patients with IBD filled out the DETAIL questionnaire. Upon rheumatological evaluation, 102 (24.4%) patients received a diagnosis of SpA. Of the 6 questions, the best performances were found in question 6 [positive likelihood ratio (LR)+ 3.77], reporting inflammatory back pain at night, and in question 3 (LR+ 3.31), exploring Achilles enthesitis. The presence of back pain lasting > 3 months (LR+ 2.91), back pain with inflammatory features (LR+ 2.55), and a history of dactylitis (LR+ 2.55), also showed a fairly good performance, whereas a history of peripheral synovitis was slightly worse (LR+ 2.16). The combination of at least 3 questions answered affirmatively yielded a posttest probability of SpA of 80% or more. The presence of alternative diagnoses, such as osteoarthritis or fibromyalgia, represented a minor confounder. CONCLUSION: The DETAIL questionnaire is a useful tool for the early detection of SpA in IBD.

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.