Martina Bonacini

Azienda Sanitaria Unità Locale di Reggio Emilia

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Stefania Croci

Azienda Sanitaria Unità Locale di Reggio Emilia

Francesco Muratore

University of Modena and Reggio Emilia

Alessandro Zerbini

Istituti di Ricovero e Cura a Carattere Scientifico

Carlo Salvarani

Azienda Sanitaria Unità Locale di Reggio Emilia

Carlo Salvarani

Azienda Sanitaria Unità Locale di Reggio Emilia

Luca Cimino

University of Modena and Reggio Emilia

Luigi Boiardi

Azienda Sanitaria Unità Locale di Reggio Emilia

Alessandra Bisagni

Azienda Sanitaria Unità Locale di Reggio Emilia

Alessandra Soriano

Azienda Sanitaria Unità Locale di Reggio Emilia

Alberto Cavazza

Azienda Sanitaria Unità Locale di Reggio Emilia

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Istituti di Ricovero e Cura a Carattere Scientifico

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Azienda Sanitaria Unità Locale di Reggio Emilia

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Ospedale Santa Maria

University of Modena and Reggio Emilia

University of Parma

Azienda Ospedaliera S.Maria

Santa Maria Nuova Hospital

University of Bologna

Tecnologie Avanzate (Italy)

University of Milan

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OP0233 CAN TOCILIZUMAB TURN OFF INFLAMMATION IN GIANT CELL ARTERITIS?

Annals of the Rheumatic Diseases (2024)

Camillo Ricordi Chiara Marvisi Pierluigi Macchioni Luigi Boiardi Alberto Cavazza

Background:

Temporal artery biopsy (TAB) nowadays is still the gold-standard for the diagnosis of giant cell arteritis (GCA). Different patterns of vessels' wall inflammation have been described and media inflammation seems to persist in some patients in clinical remission notwithstanding long-term glucocorticoids (GCs) therapy[1]. Tocilizumab (TCZ) is the most efficacious steroid-sparing agent used in both relapsing and new-onset GCA, but the optimal treatment duration remains unknown. In clinical practice, evaluation of disease activity with TCZ treatment is partially invalidated by the fact that inflammatory markers, particularly C-reactive protein (CRP), are affected by the biologic activity of the drug itself and commonly test negative.

Objectives:

To assess the residual degree of vessel inflammation in GCA patients treated with TCZ, in addition to GCs, by mean of repeating histological evaluation of the temporal artery and large vessel imaging, along with the clinical evaluation.

Methods:

We performed a second biopsy in a single cohort of GCA patients treated with GCs and TCZ, who were followed prospectively between December 2017 and December 2022. At baseline TAB and positron emission tomography/computed tomography (PET/CT) were performed in all patients. All patients were started on GCs and TCZ was added on physician's discretion. The second biopsies were performed by the same vascular surgeon in the contralateral temporal artery with respect to the already biopsied one after a minimum TCZ treatment duration of 6 months. PET/CT scans were also repeated at the time of the second biopsy. All the histological samples were reviewed by a single pathologist and classified into 4 patterns: transmural inflammation (TMI), inflammation limited to adventitia (ILA), vasa vasorum vasculitis (VVV), and small vessel vasculitis (SVV). PET/CT showing vascular fluorodeoxyglucose (FDG) uptake ≥2 according to the Meller scale in at least one vascular district was considered consistent with active vasculitis. Clinical active disease was defined as one or more of the following: recurrence of signs or symptoms of GCA or polymyalgia rheumatica; CRP >10 mg/L, or erythrocyte sedimentation rate (ESR) > 40 mm/h if these were considered by the investigator to be due to GCA; the necessity for introduction or increase in GCs dose.

Results:

13 GCA biopsy-positive patients were included. Baseline clinical features are reported in Table 1. The histopathological patterns at first and second biopsies are shown in Figure 1. 9/13 (69.2%) patients showed active large vessel vasculitis (LVV) at baseline. TCZ was introduced from disease onset in 3/13 (23.1%) patients, and in 10/13 (76.9%) at relapse. At second biopsy, the median (IQR) disease duration was 3.7 (2.2-4.3) years. The median (IQR) treatment with TCZ was 2.4 (1.2-3.9) years, and 10/13 (76.9%) patients were still on low doses of GCs. A total of 5/13 (38.5%) TABs still presented an inflammatory infiltrate at the second biopsy. 4/9 (44.4%) with TMI at first biopsy still had some form of inflammation at second biopsy: 2 (22.2%) ILA, 1 (11.1%) VVV, and 1 (11.1%) persistent TMI. 1/3 (66.7%) patient with ILA at first biopsy presented SVV at second one. PET/CT was repeated in 9/13 (69.2%) patients; 1/9 (11.1%) was consistent with active LVV. 3/13 (23.1%) patients were considered clinically active at second TAB: of those only the patient with persistent TMI, also showed an active PET/CT.

Conclusion:

Our data suggest that despite treatment with TCZ some inflammation may persist at TAB. The clinical relevance of inflammatory infiltrates other than TMI is still debated, however they might indicate different stages of the disease course. Further molecular studies and larger cohort studies may clarify the clinical significance of our observation.

REFERENCES:

[1] Cavazza A, et al. Am J Surg Pathol. 2014 Oct;38:1360-70.

Acknowledgements:

NIL.

Disclosure of Interests:

None declared.

Tocilizumab

10.1136/annrheumdis-2024-eular.3786

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What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 2: Clinic–Pathologic Correlations

Cells (2021)

Andrea Palicelli Martina Bonacini Stefania Croci Cristina Magi‐Galluzzi Sofía Cañete‐Portillo

Many studies have investigated the potential prognostic and predictive role of PD-L1 in prostatic carcinoma (PC). We performed a systematic literature review (PRISMA guidelines) to critically evaluate human tissue-based studies (immunohistochemistry, molecular analysis, etc.), experimental research (cell lines, mouse models), and clinical trials. Despite some controversial results and study limitations, PD-L1 expression by tumor cells may be related to clinic-pathologic features of adverse outcome, including advanced tumor stage (high pT, presence of lymph node, and distant metastases), positivity of surgical margins, high Grade Group, and castration resistance. Different PD-L1 positivity rates may be observed in matched primary PCs and various metastatic sites of the same patients. Over-fixation, type/duration of decalcification, and PD-L1 antibody clone may influence the immunohistochemical analysis of PD-L1 on bone metastases. PD-L1 seemed expressed more frequently by castration-resistant PCs (49%) as compared to hormone-sensitive PCs (17%). Some series found that PD-L1 positivity was associated with decreased time to castration resistance. Treatment with ipilimumab, cyclophosphamide/GVAX/degarelix, or degarelix alone may increase PD-L1 expression. Correlation of PD-L1 positivity with overall survival and outcomes related to tumor recurrence were rarely investigated; the few analyzed series produced conflicting results and sometimes showed limitations. Further studies are required. The testing and scoring of PD-L1 should be standardized.

10.3390/cells10113165

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THU0457 Interleukin-6 expression in inflamed and non-inflamed temporal arteries from patients with giant cell arteritis

Annals of the Rheumatic Diseases (2018)

Nicolò Pipitone Francesco Muratore Ione Tamagnini Alberto Cavazza Luca Cimino

Objectives

To evaluate if interleukin-6 (IL-6) expression in the temporal artery biopsy (TAB) specimens may differentiate patients with giant cell arteritis (GCA) from those without.

Methods

63 consecutive formalin-fixed, paraffin-embedded (FFPE) TABs performed between 2009 and 2012 from 32 patients with transmural biopsy-proven GCA, 8 patients with biopsy-negative GCA and 23 controls were retrieved. Demographic, clinical, and laboratory data at presentation and at each follow-up visit were collected. A pathologist reviewed all TABs. Immunohistochemistry was performed on 4 µm FFPE tissue sections with a 1:400 dilution of rabbit polyclonal anti-human IL-6 antibody (NOVUS Biologicals Littleton, Co.) for 60' at 37°. Slides of TAB specimens were independently assessed by five readers. IL-6 expression was graded as 0 (absent), 1 (mild), 2 (moderate) and 3 (marked). Inter-reader differences were resolved by consensus. Anti-IL6 staining was considered positive if staining was grade 2 or 3, since grade 1 was faint, sometimes difficult to differentiate from background, and showed the least degree of agreement between readers.

Results

TAB specimens from patients with biopsy-proven GCA, biopsy-negative GCA and controls were positive for anti-IL-6 staining in 59%, 13% and 48% of cases, respectively, the difference between biopsy-proven and biopsy-negative GCA patients being significant (p=0.04). In non-inflamed TABs, IL-6 was mainly expressed by mesenchymal cells in media and intima layers, while in inflamed TABs IL-6 was mainly expressed by mononuclear inflammatory infiltrating cells. IL-6 grade 2–3 expression was observed in all 6 patients with visual loss compared to 25 (43.9%) of 57 patients without (p=0.011). Blindness was recorded in 2 patients with biopsy-proven GCA and 4 controls (all with a final diagnosis of non-arteritic ischaemic optic neuropathy). No associations were found between IL-6 expression and demographic characteristics, GCA signs/symptoms, laboratory and histopathological TAB findings. However, there was a statistical trend (p=0.055) of increased frequency of the halo sign at temporal artery CDS in patients with IL-6 expression grade 2–3 compared to those with IL-6 expression grade 0–1. No significant differences for the expression of IL-6 were observed between patients with and without PMR (5/8%–62.5% - versus 6/15%–40% -, p=0.400) and between patients with isolated PMR and those with TAB positive GCA (62.5% vs 59%, p=1.000).

Conclusions

Our study provides evidence that IL-6 expression does not increase the sensitivity of TAB in patients with morphologically uninflamed arteries. A search for further markers that may increase the sensitivity of TAB is warranted.

Disclosure of Interest

None declared

Arteritis

10.1136/annrheumdis-2018-eular.6729

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What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 7: PD-L1 Expression in Liquid Biopsy

Journal of Personalized Medicine (2021)

Andrea Palicelli Martina Bonacini Stefania Croci Alessandra Bisagni Eleonora Zanetti

Liquid biopsy is an accessible, non-invasive diagnostic tool for advanced prostate cancer (PC) patients, potentially representing a real-time monitoring test for tumor evolution and response to treatment through the analysis of circulating tumor cells (CTCs) and exosomes. We performed a systematic literature review (PRISMA guidelines) to describe the current knowledge about PD-L1 expression in liquid biopsies of PC patients: 101/159 (64%) cases revealed a variable number of PD-L1+ CTCs. Outcome correlations should be investigated in larger series. Nuclear PD-L1 expression by CTCs was occasionally associated with worse prognosis. Treatment (abiraterone, enzalutamide, radiotherapy, checkpoint-inhibitors) influenced PD-L1+ CTC levels. Discordance in PD-L1 status was detected between primary vs. metastatic PC tissue biopsies and CTCs vs. corresponding tumor tissues. PD-L1 is also released by PC cells through soluble exosomes, which could inhibit the T cell function, causing immune evasion. PD-L1+ PC-CTC monitoring and genomic profiling may better characterize the ongoing aggressive PC forms compared to PD-L1 evaluation on primary tumor biopsies/prostatectomy specimens (sometimes sampled a long time before recurrence/progression). Myeloid-derived suppressor cells and dendritic cells (DCs), which may have immune-suppressive effects in tumor microenvironment, have been found in PC patients circulation, sometimes expressing PD-L1. Occasionally, their levels correlated to clinical outcome. Enzalutamide-progressing castration-resistant PC patients revealed increased PD-1+ T cells and circulating PD-L1/2+ DCs.

Liquid biopsy

Enzalutamide

Circulating tumor cell

10.3390/jpm11121312

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What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment

International Journal of Molecular Sciences (2021)

Andrea Palicelli Stefania Croci Alessandra Bisagni Eleonora Zanetti Dario de Biase

The tumor microenvironment (TME) includes immune (T, B, NK, dendritic), stromal, mesenchymal, endothelial, adipocytic cells, extracellular matrix, and cytokines/chemokines/soluble factors regulating various intracellular signaling pathways (ISP) in tumor cells. TME influences the survival/progression of prostate cancer (PC), enabling tumor cell immune-evasion also through the activation of the PD-1/PD-L1 axis. We have performed a systematic literature review according to the PRISMA guidelines, to investigate how the PD-1/PD-L1 pathway is influenced by TME and ISPs. Tumor immune-escape mechanisms include suppression/exhaustion of tumor infiltrating cytotoxic T lymphocytes, inhibition of tumor suppressive NK cells, increase in immune-suppressive immune cells (regulatory T, M2 macrophagic, myeloid-derived suppressor, dendritic, stromal, and adipocytic cells). IFN-γ (the most investigated factor), TGF-β, TNF-α, IL-6, IL-17, IL-15, IL-27, complement factor C5a, and other soluble molecules secreted by TME components (and sometimes increased in patients' serum), as well as and hypoxia, influenced the regulation of PD-L1. Experimental studies using human and mouse PC cell lines (derived from either androgen-sensitive or androgen-resistant tumors) revealed that the intracellular ERK/MEK, Akt-mTOR, NF-kB, WNT and JAK/STAT pathways were involved in PD-L1 upregulation in PC. Blocking the PD-1/PD-L1 signaling by using immunotherapy drugs can prevent tumor immune-escape, increasing the anti-tumor activity of immune cells.

10.3390/ijms222212330

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Aqueous Humor Analysis in Overlapping Clinical Diagnosis of Cytomegalovirus and Rubella Virus Anterior Uveitis

Medicina (2022)

Fabrizio Gozzi L Belloni Raffaella Aldigeri Pietro Gentile Valentina Mastrofilippo

Background and Objectives: A cross-sectional single-center study was conducted to investigate the etiology in hypertensive anterior uveitis whose clinical features are not fully distinctive from cytomegalovirus or from rubella virus and to demonstrate the possible coexistence of both these viruses in causing anterior uveitis. Materials and Methods: The clinical charts of a cohort of patients with hypertensive viral anterior uveitis of uncertain origin consecutively seen in a single center from 2019 to 2022 were retrospectively reviewed; data on the clinical features, aqueous polymerase chain reaction, and antibody response to cytomegalovirus and rubella virus were collected. Results: Forty-three eyes of as many subjects with viral anterior uveitis of uncertain origin were included. Thirty-two patients had an aqueous polymerase chain reaction or antibody index positive to cytomegalovirus only, while 11 cases had an aqueous antibody response to both cytomegalovirus and rubella virus. This latter overlapping group had a statistically significant higher rate of hypochromia and anterior vitritis (p-value: 0.02 and < 0.001, respectively). Conclusions: The simultaneous presence of intraocular antibodies against cytomegalovirus and rubella virus could redefine the differential diagnosis of hypertensive viral anterior uveitis, demonstrating a possible “converged” immune pathway consisting in a variety of stimuli.

Cytomegalovirus

Rubella virus

Cytomegalovirus retinitis

10.3390/medicina58081054

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Role of PD-L1 in licensing immunoregulatory function of dental pulp mesenchymal stem cells

Stem Cell Research & Therapy (2021)

Rosanna Di Tinco Giulia Bertani Alessandra Pisciotta Laura Bertoni Elisa Pignatti

Abstract Background Dental pulp stem cells (DPSCs) are low immunogenic and hold immunomodulatory properties that, along with their well-established multi-potency, might enhance their potential application in autoimmune and inflammatory diseases. The present study focused on the ability of DPSCs to modulate the inflammatory microenvironment through PD1/PD-L1 pathway. Methods Inflammatory microenvironment was created in vitro by the activation of T cells isolated from healthy donors and rheumatoid arthritis (RA) patients with anti-CD3 and anti-CD28 antibodies. Direct and indirect co-cultures between DPSCs and PBMCs were carried out to evaluate the activation of immunomodulatory checkpoints in DPSCs and the inflammatory pattern in PBMCs. Results Our data suggest that the inflammatory stimuli trigger DPSCs immunoregulatory functions that can be exerted by both direct and indirect contact. As demonstrated by using a selective PD-L1 inhibitor, DPSCs were able to activate compensatory pathways targeting to orchestrate the inflammatory process by modulating pro-inflammatory cytokines in pre-activated T lymphocytes. The involvement of PD-L1 mechanism was also observed in autologous inflammatory status (pulpitis) and after direct exposure to pre-activated T cells from RA patients suggesting that immunomodulatory/anti-inflammatory properties are strictly related to their stemness status. Conclusions Our findings point out that the communication with the inflammatory microenvironment is essential in licensing their immunomodulatory properties.

10.1186/s13287-021-02664-4

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Cytokine Profiling in Aqueous Humor Samples From Patients With Non-Infectious Uveitis Associated With Systemic Inflammatory Diseases

Frontiers in Immunology (2020)

Martina Bonacini Alessandra Soriano Luca Cimino Luca De Simone Elena Bolletta

Non-infectious uveitis are intraocular inflammatory conditions caused by dysregulated activation of the immune response without any detectable infectious agents. The aim of this study was to explore potential markers and therapeutic targets for two distinct types of non-infectious uveitis associated with Behcet's disease (BD) and Vogt Koyanagi Harada (VKH) disease. Concentrations of 27 cytokines were investigated in aqueous humor (AH) samples from patients with active uveitis versus healthy controls (HC) (n = 10 patients with BD-associated uveitis; n = 10 patients with VKH-associated uveitis; n = 10 HC) using the Bio-Plex ProTM human cytokine group I panel. Additionally, leukocytes in AH samples were counted with hemocytometers and characterized by flow cytometry. 11 cytokines resulted differentially expressed between patients with uveitis and HC with a median concentration greater than 10 pg/ml. IL-6, IP-10, G-CSF and IFNg showed higher concentrations in AH samples from both BD and VKH patients while IL-2, IL-8, IL-13, TNFa, eotaxin, IL-1ra showed statistically significant higher concentrations only in AH samples from BD patients. GM-CSF was the sole cytokine with an opposite profile showing decreased levels in AH samples from BD patients. IL-1ra and IL-6 were detected at higher frequencies in AH samples from BD and VKH patients compared with those from HC while IFNg and TNFa were not detected in HC. The concentrations of IL-6, IL-8, IP-10, G-CSF, IFNg, TNFa, eotaxin, IL-1ra positively correlated with the concentrations of leukocytes in AH, suggesting that such cytokines can be produced by immune cells and/or attract and/or promote proliferation and survival of immune cells in these types of uveitis. The correlation matrix of cytokine concentrations in AH samples revealed that IFNg, TNFa, eotaxin, IL-6, G-CSF highly correlated each other. The ratios of cytokine concentrations between AH and plasma intra-individuals showed that IL-2, IL-6, IP-10, GM-CSF were increased intraocularly. In conclusion, AH sampling followed by multiplex analysis of cytokines should be fostered in non-infectious uveitis to identify cytokines dysregulated intraocularly in each individual laying the groundwork for precision medicine.

10.3389/fimmu.2020.00358

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Vogt–Koyanagi–Harada patients show higher frequencies of circulating NKG2Dpos NK and NK T cells

Clinical & Experimental Immunology (2020)

Martina Bonacini Luca Cimino Luca De Simone Elena Bolletta Fabrizio Gozzi

Vogt-Koyanagi-Harada (VKH) is an autoimmune disease characterized by inflammation in tissues that contain melanocytes. We aimed to increase the knowledge regarding immunological pathways deregulated in VKH disease. We compared the percentages of circulating natural killer (NK), NK T and T cells expressing the activatory markers: CD16, CD69, NK group 2D (NKG2D), natural cytotoxicity triggering receptor 3 (Nkp30), natural cytotoxicity triggering receptor 1 (Nkp46) and the inhibitory marker: NK group 2 member A (NKG2A) in 10 active VKH patients, 20 control subjects (CTR) and seven patients with Behçet disease (BD) by flow cytometry. Cytotoxic potential of NK cells was determined through the degranulation marker CD107a expression after contact with K562 cells by flow cytometry. Moreover, plasmatic levels of 27 cytokines were determined with a multiplex bead-based assay. VKH patients showed higher percentages of NKG2Dpos NK and NK T cells versus CTR. The cytotoxic potential of NK cells induced by K562 cells was comparable between VKH patients and CTR. Finally, higher concentrations of interleukin (IL)-4, IL-5, IL-7, IL-17 and platelet-derived growth factor-subunits B (PDGF-bb) were detected in plasma of VKH patients versus CTR. The immune profile of VKH patients was similar to that of BD patients.

CD16

NKG2D

10.1111/cei.13563

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Complement activation predicts negative outcomes in COVID-19: The experience from Northen Italian patients.

Autoimmunity Reviews (2022)

Pier Luigi Meroni Stefania Croci Paola Adele Lonati Francesca Pregnolato Lucia Spaggiari

Prothrombin time

D-dimer

White blood cell

10.1016/j.autrev.2022.103232

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