CD47 blockade ameliorates autoimmune vasculitis via efferocytosis of neutrophil extracellular traps.

Neutrophil extracellular trap (NET) formation contributes to immune defense and is a distinct form of cell death. Excessive NET formation is found in patients with anti-neutrophil cytoplasmic antibody-associated (ANCA-associated) vasculitis (AAV), contributing to disease progression. The clearance of dead cells by macrophages, a process known as efferocytosis, is regulated by the CD47-mediated "don't eat me" signal. Hence, we hypothesized that pathogenic NETs in AAV escape from efferocytosis via the CD47 signaling pathway, resulting in the development of necrotizing vasculitis. Immunostaining for CD47 in human renal tissues revealed high CD47 expression in crescentic glomerular lesions of patients with AAV. In ex vivo studies, ANCA-induced netting neutrophils increased the expression of CD47 with the reduction of efferocytosis. After efferocytosis, macrophages displayed proinflammatory phenotypes. The blockade of CD47 in spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mice ameliorated renal disease and reduced myeloperoxidase-ANCA (MPO-ANCA) titers with a reduction in NET formation. Thus, CD47 blockade would protect against developing glomerulonephritis in AAV via restored efferocytosis of ANCA-induced NETs.

Human monocyte-derived suppressive cells (HuMoSC) for cell therapy in giant cell arteritis.

Introduction: The pathogenesis of Giant Cell Arteritis (GCA) relies on vascular inflammation and vascular remodeling, the latter being poorly controlled by current treatments. Methods: This study aimed to evaluate the effect of a novel cell therapy, Human Monocyte-derived Suppressor Cells (HuMoSC), on inflammation and vascular remodeling to improve GCA treatment. Fragments of temporal arteries (TAs) from GCA patients were cultured alone or in the presence of HuMoSCs or their supernatant. After five days, mRNA expression was measured in the TAs and proteins were measured in culture supernatant. The proliferation and migration capacity of vascular smooth muscle cells (VSMCs) were also analyzed with or without HuMoSC supernatant. Results: Transcripts of genes implicated in vascular inflammation (CCL2, CCR2, CXCR3, HLADR), vascular remodeling (PDGF, PDGFR), angiogenesis (VEGF) and extracellular matrix composition (COL1A1, COL3A1 and FN1) were decreased in arteries treated with HuMoSCs or their supernatant. Likewise, concentrations of collagen-1 and VEGF were lower in the supernatants of TAs cultivated with HuMoSCs. In the presence of PDGF, the proliferation and migration of VSMCs were both decreased after treatment with HuMoSC supernatant. Study of the PDGF pathway suggests that HuMoSCs act through inhibition of mTOR activity. Finally, we show that HuMoSCs could be recruited in the arterial wall through the implication of CCR5 and its ligands. Conclusion: Altogether, our results suggest that HuMoSCs or their supernatant could be useful to decrease vascular in flammation and remodeling in GCA, the latter being an unmet need in GCA treatment.

Neutrophil extracellular trap formation in anti-neutrophil cytoplasmic antibody-associated and large-vessel vasculitis.

Levels of neutrophil extracellular traps (NETs) were measured in plasma of healthy controls (HC, n = 30) and patients with granulomatosis with polyangiitis (GPA, n = 123), microscopic polyangiitis (MPA, n = 61), Takayasu's arteritis (TAK, n = 58), and giant cell arteritis (GCA, n = 68), at times of remission or activity and correlated with levels of the platelet-derived thrombospondin-1 (TSP-1). Levels of NETs were elevated during active disease in patients with GPA (p < 0.0001), MPA (p = 0.0038), TAK (p < 0.0001), and GCA (p < 0.0001), and in remission for GPA, p < 0.0001, MPA, p = 0.005, TAK, p = 0.03, and GCA, p = 0.0009. All cohorts demonstrated impaired NET degradation. Patients with GPA (p = 0.0045) and MPA (p = 0.005) had anti-NET IgG antibodies. Patients with TAK had anti-histone antibodies (p < 0.01), correlating with presence of NETs. Levels of TSP-1 were increased in all patients with vasculitis, and associated with NET formation. NET formation is a common process in vasculitides. Targeting NET formation or degradation could be potential therapeutic approaches for vasculitides.

Dysregulated Expression of Arterial MicroRNAs and Their Target Gene Networks in Temporal Arteries of Treatment-Naïve Patients with Giant Cell Arteritis.

In this study, we explored expression of microRNA (miR), miR-target genes and matrix remodelling molecules in temporal artery biopsies (TABs) from treatment-naïve patients with giant cell arteritis (GCA, n = 41) and integrated these analyses with clinical, laboratory, ultrasound and histological manifestations of GCA. NonGCA patients (n = 4) served as controls. GCA TABs exhibited deregulated expression of several miRs (miR-21-5p, -145-5p, -146a-5p, -146b-5p, -155-5p, 424-3p, -424-5p, -503-5p), putative miR-target genes (YAP1, PELI1, FGF2, VEGFA, KLF4) and matrix remodelling factors (MMP2, MMP9, TIMP1, TIPM2) with key roles in Toll-like receptor signaling, mechanotransduction and extracellular matrix biology. MiR-424-3p, -503-5p, KLF4, PELI1 and YAP1 were identified as new deregulated molecular factors in GCA TABs. Quantities of miR-146a-5p, YAP1, PELI1, FGF2, TIMP2 and MMP9 were particularly high in histologically positive GCA TABs with occluded temporal artery lumen. MiR-424-5p expression in TABs and the presence of facial or carotid arteritis on ultrasound were associated with vision disturbances in GCA patients. Correlative analysis of miR-mRNA quantities demonstrated a highly interrelated expression network of deregulated miRs and mRNAs in temporal arteries and identified KLF4 as a candidate target gene of deregulated miR-21-5p, -146a-5p and -155-5p network in GCA TABs. Meanwhile, arterial miR and mRNA expression did not correlate with constitutive symptoms and signs of GCA, elevated markers of systemic inflammation nor sonographic characteristics of GCA. Our study provides new insights into GCA pathophysiology and uncovers new candidate biomarkers of vision impairment in GCA.

A Distinct Macrophage Subset Mediating Tissue Destruction and Neovascularization in Giant Cell Arteritis: Implication of the YKL-40/Interleukin-13 Receptor α2 Axis.

OBJECTIVE: Macrophages mediate inflammation, angiogenesis, and tissue destruction in giant cell arteritis (GCA). Serum levels of the macrophage-associated protein YKL-40 (chitinase 3-like protein 1), previously linked to angiogenesis and tissue remodeling, remain elevated in GCA despite glucocorticoid treatment. This study was undertaken to investigate the contribution of YKL-40 to vasculopathy in GCA. METHODS: Immunohistochemistry was performed on GCA temporal artery biopsy specimens (n = 12) and aortas (n = 10) for detection of YKL-40, its receptor interleukin-13 receptor α2 (IL-13Rα2), macrophage markers PU.1 and CD206, and the tissue-destructive protein matrix metalloproteinase 9 (MMP-9). Ten noninflamed temporal artery biopsy specimens served as controls. In vitro experiments with granulocyte-macrophage colony-stimulating factor (GM-CSF)- or macrophage colony-stimulating factor (M-CSF)-skewed monocyte-derived macrophages were conducted to study the dynamics of YKL-40 production. Next, small interfering RNA-mediated knockdown of YKL-40 in GM-CSF-skewed macrophages was performed to study its effect on MMP-9 production. Finally, the angiogenic potential of YKL-40 was investigated by tube formation experiments using human microvascular endothelial cells (HMVECs). RESULTS: YKL-40 was abundantly expressed by a CD206+MMP-9+ macrophage subset in inflamed temporal arteries and aortas. GM-CSF-skewed macrophages from GCA patients, but not healthy controls, released significantly higher levels of YKL-40 compared to M-CSF-skewed macrophages (P = 0.039). In inflamed temporal arteries, IL-13Rα2 was expressed by macrophages and endothelial cells. Functionally, knockdown of YKL-40 led to a 10-50% reduction in MMP-9 production by macrophages, whereas exposure of HMVECS to YKL-40 led to significantly increased tube formation. CONCLUSION: In GCA, a GM-CSF-skewed, CD206+MMP-9+ macrophage subset expresses high levels of YKL-40 which may stimulate tissue destruction and angiogenesis through IL-13Rα2 signaling. Targeting YKL-40 or GM-CSF may inhibit macrophages that are currently insufficiently suppressed by glucocorticoids.

CD8+ T Cells in GCA and GPA: Bystanders or Active Contributors?

Vasculitis refers to inflammation of blood vessels and can cause a variety of serious complications depending on which vessels are affected. Two different forms of vasculitis are Giant Cell Arteritis (GCA) and Granulomatosis with Polyangiitis (GPA). GCA is the most common form of vasculitis in adults affecting the large arteries and can lead to visual impairment and development of aneurysms. GPA affects small- and medium-sized blood vessels predominantly in the lungs and kidneys resulting in organ failure. Both diseases can potentially be fatal. Although the pathogenesis of GCA and GPA are incompletely understood, a prominent role for CD4+ T cells has been implicated in both diseases. More recently, the role of CD8+ T cells has gained renewed interest. CD8+ T cells are important players in the adaptive immune response against intracellular microorganisms. After a general introduction on the different forms of vasculitis and their association with infections and CD8+ T cells, we review the current knowledge on CD8+ T-cell involvement in the immunopathogenesis of GCA and GPA focusing on phenotypic and functional features of circulating and lesional CD8+ T cells. Furthermore, we discuss to which extent aging is associated with CD8+ T-cell phenotype and function in GCA and GPA.

The Immunopathology of Giant Cell Arteritis Across Disease Spectra.

Giant cell arteritis (GCA) is a granulomatous systemic vasculitis of large- and medium-sized arteries that affects the elderly. In recent years, advances in diagnostic imaging have revealed a greater degree of large vessel involvement than previously recognized, distinguishing classical cranial- from large vessel (LV)- GCA. GCA often co-occurs with the poorly understood inflammatory arthritis/bursitis condition polymyalgia rheumatica (PMR) and has overlapping features with other non-infectious granulomatous vasculitides that affect the aorta, namely Takayasu Arteritis (TAK) and the more recently described clinically isolated aortitis (CIA). Here, we review the literature focused on the immunopathology of GCA on the background of the three settings in which comparisons are informative: LV and cranial variants of GCA; PMR and GCA; the three granulomatous vasculitides (GCA, TAK, and CIA). We discuss overlapping and unique features between these conditions across clinical presentation, epidemiology, imaging, and conventional histology. We propose a model of GCA where abnormally activated circulating cells, especially monocytes and CD4+ T cells, enter arteries after an unknown stimulus and cooperate to destroy it and review the evidence for how this mechanistically occurs in active disease and improves with treatment.

Temporal artery involvement in AL amyloidosis: an important differential diagnosis for giant cell arteritis. A case report and literature review.

AL amyloidosis (AL) is a systemic disorder due to extracellular tissue deposition of amyloid fibrils, composed of immunoglobulin light chains. Since the description of AL involving temporal arteries in 1986, this disorder has been known as one of the differential diagnoses of giant cell arteritis (GCA). We encountered a case of an elderly female presenting with headache and tender and enlarged temporal arteries, that was pathologically diagnosed with temporal artery involvement of AL due to Bence-Jones-type MM. To our knowledge, this was the first case of AL with temporal artery involvement in Japan, that presented with GCA-like features. Literature review of AL cases with temporal artery involvement showed close similarity between these disorders, but suggested that vasculature involvement (extremity claudication, kidney or heart), macroglossia, carpal tunnel syndrome and normal or low (<0.5 mg/dL) CRP levels may predict AL rather than GCA. Physicians should keep in mind that AL involving temporal arteries can be a pitfall in the diagnosis of GCA, as seen in our and previous cases.

ROS-producing immature neutrophils in giant cell arteritis are linked to vascular pathologies.

Giant cell arteritis (GCA) is a common form of primary systemic vasculitis in adults, with no reliable indicators of prognosis or treatment responses. We used single cell technologies to comprehensively map immune cell populations in the blood of patients with GCA and identified the CD66b+CD15+CD10lo/-CD64- band neutrophils and CD66bhiCD15+CD10lo/-CD64+/bright myelocytes/metamyelocytes to be unequivocally associated with both the clinical phenotype and response to treatment. Immature neutrophils were resistant to apoptosis, remained in the vasculature for a prolonged period of time, interacted with platelets, and extravasated into the tissue surrounding the temporal arteries of patients with GCA. We discovered that immature neutrophils generated high levels of extracellular reactive oxygen species, leading to enhanced protein oxidation and permeability of endothelial barrier in an in vitro coculture system. The same populations were also detected in other systemic vasculitides. These findings link functions of immature neutrophils to disease pathogenesis, establishing a clinical cellular signature of GCA and suggesting different therapeutic approaches in systemic vascular inflammation.

Leukocyte Dynamics Reveal a Persistent Myeloid Dominance in Giant Cell Arteritis and Polymyalgia Rheumatica.

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are inflammatory diseases requiring long-term glucocorticoid treatment. Limited data on dynamics in leukocyte counts before, during and after treatment are available. Leukocyte counts were measured, as cellular markers of inflammation, at fixed time points in our prospectively studied cohort of pre-treatment glucocorticoid-naive GCA (N = 42) and PMR (N = 31) patients. Values were compared with age-matched healthy controls (HCs; N = 51) and infection controls (N = 16). We report that before start of treatment monocyte and neutrophil counts were higher in GCA and PMR patients than in HCs, while NK- and B-cell counts were lower. C-reactive protein (CRP) levels correlated positively with monocyte counts in GCA, and negatively with B-cell and NK-cell counts in PMR. During glucocorticoid treatment, myeloid subsets remained elevated whereas lymphoid subsets tended to fluctuate. Interestingly, erythrocyte sedimentation rate (ESR) outperformed CRP as marker for relapses in GCA. We defined stable treatment-free remission groups in both GCA and PMR. GCA patients in treatment-free remission still demonstrated elevated monocytes, neutrophils, ESR, and platelets. PMR patients in treatment-free remission had normalized levels of inflammation markers, but did have elevated monocytes, lowered CD8+ T-cell counts and lowered NK-cell counts. Finally, we showed that low hemoglobin level was predictive for long-term GC treatment in PMR. Overall, leukocyte composition shifts toward the myeloid lineage in GCA and PMR. This myeloid profile, likely induced by effects of inflammation on hematopoietic stem cell differentiation, persisted during glucocorticoid treatment. Surprisingly, the myeloid profile was retained in treatment-free remission, which may reflect ongoing subclinical inflammation.

Cytokine expression in temporal arteries: comparative analysis between patients with biopsy-positive giant cell arteritis, biopsy-negative giant cell arteritis and biopsy-negative without arteritis.

OBJECTIVES: To investigate whether expression of pro-inflammatory cytokines in the temporal artery may aid in differentiating biopsy-negative giant cell arteritis (GCA) patients from those with a negative biopsy without arteritis. METHODS: We investigated cytokine expression in temporal artery biopsy (TAB) of 54 consecutive patients: 17 with biopsy-positive GCA, 17 with biopsy-negative GCA, and 20 biopsy-negative without arteritis. We compared the expression rate of the following cytokines among these 3 groups of patients: interleukin-6 (IL-6), osteopontin (OPN), COX-2, and TNF-α. RESULTS: IL-6 was expressed in 13 (76%) patients with biopsy-positive GCA, 0 patients in biopsy-negative GCA, and 1(5%) patient with biopsy-negative without arteritis (p<0.05). OPN was expressed in 17 (100%) patients with biopsy-positive GCA, 2 (12%) patients with biopsy-negative GCA, and 0 patients with biopsy-negative without arteritis (p<0.05). Cox-2 was expressed in 16 (94%) patients with biopsy-positive GCA, 0 patients with biopsy-negative GCA, and 3 (15%) patients with biopsy-negative without arteritis (p<0.05). TNF- α was expressed in 17 (100%) patients with biopsy-positive GCA, 14 (82%) patients with biopsy-negative GCA, and 8 (40%) patients with biopsy-negative without arteritis (p<0.05). CONCLUSIONS: IL-6, COX-2 and OPN are significantly more expressed in the presence of a positive TAB compared to a negative TAB. TNF-α is significantly more expressed in GCA patients compared to non-GCA patients. Thus, TNF-α expression may suggest a diagnosis of GCA despite a negative TAB. Further larger studies are needed to confirm these findings.

Treatment of giant cell arteritis.

Giant cell arteritis (GCA) is the most common form of vasculitis in adults. Cranial manifestations are typical clinical features of this vasculitis. Sometimes the presenting symptoms are nonspecific and, in some cases, large-vessel involvement may prevail. Polymyalgia rheumatica is a frequent manifestation that in some cases may be the presenting symptom of GCA. Visual complications, in particular the risk of blindness, constitute the most feared manifestations of GCA. Prompt recognition of this vasculitis is required to avoid irreversible complications. Prednisone/prednisolone at a dose of 40-60 mg/day is the cornerstone therapy in GCA. Glucocorticoids lead to rapid improvement of symptoms and may reduce the risk of irreversible visual loss. However, relapses are common when the prednisone dose is tapered. Therefore, additional therapies are required in relapsing GCA or when a rapid reduction of glucocorticoids is needed. The most widely used conventional immunosuppressive drug is methotrexate Adjunctive treatment with methotrexate may decrease the risk of relapses and reduce glucocorticoid exposure. However, comprehensive reviews indicate that the efficacy of methotrexate in GCA is modest. The experience with other conventional immunosuppressive drugs in GCA patients is scarce. In some cases, the new biologic agents are required. Among them, the most frequently used is the recombinant humanized anti-IL-6 receptor antibody tocilizumab. It improves clinical symptoms, reduce the cumulative prednisone dose and the frequency of relapses in GCA patients. However, anti-tumor necrosis factor-α therapy is not useful in GCA. Promising results on other biologic agents, such as abatacept, ustekinumab or anakinra, require further confirmatory studies.

An Immunohistopathologic Study to Profile the Folate Receptor Beta Macrophage and Vascular Immune Microenvironment in Giant Cell Arteritis.

Giant cell arteritis (GCA) is a chronic immune-mediated disease of medium-to-large sized arteries that affects older adults. GCA manifests with arthritis and occlusive symptoms of headaches, stroke or vision loss. Macrophages and T-helper lymphocytes infiltrate the vascular wall and produce a pro-inflammatory response that lead to vessel damage and ischemia. To date, there is no GCA biomarker that can monitor disease activity and guide therapeutic response. Folate receptor beta (FRB) is a glycosylphosphatidylinositol protein that is anchored on cell membranes and normally expressed in the myelomonocytic lineage and in the majority of myeloid leukemia cells as well as in tumor and rheumatoid synovial macrophages, where its expression correlates with disease severity. The ability of FRB to bind folate compounds, folic acid-conjugates and antifolate drugs has made it a druggable target in cancer and inflammatory disease research. This report describes the histopathologic and immunohistochemical methods used to assess expression and distribution of FRB in relation to GCAimmunopathology. Formalin-fixed and paraffin-embedded temporal artery biopsies from GCA and normal controls were stained with Hematoxylin and Eosin to review tissue histology and identify pathognomonic features.Immunohistochemistry was used to detect FRB, CD68 and CD3 expression. A microscopic analysis was performed to quantify the number of positively stained cells on 10 selected high-power-field sections and their respective locations in the arterial wall. Lymphohistiocytic (LH) inflammation accompanied by intimal hyperplasia and disrupted elastic lamina was seen in GCA with none found in controls. The LH infiltrate was composed of approximately 60% lymphocytes and 40% macrophages. FRB expression was restricted to macrophages, comprising 31% of the total CD68+ macrophage population and localized to the media and adventitia. No FRB was seen in controls. This protocol demonstrated a distinct numerical and spatial pattern of the FRB macrophage relative to the vascular immune microenvironment in GCA.

Retrospective, Multicenter Comparison of the Clinical Presentation of Patients Presenting With Diplopia From Giant Cell Arteritis vs Other Causes.

BACKGROUND: Although giant cell arteritis (GCA) is a well-known cause of transient and permanent vision loss, diplopia as a presenting symptom of this condition is uncommon. We compared symptoms and signs of patients presenting with diplopia from GCA to those from other causes. METHODS: This was a multicenter, retrospective study comparing the clinical characteristics of patients presenting with diplopia from GCA with age-matched controls. Demographic information, review of symptoms, ophthalmic examination, and laboratory data of biopsy-proven patients with GCA were compared with those of age-matched controls presenting with diplopia. RESULTS: A total of 27 patients presented with diplopia from GCA, 19 with constant diplopia, and 8 with transient diplopia. All patients with constant diplopia from GCA were matched with 67 control subjects who had diplopia from other etiologies. Patients with GCA were more likely to describe other accompanying visual symptoms (58% vs 25%, P = 0.008), a greater number of systemic GCA symptoms (3.5, GCA vs 0.6, controls, P < 0.001) such as headache (94% [17/18] vs 39% [23/67]; P < 0.001), jaw claudication (80% [12/15] vs 0% [0/36]; P < 0.001), and scalp tenderness (44% [7/16] vs 7% [3/43]; P < 0.001). Ocular ischemic lesions (26% vs 1%, P < 0.001) were also common in patients with diplopia from GCA. Inflammatory markers were elevated significantly in patients with GCA vs controls (erythrocyte sedimentation rate: 91% [10/11] vs 12% [3/25], P < 0.001; C-reactive protein: 89% [8/9] vs 11% [2/19], P < 0.001). CONCLUSIONS: GCA is a rare but serious cause of diplopia among older adults and must be differentiated from other more common benign etiologies. Our study suggests that most patients with diplopia from GCA have concerning systemic symptoms and/or elevated inflammatory markers that should trigger further work-up. Moreover, careful ophthalmoscopic examination should be performed to look for presence of ocular ischemic lesions in older patients presenting with acute diplopia.

Pathologic Markers Determining Prognosis in Patients With Treated or Healing Giant Cell Arteritis.

PURPOSE: To provide quantitative evidence linking the CD68 (cluster of differentiation 68)+ macrophage marker found on temporal artery biopsies (TABs) with disease prognosis. DESIGN: Retrospective, cross-sectional study. METHODS: We examined 42 consecutive patients who had undergone unilateral TABs at a single hospital in 2015. Clinical data, laboratory data, and histopathologic features of TABs were recorded. Inclusion criteria were clinical diagnosis of giant cell arteritis (GCA) with TAB performed at the same center. CD68 immunohistochemistry was used to label macrophages in the TABs. Primary outcome was multiple logistic regression and bivariate comparisons to measure the association between CD68+ cells per histologic section with placement on immunomodulatory therapy (IMT). RESULTS: Twenty seven patients were female (64%), with a mean age of 72 (standard deviation [SD.] ±7.7). Eleven patients (26%) were placed on IMT, 17 (40%) had disease recurrence during steroid taper, and 25 (60%) were referred to rheumatology. Of 42 biopsies, 35 underwent staining with CD68 to confirm active inflammation in suspicious, but not diagnostic, specimens. Patients eventually placed on IMT had increased CD68+ cells per slice compared to those not on IMT (median 5.00 [25th-75th quartile 2.00-7.15] vs 1.21 [0.38-2.57], P = .031, respectively). A receiver operating characteristic (ROC) curve demonstrates that 2.17 CD68+ cells/slice predicts placement on IMT with an odds ratio of 1.54 (95% confidence interval 1.02-2.33, P = .038). CONCLUSIONS: Patients refractory to initial steroid tapers and those eventually placed on IMT had increased CD68 cells per section. CD68+ macrophages and their location on the internal elastic lamina may predict disease severity in patients with presumed GCA. Our results suggest that this marker may expedite patient triaging to alternate treatment to the usual steroid therapy.

Temporal small arterial inflammation is common in patients with giant cell arteritis.

Giant cell arteritis (GCA) primarily involves medium-to-large arteries. Small-vessel inflammation is a recognized phenomenon occurring in association with GCA. However, its significance is poorly elucidated. Histologic sections and medical records of105 temporal artery specimens were retrospectively reviewed between 2008 and 2017 to examine associated clinical manifestations and laboratory data including antinuclear antibody and p-antineutrophilic cytoplasmic antibody titers. Immunohistochemical staining for CD4 and CD8 was performed in select cases to assess the nature of the inflammatory response. Seventy-eight patients meeting the diagnostic criteria of temporal arteritis were included in the analysis. Twenty-eight specimens demonstrated temporal arteritis with small arterial inflammation (SAI), and 50 specimens showed temporal arteritis without SAI. Eight (28.6%) of 28 patients with SAI presented with jaw claudication, whereas 5 (17.9%) were febrile at presentation. In contrast, in 50 patients without SAI, jaw claudication and fever were seen in 11 and 2 cases, respectively (P = .01 and P = .0047, respectively). No statistically significant difference was noted between other symptoms and laboratory indices between the 2 groups. Elevated p-antineutrophilic cytoplasmic antibody titers in GCA may be associated with concomitant polymyalgia rheumatica or treatment-resistant disease. We also identified a higher count of CD4 and CD8 T cells in SAI cases, although the ratio of CD4/CD8 T lymphocytes was within normal limits. In conclusion, simultaneous involvement of arterioles and medium- to large-sized arteries is common in GCA and may be associated with treatment-refractory disease. Documentation of small arterial involvement in GCA will help the clinicians to manage the disease more effectively.

CD3 immunohistochemistry is helpful in the diagnosis of giant cell arteritis.

OBJECTIVE: To evaluate whether CD3 staining performed routinely on temporal artery biopsy specimens might improve the sensitivity of temporal artery biopsy in patients with biopsy-negative GCA. METHODS: Two hundred and seventy biopsies were considered for this study, stained with haematoxylin and eosin and with an anti-CD3 antibody. RESULTS: The addition of CD3 staining modified the sensibility and the specificity of the histologic examination in 89.47 and 95.00%, respectively, with a positive and negative predictive values of 97.00 and 79.78% . CONCLUSION: The addition of CD3 immunostaining to the classic histologic evaluation is accompanied by a significant increase in the sensibility with a comparable specificity.

Tocilizumab for the treatment of giant cell arteritis.

INTRODUCTION: Giant cell arteritis (GCA) is the most frequent type of vasculitis, occurring in people older than 50 years. So far, treatment has been limited to corticosteroids and methotrexate only. Areas covered: Interleukin-6 (IL-6) plays a role in the pathophysiology of GCA. This review covers recent advances in the treatment of GCA with tocilizumab (TCZ), which specifically binds to both soluble and membrane-bound IL-6R and inhibits IL-6R-mediated signaling. Expert commentary: Two randomized controlled trials recently showed the efficacy of the IL-6 receptors inhibitor monoclonal antibody TCZ for the induction and maintenance of remission in patients with new-onset and relapsing GCA. Furthermore, addition of TCZ to prednisone led to a reduction in the cumulative prednisone doses required to control GCA. The profile of adverse events was balanced across treatment groups and no safety concerns were raised during the trial.

Increased expression of interleukin-22 in patients with giant cell arteritis.

Objectives: GCA is characterized by arterial remodelling driven by inflammation. IL-22 is an attractive cytokine which acts at the crosstalk between immune and stromal cells. We hypothesized that IL-22 might be induced in GCA and might be involved in disease pathogenesis. Methods: Patients subjected to temporal artery biopsies (TABs) naïve from therapy were enrolled: 27 biopsy-proven GCA, 8 biopsy-negative GCA, 21 biopsy-negative non-GCA patients. Expression of IL-22 was determined in TABs by immunohystochemistry, in plasma by ELISA, in peripheral blood mononuclear cells by real-time PCR and flow cytometry. Effects of IL-22 on viability and gene expression of primary cultures obtained from TABs were also evaluated. Results: Inflamed TABs from GCA patients showed a higher expression of IL-22 and IL-22 specific receptor subunit (IL-22R1) than non-inflamed TABs. IL-22 was expressed in infiltrating immune cells and spindle shaped cells, IL-22R1 was expressed in endothelial cells. Patients with biopsy-proven GCA showed increased levels of IL-22 in plasma than patients with biopsy-negative GCA, without GCA and healthy subjects. Peripheral blood mononuclear cells from GCA patients expressed higher IL-22 transcript than healthy subjects. After stimulation in vitro with phorbol 12-myristate 13-acetate and ionomycin, the frequencies of Th22 and IL-22+ CD4+ lymphocytes were similar between patients with and without GCA. Treatment with IL-22 of primary cultures obtained from TABs increased cell viability under stress conditions and expression of B-cell activating factor. Conclusion: IL-22 is increased in patients with GCA and affects viability and gene expression of arterial cells, supporting a potential role in disease pathogenesis.