Markers of angiogenesis and macrophage products for predicting disease course and monitoring vascular inflammation in giant cell arteritis

Sleen, Yannick van; Sandovici, Maria; Abdulahad, Wayel H.; Bijzet, Johan; Geest, Kornelis S M van der; Boots, Annemieke M. H.; Brouwer, Elisabeth

doi:10.1093/rheumatology/kez034

Cited by 44 publications

(54 citation statements)

References 45 publications

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“…This unmet need has led to the research of new biomarkers unrelated to the IL-6 pathway [ 12 – 14 ], but their reliability needs to be verified in larger studies.…”

Section: Discussionmentioning

confidence: 99%

The Role of Multimodality Imaging in Monitoring Disease Activity and Therapeutic Response to Tocilizumab in Giant Cell Arteritis

Conticini

Sota

Falsetti

et al. 2020

Mediators of Inflammation

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Introduction. Giant cell arteritis (GCA) is a large vessel (LV) vasculitis, mainly affecting elder patients. Monitoring GCA activity during tocilizumab (TCZ) treatment is an unmet need, since low serum levels of C-reactive protein (CRP) during treatment may underestimate disease activity. To date, few data are available on the role of different imaging techniques in monitoring GCA activity and response to treatment. We report herein a cohort of GCA patients treated with TCZ and followed up with multimodal imaging. Patients and Methods. We collected clinical, laboratory, and imaging data of 11 GCA patients treated with TCZ 162 mg subcutaneously every week. Disease activity was assessed at baseline and within 12 months from the start of treatment using different imaging techniques such as color Doppler ultrasonography (CDUS), magnetic resonance imaging/angiography (MRI/MRA), computed tomography angiography (CTA), and/or positron emission tomography (PET). Results. Four patients were affected by cranial and 7 by LV-GCA. All patients were treated with oral glucocorticoids (GCs) (mean dose 55.68 mg±8.19 of prednisone or equivalent) in combination with TCZ. Treatment was preceded in 5 cases by 3 intravenous boluses of 1000 mg methylprednisolone. A significant decrease of the mean dose of oral GCs was observed between baseline and the last follow-up visit (4.65±3.69 mg) (p=0.003). TCZ treatment significantly decreased erythrocyte sedimentation rate (p<0.01) and CRP levels (p<0.01). At follow-up (mean 8.18±3.63 months), all patients were in clinical and serological remission. Moreover, PET, CDUS, MRI/MRA, and CTA did not show any LVV finding. Conclusions. Our study highlights TCZ efficacy in inducing GCA remission and its steroid-sparing effect. We highlighted a reliability of imaging procedures in the evaluation of disease activity and treatment response. A close disease monitoring with imaging techniques should be taken into account in GCA patients during TCZ treatment.

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“…This unmet need has led to the research of new biomarkers unrelated to the IL-6 pathway [ 12 – 14 ], but their reliability needs to be verified in larger studies.…”

Section: Discussionmentioning

confidence: 99%

The Role of Multimodality Imaging in Monitoring Disease Activity and Therapeutic Response to Tocilizumab in Giant Cell Arteritis

Conticini

Sota

Falsetti

et al. 2020

Mediators of Inflammation

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“…Although macrophages are one of the dominant inflammatory cellular infiltrates in GCA lesions, 6,[16][17][18][19] little is known about their phenotypic heterogeneity and spatial distribution within the affected vessel wall. We hypothesised that within GCA lesions, distinct macrophage phenotypes are associated with distinct functions and lesion morphology, dictated by local GM-CSF and M-CSF production.…”

Section: Introductionmentioning

confidence: 99%

Distinct macrophage phenotypes skewed by local granulocyte macrophage colony‐stimulating factor (GM‐CSF) and macrophage colony‐stimulating factor (M‐CSF) are associated with tissue destruction and intimal hyperplasia in giant cell arteritis

et al. 2020

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Objective To determine the presence and spatial distribution of different macrophage phenotypes, governed by granulocyte macrophage colony‐stimulating factor (GM‐CSF) and macrophage colony‐stimulating factor (M‐CSF) skewing signals, in giant cell arteritis (GCA) lesions. Methods Temporal artery biopsies (TABs, n = 11) from treatment‐naive GCA patients, aorta samples from GCA‐related aneurysms (n = 10) and atherosclerosis (n = 10) were stained by immunohistochemistry targeting selected macrophage phenotypic markers, cytokines, matrix metalloproteinases (MMPs) and growth factors. In vitro macrophage differentiation (n = 10) followed by flow cytometry, Luminex assay and ELISA were performed to assess whether GM‐CSF and M‐CSF are drivers of macrophage phenotypic heterogeneity. Results A distinct spatial distribution pattern of macrophage phenotypes in TABs was identified. CD206+/MMP‐9+ macrophages were located at the site of tissue destruction, whereas FRβ+ macrophages were located in the inner intima of arteries with high degrees of intimal hyperplasia. Notably, this pattern was also observed in macrophage‐rich areas in GCA aortas but not in atherosclerotic aortas. Flow cytometry showed that GM‐CSF treatment highly upregulated CD206 expression, while FRβ was expressed by M‐CSF‐skewed macrophages, only. Furthermore, localised expression of GM‐CSF and M‐CSF was detected, likely contributing to macrophage heterogeneity in the vascular wall. Conclusions Our data document a distinct spatial distribution pattern of CD206+/MMP‐9+ macrophages and FRβ+ macrophages in GCA linked to tissue destruction and intimal proliferation, respectively. We suggest that these distinct macrophage phenotypes are skewed by sequential GM‐CSF and M‐CSF signals. Our study adds to a better understanding of the development and functional role of macrophage phenotypes in the pathogenesis of GCA and opens opportunities for the design of macrophage‐targeted therapies.

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“…Increased levels of calprotectin were detected in the adventitia and media of temporal arteries as well as in serum from patients with GCA 50 , and mRNA expression of S100A8 (one of the two heterodimers of calprotectin, also denominated as calgranulin A or MRP8) was increased in temporal artery biopsy samples from patients with GCA with relapsing disease 51 . Monitoring studies investigating the change of calprotectin levels under therapy have been undertaken for patients with GCA receiving glucocorticoids (but not tocilizumab) 52 . In addition, in a cross-sectional study on 33 patients with RA treated with tocilizumab, levels of calprotectin were substantially lower in patients achieving remission than in those with active disease; on the contrary, ESR and CRP of these two groups were comparable 53 .…”

Section: Box 1 | Unanswered Questions In Gca and Pmr And Proposal Formentioning

confidence: 99%

“…Can be normal in >20% of patients with a relapse; influenced by many concomitant conditions (e.g. anaemia, age, infection, hypergammaglobulinaemia); false-negative results possible in patients treated with tocilizumab CRP [45][46][47]121 Together with ESR, one of the most commonly used biomarkers for monitoring disease activity; more specific than ESR; widely available Can be normal in >20% of patients with a relapse; false-negative results in patients treated with tocilizumab; increased during infection IL-6 57,[185][186][187][188][189] Possible correlation with disease activity; in patients treated with tocilizumab, persistently high levels of IL-6 might predict future relapse Strongly influenced by treatment with glucocorticoid and tocilizumab, as well as infections; low availability Calprotectin 52,190 More sensitive marker of inflammation than ESR and CRP; possible role for monitoring disease activity in patients treated with tocilizumab…”

Section: Imagingmentioning

confidence: 99%

Monitoring and long-term management of giant cell arteritis and polymyalgia rheumatica

et al. 2020

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Giant cell arteritis (GCA) is the most common type of primary vasculitis in Western countries 1,2. Polymyalgia rheumatica (PMR) is the second most common inflammatory rheumatic disease of the elderly after rheumatoid arthritis (RA) 3. The two diseases are interrelated: 40-60% of patients with GCA have symptoms of PMR 3 , and histological features consistent with GCA have been found in 16-21% of temporal artery biopsy samples from patients with PMR 3. Most of these patients with PMR, however, presented with additional features of GCA, whereas the prevalence of positive histology in unselected patients with PMR is unknown. Both GCA and PMR are heterogeneous diseases. Although systemic manifestations (such as fever, malaise and weight loss) are common in both diseases, they are not present in all patients 4-6. Up to 1 in 5 patients with GCA with ocular involvement can present without systemic manifestations of the disease 7. GCA is the most common form of large-vessel vasculitis (LVV) and has a broad spectrum of disease manifestations, which are frequently overlapping. In the majority of cases, cranial and extracranial large arteries are involved to varying degrees, leading to different clinical phenotypes 8,9. Isolated cranial or extracranial GCA, which are at either end of this continuum, are relatively uncommon 10. Predominant cranial GCA is characterized by headache, jaw claudication and visual manifestations (representing the prototypical clinical picture of temporal arteritis). By contrast, predominant large-vessel GCA is characterized by more pronounced systemic manifestations, PMR, vascular bruits, limb claudication and imaging signs of inflammation in the aorta and its major branches 10. In some of these patients, vascular stenoses or aneurysms in association with other GCA features are the presenting clinical manifestations 9,11. PMR is characterized by pain and stiffness in the shoulder and pelvic girdles, which can have an abrupt or a subtle onset 3. Up to 20% of patients with PMR can present with a normal erythrocyte sedimentation rate (ESR) 12 , although the presence of both normal ESR and C-reactive protein (CRP) levels is rare 13-15. Glucocorticoids are the cornerstone of treatment for GCA and PMR. They are effective, but glucocorticoidrelated adverse effects occur in up to 85% of patients with GCA and 65% of patients with PMR, respectively 16-22. The IL-6 receptor inhibitor tocilizumab has become available as a glucocorticoid-sparing strategy in patients with GCA 23,24 , an approach that is also being evaluated for PMR 25,26. Management of both GCA and PMR is hampered by the lack of universally accepted definitions of remission and other disease states (such as low disease activity or vessel damage without active disease). Many questions about monitoring and long-term management are still unanswered (Box 1).

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Markers of angiogenesis and macrophage products for predicting disease course and monitoring vascular inflammation in giant cell arteritis

Cited by 44 publications

References 45 publications

The Role of Multimodality Imaging in Monitoring Disease Activity and Therapeutic Response to Tocilizumab in Giant Cell Arteritis

The Role of Multimodality Imaging in Monitoring Disease Activity and Therapeutic Response to Tocilizumab in Giant Cell Arteritis

Distinct macrophage phenotypes skewed by local granulocyte macrophage colony‐stimulating factor (GM‐CSF) and macrophage colony‐stimulating factor (M‐CSF) are associated with tissue destruction and intimal hyperplasia in giant cell arteritis

Monitoring and long-term management of giant cell arteritis and polymyalgia rheumatica

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