Early giant cell arteritis: Identifying duration from symptoms to diagnosis, possible
therapies and clinically-relevant cell dynamics
Blaž Burja,
1Alojzija Hočevar,
1Snežna Sodin Šemrl,
1,2Katja Lakota,
1,2Žiga Rotar,
1Rok Ješe,
1Polona Žigon,
1Saša Čučnik,
1,3Suchita Nadkarni,
4Mauro Peretti,
4Sonja Praprotnik,
1Matija Tomšič
1Abstract
Giant cell arteritis (GCA) is the most prevalent primary systemic vasculitis in adults over 50 ye- ars of age in Europe. It affects large and medium sized arteries; the inflammatory process can ultimately lead to stenosis or occlusion of arterial lumen, resulting in severe clinical complica- tions. In the last decade, imaging in diagnostics has importantly shortened the time to disease recognition (e.g. early GCA). Fast track clinics have led to a decrease in appearance of the most severe ischemic disease complications and lower costs of therapy. Despite fast access to approp- riate therapy, the disease is chronic, and patients can experience relapses, which together with glucocorticoid therapy may lead to organ and tissue damage. Therefore, viable molecular and cellular target therapies are intensely explored. The major aims of our review were to: a) identify studies with indicated time from symptom development to diagnosis, b) explore promising mo- lecular targets for GCA therapy, and c) identify clinically-relevant cellular phenotypes. The most promising molecular targets are IL-6, IL-12/IL-23, cytotoxic T–lymphocyte-associated protein-4, while therapies against TNF-α showed limited value and no clinical studies with secukimumab targeting IL-17 in GCA have been reported to date. Potential future therapeutic targets have been discussed, including targets in signaling pathways.
Cite as: Burja B, Hočevar A, Sodin Šemrl S, Lakota K, Rotar Ž, Ješe R, Žigon P, Čučnik S, Nadkarni S, Peretti M, Praprotnik S, Tomšič M. [Early giant cell arteritis: Identifying duration from symptoms to diagnosis, possible therapies and clinically-relevant cell dynamics]. Zdrav Vestn. 2018;87(7–8):335–48.
DOI: 10.6016/ZdravVestn.2642
1 Background
The article presents a systematic revi- ew of giant cell arteritis (GCA): its cli- nical course and the importance of early diagnosis and treatment for the preven- tion of complications such as blindness and stroke.
2 Introduction
Giant cell arteritis (GCA) is the most prevalent systemic vasculitis of the adult population (persons over 50 years of age) in the western world (1). It is an in- flammatory autoimmune disease with predominant involvement of large and
1 Department of Rheumatology, Division of Internal Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia
2 Faculty of Mathematics, Natural Science and Information Technologies, University of Primorska, Koper, Slovenia
3 Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
4 William Harvey Research institute, Queen Mary University of London, United Kingdom Correspondence:
Snežna Sodin Šemrl, e: ssodin1@yahoo.com Key words:
early giant cell arteritis;
biomarkers; therapy targets; cellular phenotypes; T cells Received: 13. 8. 2017 Accepted: 30. 11. 2017
medium sized arteries. It typically affects branches of the external carotid artery, as indicated also by its old name: temporal arteritis (2,3). This term was abandoned as a synonym for GCA already in 1994 at the Chapel Hill Consensus Conference (CHCC), because the disease may affect also other arteries, mainly the aorta and large branches of the aortic arch (e.g.
subclavian arteries, axillary arteries, ini- tial segment of brachial arteries). This is recognized in the updated definition adopted at the CHCC in 2012 (4,5). The estimated prevalence of GCA in per- sons over 50 years of age is 1:750, whi- le its incidence increases about 25-fold between the age groups 50–59 years and over 80 (6). The estimated annual inci- dence of GCA in Slovenia is 9.7 (95 % CI 8.1–15.5)/10
5in persons over 50 years of age (7).
Gender are race are risk factors for GCA; between 65 % and 75 % of patients are women (8). The incidence is highest in the Caucasian population of northern Europe (about 20/10
5persons over 50) and decreases towards the south.
Because of the late onset, environmental factors and life style (smoking, slender build) are believed to affect the suscep- tibility for the disease (8).
2.1 Clinical picture
The clinical picture of GCA inclu- des a wide range of symptoms and si- gns, which are partly general, caused by systemic inflammation, and partly specific, directly related to ischaemia due to reduced patency of arteries (3).
The most common specific symptom is newly developed headache. Other fre- quent complaints are claudication pain while chewing, scalp tenderness, and pain when combing hair. The tempo- ral artery may be swollen and tender to pressure. Occlusion of arteries nouri-
shing the eye may lead to visual symp- toms, most often manifested as double vision, blurred vision, or sudden tran- sient (amaurosis fugax) or permanent loss of vision. Permanent visual loss is often preceded by other transient symp- toms, and such warning signals warrant our full attention. Timely treatment can prevent permanent blindness. Untreated patients with unilateral loss of vision have a 50 % risk of losing sight in the other eye within a few days (9). A large meta-analysis has identified jaw claudi- cation and double vision as the best pre- dictors of GCA (10). Because of the high risk of permanent blindness (14–20 % of patients) (11-13) and stroke (2–4 % of patients) (14), GCA is classified as a rhe- umatological emergency.
Involvement of large arteries, pre- sent in 30–83 % of patients, is most often manifested by limb claudication and asymmetrical or absent limb pulses (15).
Involvement of the aorta, established in 10–18 % of cases, may lead to the de- velopment of an aneurysm and aortic dissection (15). Another characteristic of the disease is systemic inflammation with elevated inflammatory parameters, which may dominate the clinical pictu- re with general symptoms, such as fever, weight loss, anorexia, fatigue and myal- gia. Rheumatic polymyalgia (PMR) is closely related to GCA; it occurs in 40–
50 % of GCA patients (16,17), while GCA is diagnosed in 15 % of patients with PMR (18). Some authors describe the two conditions as different manifestati- ons of the same illness.
2.2 Diagnosis
Age over 50 years is one of the five
classification criteria for GCA pu-
blished by the American College of
Rheumatology (ACR). The others are
newly developed headache, clinical- ly abnormal temporal artery, eleva- ted erythrocyte sedimentation rate (ESR ≥ 50 mm/h), and abnormal tem- poral artery biopsy (19). For vasculitis to be classified as GCA, at least three of the five criteria must be met, which gi- ves a sensitivity of 93 % and a specificity of 91 %. It must be pointed out that the- se are classification criteria rather than diagnostic ones. Thus, they do not allow early recognition of the disease. We use them as an aid in diagnostic evaluation, but the diagnosis is clinical (20).
Until recently, temporal artery biopsy was the only “gold standard” for confir- ming the diagnosis of GCA. Today we know, however, that histopathological findings in the vessel wall are not easy to interpret, that the vascular inflammation is segmental (the inflamed segment may be missed on biopsy), and temporal arte- ry biopsy is negative in more than half of cases of extracranial involvement. Thus, temporal artery biopsy is currently losing its importance as the main and only con- firmation method for GCA (8). At pre- sent, the diagnosis is based on imaging studies, such as arterial ultrasound (US), computed tomography and/or magnetic resonance (CT/MR) angiography, and positron emission tomography (PET/
CT). Besides establishing the diagnosis, these examinations allow us to localize the disease and, at least partly, monitor its course. With the first three investiga- tions, we are able to estimate structural changes (vessel wall thickening, stenosis/
occlusion, thrombosis etc.), while PET permits early assessment of functional/
inflammatory activity of the disease in the vessel wall - possibly even before the occurrence of structural changes. US has priority over other imaging tech- niques because it is non-invasive, wi- dely accessible, inexpensive, and does not expose the patient to ionizing radi-
ation. It is suitable for evaluation of all large arteries except the thoracic aorta.
Two characteristic US findings in GCA are the halo sign and the compression sign (swelling of inflamed vessel wall does not disappear on application of pressure). The first multicentre study on the usefulness of ultrasonography in the diagnosis of GCA (TABUL) has con- firmed the important role of US in early recognition of the disease. It showed that US examination of the temporal artery has higher sensitivity and similar spe- cificity compared to biopsy (21,22). US follow-up is important in predicting treatment outcome (23). Besides US examination, PET/CT is an important diagnostic method in suspected involve- ment of extracranial large arteries, often manifested by fever of unclear origin or unexplained inflammatory syndrome.
PET imaging allows us to localize the di- sease, but its role in predicting treatment outcome is still unclear (23).
2.3 Treatment
Glucocorticoid (GC) therapy effecti- vely controls systemic infection and in most cases prevents the development of acute complications, e.g. permanent loss of vision. Nevertheless, about 50 % of patients experience relapses du- ring tapering of the GC dose (24). New drugs capable of maintaining disease remission are intensely explored (25).
Recommendations of the European League against Rheumatism (EULAR) from 2008 for GCA management include the use of immunosuppressive agents to reduce the side effects of glucocorticoids and maintain better disease control (26).
Methotrexate (MTX), formerly reported
to have low efficacy, is now often used in
relapses, since recent studies have do-
cumented considerable reductions in re-
lapse rates when MTX is given early as an
adjunct to GC (27-30). Some authors also use leflunomide as a corticosteroid-spa- ring agent in GCA (31). Recently, the U.S.
Food and Drug Administration (FDA) has approved the use of tocilizumab, a
monoclonal interleukin (IL) 6 receptor antibody, as the first biological drug for targeted treatment of GCA (32,33); trials with ustekinumab, an IL-12/23 inhibitor, are also underway (34,35).
Table 1: Studies with indicated time from onset of symptoms to diagnosis of GCA.
Source Title No. of GCA
patients Time from onset of symptoms to diagnosis Carbonella A. et al., J Am
Geriatr Soc. 2016(37) Immunosuppressive Therapy (Methotrexate or
Cyclophosphamide) in Combination with Corticosteroids in the Treatment of GCA: Comparison with Corticosteroids Alone
47 3.0 ± 1.9 weeks
Hocevar A.
et al., Medicine (Baltimore), 2016 (24)
Do Early Diagnosis and Glucocorticoid Treatment Decrease the Risk of Permanent Visual Loss and Early Relapses in Giant Cell Arteritis: A Prospective Longitudinal Study
68 30 (14-71) days
Seelinger B
et al., Rheumatology, 2015(38)
Predictors of Delay in Diagnosis of Giant Cell Arteritis and Antineutrophil Cytoplasm Antibody Associated Vasculitides:
Analysis of Data from the Diagnostic & Classification Criteria in Vasculitis Study
230 31 (13-85) days
Ezeonyeji A.N. et al., Clin
Rheumatology, 2011(39) Delays in recognition and management of GCA: results from a
retrospective audit 65 35 (2-140) days
Chandran A.K. et al., Scand J Rheumatol, 2015(40)
The Incidence of GCA in olmsted County Minnesota, over a
Sixty year Period 1950–2009 74 1.6 ± 2.6 months
Baldini M. et al., Arthritis
& Rheumatism, 2012(41) Selective Up-Regulation of the Soluble Pattern-Recognition
Receptor Pentraxin 3 and of VEGF in GCA 30 1.90 ± 0.35
(0.12–8) months Ciccia F. et al., Ann
Rheum Dis, 2016(42) Ectopic expression of CXCL13, BAFF, APRIL and LT-β is
associated with artery tertiary lymphoid organs in GCA 50 2 ± 11 months Labarca C.
et al., Rheumatology (oxford), 2016(43)
Predictors of relapse and treatment outcomes in biopsy-
proven giant cell arteritis: a retrospective cohort study 286 2.1 (0.9–4.4) months Muller G. et al., Geriatr
Gerontol Int, 2015(44) GCA (Horton’s disease) in very elderly patients aged 80 years
and older: A study of 25 cases 25 2.2 months
Muratore F.
et al., Rheumatology (oxford), 2015(45)
Large-vessel GCA: a cohort study 120 LV-GCA 3.5 (2–7.2) months
Alba M.A. et al., J Clin
Rheumatol. 2012(46) GCA in Mexican patients 22 67 ± 83.6 days
Alba M.A. et al., Medicine
(Baltimore). 2014(47) Relapses in Patients with GCA: Prevalence, characteristics and associated clinical findings in a longitudinally followed cohort of 106 patients
106 16 ± 21 tednov
Legend: BAFF: B-cell activating factor; CXCL13: chemokine (C-X-C motif) ligand 13; NA: not available; HBD: apparently healthy blood donors; GCA: giant cell arteritis; LT-β: Limfotoksin-beta; LV-GCA: large-vessel GCA; PMR: polymyalgia rheumatica. The data were taken from sources »ad verbum«.
3 Early GCA
Early diagnosis and treatment of GCA have a key influence on disease ou- tcome (36). We gathered data from stu- dies with indicated time from onset of symptoms to diagnosis (24,37-47). The selected studies were performed after the year 2010 and included at least 20 pati- ents (Table 1). In most of these studies, time to diagnosis was longer than one month. The shortest times to diagnosis were reported in 2016 by Carbonella A et al. (37) (average 3 ± 1.9 weeks) and by Hočevar A et al. (24) (median value 30 days, interquartile range 12–71). Early diagnosis is important because early ini- tiation of treatment increases the likeli- hood of preventing serious complicati- ons. Waiting times for a rheumatology consultation vary from country to cou- ntry. In some countries, patients receive glucocorticoids from their primary care physicians before referral to a rheumato- logist, whereas in some other countries, fast-track specialized outpatient clinics for GCA permit rapid diagnostic as- sessment.
Analysis of ocular complications re- veals a somewhat different picture. Singh et al. (2015) found no differences in time from onset of symptoms to diagnosis between patients with visual complica- tions or without them (median 26 and 24 days, respectively) (48). In a 25-year longitudinal study conducted in Spain, time to diagnosis was 10.3 (± 11) weeks, and the results showed that a decrease in the frequency of visual complications could not be attributed to a shorter time to diagnosis (49). Recent studies, howe- ver, suggest the opposite. One of them, performed by Hočevar et al., found uni- lateral blindness in 5.9 % (4/68) of GCA patients. The number of cases of perma- nent visual loss has decreased over the past few years, mainly as a consequen-
ce of increased physician awareness of GCA (50). Early recognition of the dise- ase and prompt initiation of glucocorti- coid therapy are the key to reducing se- rious complications.
4 Molecular targets in GCA therapy
GCA is currently treated with high initial doses of glucocorticoids, which are very effective. The GC dose is then gradually reduced. The entire treatment usually lasts 2 years. Because of the side effects of prolonged GC therapy and fre- quent relapses upon dose reduction, new treatment options are intensely explored.
Potential therapeutic targets are both cytokine and non-cytokine molecules.
4.1 Therapies targeting cytokine molecules
Interleukin (IL)-6. Serum levels of IL-6, the main trigger for the synthesis of C-reactive protein (CRP) and serum amyloid A (SAA), are significantly ele- vated in untreated patients with GCA;
the levels transiently decrease after tre- atment, and are often higher in patients with chronic disease compared to he- althy subjects (8). Significantly higher IL-6 levels in GCA patients compared to healthy blood donors were demonstra- ted by several methods in a number of studies (51-59). Similarly, expression le- vels of IL-6 messenger ribonucleic acid (mRNK) in temporal artery biopsies from GCA patients were significantly higher compared to controls (52,60,61).
Dasgupta B and Panayi GS (62) re-
ported that IL-6 activity was elevated in
all patients with untreated GCA. Six ye-
ars ago, anti–IL-6 receptor therapy was
proposed for the treatment of GCA (63),
following the publication of several ca-
ses of rapidly induced remission by IL-6
blockade (64). In 2013, Unizony SH et al. (25) published a justification, design and protocol for a large clinical trial of tocilizumab (anti-IL-6R) with 250 inclu- ded patients. The authors proposed the hypothesis that disruption of the IL-6 signalling pathway could have a favoura- ble effect on GCA outcome. Preliminary results on the use of anti-IL-6 are encou- raging (65). A recent phase 2 randomized double-blind placebo-controlled trial was the first to demonstrate the efficacy of tocilizumab in inducing and main- taining remission (66). The same group of researchers also found a 55 % relapse rate in patients after termination of to- cilizumab treatment, the median time to relapse being 5 months. Their results showed that long-term administration of tocilizumab is necessary for the main- tenance of remission. In a recent report, Stone et al. evaluated the efficacy and safety of tocilizumab in patients recei- ving the drug for up to 52 weeks as part of the GiACTA randomized double-blind placebo-controlled trial, and concluded that tocilizumab in combination with 26-week GC treatment was more effecti- ve than GC monotherapy (68). On the other hand, a multicentre retrospective study of tocilizumab in 34 patients with GCA called attention to serious side effects of the drug that occurred in 17 % of the patients: neutropenia (3 patients), infection (1 patient developed tuber- culous pericarditis and 1 died of septic shock), and liver cirrhosis (in a patient with concurrent MTX therapy) (69).
IL-1 receptor antagonist. In a study including 3 patients with GCA, tre- atment with an IL-1 receptor antagonist (anakinra) led to improvement in symp- toms and inflammatory markers (70,71).
Also relevant is the finding that IL-1Ra knockout mice developed large-vessel vasculitis (72). Additional studies are necessary for further evaluation of the
drug, since IL-1 receptor antagonist has less favourable pharmacokinetic pro- perties, and an excess over endogenous IL-1 is required for its efficacy (70,71).
Preparations are underway for a pha- se 3 GiAnT trial of anakinra (US Clin trial.gov identifier NCT02902731) with the main aim to determine whether the addition of anakinra to GC therapy can prevent GCA relapses.
IL-1β. A clinical trial of gevokizumab (an anti-IL-1β monoclonal antibody) in patients with relapsing GCA (European Clinical Trials Database identifier 2013–
002778–38) is in progress. Dasgupta B, reporting on the use of anti-I-1β, stated that IL-1 is produced by the majority of activated circulatory monocytes (72).
IL-1 originating from the vessel wall cor- relates with the systemic inflammatory response in patients with GCA.
IL-12/IL-23. Ustekinumab, a mo- noclonal antibody against IL-12/23p40, is effective in the treatment of Crohn’s disease and psoriasis. Since it inhibits Th1 (IL-12, IFN-γ) and Th17 (IL-23, IL-1) cell responses, it could be effective also in the treatment of large-vessel vasculi- tides, such as GCA. Conway R et al. re- ported on a study of 14 patients with re- fractory GCA (34), defined as failure to taper GC (prednisolone) below 10 mg/
day or symptoms of active disease with at least two relapses (19). Ustekinumab allowed a significant reduction of the GC dose and discontinuation of other immunosuppressive drugs. In 2016, Conway R et al. published data on long- -term efficacy of ustekinumab, which led to significant reductions in doses of glu- cocorticoids and acute-phase proteins in patients with refractory GCA (35).
IL-17. This cytokine is thought to play an important role in the development of vascular wall inflammation in GCA.
Significantly increased expression of IL-
17 has been measured in temporal arte-
ry biopsies from patients with GCA by the method of quantitative polymerase chain reaction (QPCR) (42,52,73,74).
Moreover, mice deficient in interferon regulatory factor 4 binding protein, which inhibits IL-17A, have been shown to develop large vessel vasculitis (75).
Marquez et al. (2014) published a large meta-analysis, which included 1,266 bi- opsy-proven GCA patients and 3,779 he- althy blood donors from four European countries (Spain, Italy, Germany and Norway). The authors reported a novel association between polymorphisms within the IL-17A locus and GCA (76).
From peripheral white blood cells, they extracted genomic deoxyribonucleic acid (DNA) and analysed it for five sin- gle nucleotide polymorphisms (SNPs) located at the IL-17A locus. They iden- tified three polymorphisms that repre- sent a risk for the development of GCA.
Surprisingly, they found the strongest as- sociation with rs2275913, located within a binding motif for the transcription nu- clear factor of activated T cells (NFAT), a central regulator of the IL-17A promo- ter (76).
IL-17 inhibition has been tested in several clinical studies of different auto- immune diseases, using different biolo- gical drugs (sekukinumab, ixekizumab, and brodalumab) and agents (ABT-122, RG4934, RG7624, SHC-900117, and SHC- 900222, also called MK-3222). Positive and negative results were obtained, and the complexity in predicting the patient’s response to treatment directed against IL-17 was described. Despite conflicting results, it is clear that the circulating va- lues of IL-17A in healthy blood donors and GCA patients are very low (77). The role of IL-17A as a target molecule in the treatment of patients with GCA is cur- rently unclear. There have been no stu- dies with IL-17 inhibitors published to date.
TNF-α. TNF-α is significantly increa- sed in blood serum and temporal artery biopsies from patients with GCA, both at the protein level (53,59,78) and the mRNA level (60,79). However, it has not proved to be a good candidate for the- rapy. Clinical trials of TNF-α inhibitors (infliximab, etanercept and adalimumab) in patients with GCA failed to achie- ve good treatment outcomes (80-82).
EULAR guidelines from the year 2009 do not recommend using TNF-α inhibi- tors in the treatment of GCA.
4.2 Other non-cytokine molecules
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) – abatacept.
Abatacept is a fusion protein composed
of an IgG1 fragment fused to the extra-
cellular domain of CTLA-4. It binds to
CD80/86 on antigen presenting cells
and prevents their binding to CD28 on
the T cell and their activation. Langford
et al. (83) recently completed a multicen-
tre clinical trial (Clinicaltrials.gov iden-
tifier: NCT00556439) in which patients
with GCA and Takayasu arteritis recei-
ved induction treatment with abatacept
10 mg/kg intravenously on days 1, 15, 29
and week 8, together with oral predni-
solone. From the preliminary data for
GCA published in abstract form (83), it
appears that 41 patients with GCA un-
derwent randomization at week 12; 20
patients continued to receive abatacept
and 21 were switched to placebo. The pa-
tients treated with abatacept had a signi-
ficantly higher relapse-free survival rate
at 12 months (48 % vs. 31 %) and a signifi-
cantly longer duration of remission (9.9
vs. 3.9 months) than the patients who
received placebo. Although the results
are promising, they will require further
confirmation in a larger series. A criti-
cal review of abatacept and other latest
advances in the management of GCA was recently published by Koster MJ et al. (84).
CD20. GCA is considered primarily a T-cell disease, but B-cell dysregulation is present as well (84). The potential use of rituksimab in GCA was proposed in 2 case reports in 2005 (85) and 2007 (86).
Rho kinase (ROCK). Expression of ROCK mRNA is elevated in tempo- ral artery biopsies from patients with GCA (87). Altered ROCK activity cou- ld play a role in vascular inflammation.
Future studies should address the questi- ons: how to inhibit ROCK activity, and how this would affect the physiological characteristics of immune cells, such as signalling and phagocytosis.
Neurogenic locus notch homolo- gue protein (NOTCH). In humanized mouse models, NOTHC inhibition was effective in downregulating the Th17 re- sponse and suppressing the Th1 respon- se while depleting T-cell infiltrates from the vascular lesion (88). Disruption of the NOTCH signalling pathway stron- gly inhibits T-cell activation in the early and established phases of vascu- lar inflammation. Modulation of the NOTCH response has been proposed as a new strategy for immunosuppressi- ve treatment of large vessel vasculitides.
Since studies of both the ROCK and the NOTCH pathways are still at a pre-cli- nical stage, the two pathways are for the time being only potential therapeutic targets in GCA.
Janus kinase inhibitor (JAK). A clinical study evaluating the safety and efficacy of baricitinib (a JAK1 and JAK2 inhibitor) in patients with GCA is in progress (Clinical trial identifier NCT03026504).
5 Clinically significant cell dynamics involved in the development of GCA – selected studies
Of primary importance for GCA im- munopathology at the cell level are the Th1 (in the chronic phase of the disea- se) and Th17 (in the early phase) cell responses (89). Fernandez-Fernandez FJ (90) recently proposed using alfacal- cidol, a hormone preparation of vitamin D, which unlike vitamin D2 or D3, has in vivo and in vitro immunomodulatory effects, as adjuvant treatment in GCA.
Alfacalcidol could affect the Treg/Th17 cell ratio. This was confirmed by Zold et al. (91), who showed that 1 µg of alfa- calcidol daily reduced the levels of IL-6.
IL-17, IL-12 and IFN-γ, as well as the pro- portion of circulating Th1 and Th17 cells, while increasing the number of circula- ting Treg cells and restoring their inhibi- tory function. The role of alfacalcidol in the treatment of GCA warrants further study. The active form of vitamin D (1,25 dihydroxycholecalciferol), in combina- tion with IL-2, has also been shown to suppress the Th1 and Th17 cell responses and stimulate Treg cells (92).
Samson M et al. (93) were the first to show that the number of Treg cells is decreased in patients with GCA, and that CD161+CD4+ T lymphocytes, di- fferentiated into Th1 and Th17 cells, are involved in the pathogenesis of GCA.
Fundamental differences were found
between Th1 cells and Th17 cells regar-
ding their dependency on acetyl-coA
carboxylase 1-mediated de novo fatty
acid synthesis, which might be exploited
as a new strategy for metabolic immu-
ne modulation of Th17 cell-mediated
inflammatory diseases (94). Circulating
T cell (CD8+) values are decreased
in GCA, and the decrease correlates
with the degree of carotid artery ste- nosis (95,96). Samson M et al. (97) also reported on the predictive role of CD8+
T cells. Interestingly, neutrophils are also thought to have a potential role in the development of GCA, as reported in 2014 by Nadkarni S et al. (98), who described the existence of an increased inflammatory phenotype during tape- ring of the GC dose. The authors descri- bed a specific neutrophil phenotype (high expression of CD62L and Annexin A1 (AnxA1) and low CD11b) appearing early in the course of the disease during treatment with high GC doses. Upon tapering of GC doses, they observed an inflammatory phenotype (low CD62L, high CD11b, high AnxA1) appearing in a certain group of patients, which cou- ld predict undesired complications and relapses. It must be pointed out that the study included a small number of pati- ents. Thus, a greater number of patients will be necessary to assess the potential predictive role of this neutrophil phe- notype. The study also highlighted an interesting association between certa- in previously mentioned cytokines, as it analysed the values of IL-6 and IL-17 during tapering of GC doses. Incubation of healthy neutrophil granulocytes with pathological concentrations of the two cytokines (such as are present in GCA)
promotes the inflammatory neutrophil phenotype, which represents a possible causative relationship between circula- tory and cellular mechanisms involved in the development of relapsing disease and adverse cardiovascular events.
6 Conclusion
Shortening the time interval from symptom onset to diagnosis and intro- ducing new treatment options could im- prove the prevention of serious compli- cations in patients with GCA. Fast-track specialized diagnostic outpatient clinics for GCA are currently the most effective approach to the prevention of complica- tions and better control of the disease.
Clinical trials of new therapeutic opti- ons are underway, the most promising currently being tocilizumab. Although newer approaches to treatment are ma- inly directed against single target mo- lecules, GCA calls for a broad view, the disease being complex and of multifacto- rial aetiology, with the defect at several levels of cellular and humoral immunity.
Therefore, we believe that knowledge of the cell dynamics and determination of neutrophil granulocytes and the T cell and B cell populations could contribute to predicting the disease process, relap- ses, and the patient’s response to therapy.
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