Review One year in review 2021: systemic vasculitis - Clinical ...
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Review
One year in review 2021: systemic vasculitis
F. Ferro1, L. Quartuccio2, S. Monti3, P. Delvino3, F. Di Cianni1, S. Fonzetti1,
G. La Rocca1, C. Posarelli4, E. Treppo2, R. Talarico1, C. Baldini1
1
Rheumatology Unit, Department of ABSTRACT current clinical research is focusing on
Clinical and Experimental Medicine, Large- and small-vessel vasculitis are searching for a biomarker “signature”
University of Pisa; complex potentially life-threatening able to reveal the complex sequence of
2
Rheumatology Clinic, Department of
systemic autoimmune diseases that have events leading from inflammation to
Medical and Biological Sciences,
University Hospital Santa Maria della recently been subjected to considerable lymphoma.
Misericordia, Udine; immunologic and clinical research. From this perspective, it is widely rec-
3
Department of Rheumatology, University Following the other reviews of this se- ognised that genetic background can
of Pavia, IRCCS Policlinico S. Matteo ries, here we aim to summarise some influence the phenotype and outcome
Foundation, Pavia; of the most significant studies that have of HCV-related diseases. De Re et al.
4
Ophthalmology Unit, Department of been recently published on the patho- (4) lately highlighted an epistatic con-
Surgical, Medical, Molecular Pathology
genesis, clinical features and novel tribution of IFNL4 and PDCD1 genes
and Emergency, University of Pisa, Italy.
treatments of systemic vasculitis. in patients with MC. Particularly, PD-
Francesco Ferro, MD
1[ACG]-IFNL4[C] is positively as-
Luca Quartuccio, MD, PhD
Sara Monti, MD Introduction sociated with MC (OR=4.237), and
Paolo Delvino, MD Systemic vasculitis are complex and the opposite haplotype PD-1[GTA]-
Federica Di Cianni, MD heterogeneous diseases potentially IFNL4[T] (OR=0.458) is negatively
Silvia Fonzetti, MD leading to severe morbidity and mor- associated with MC. The association
Gaetano La Rocca, MD tality. Following the previous annual between PDCD1 polymorphisms and
Chiara Posarelli, MD, PhD reviews (1-3) of this publishing series, the risk of HCV-related lymphopro-
Elena Treppo, MD
we will here provide a critical digest of liferative disorders should be further
Rosarai Talarico, MD
Chiara Baldini, MD, PhD the most relevant literature on epide- investigated.
Please address correspondence to:
miology, classification, pathogenesis, Besides genetics, several biological
Francesco Ferro, clinical features and novel treatments biomarkers have been also investigat-
Reumatologia, Dipartimento di of small- and large-vessel (LVV) sys- ed. Basile et al. (5) confirmed that se-
Medicina Clinica e Sperimentale, temic vasculitis. All the articles were rum levels of IgG3 subclass were high-
Università di Pisa critically analysed in order to select er in HCV-MC patients compared with
Via Roma 67, the most relevant contributions on rheumatoid arthritis (RA)-patients, re-
56126 Pisa, Italy. theese topics. inforcing the key role of IgG3 as the in-
E-mail: francescoferrodoc@gmail.com
itial trigger of cryoglobulins formation
Received on April 25, 2021; accepted in Cryoglobulinaemic vasculitis and, in turn, in the vasculitic process
revised form on May 4, 2021.
Pathophysiology advances in hepatitis underlying cryoglobulinaemic vascu-
Clin Exp Rheumatol 2021; 39 (Suppl. 129): C virus-cryoglobulinaemic vasculitis litis (CV). Another Italian study (6),
S3-S12.
Mixed cryoglobulinaemia (MC) syn- demonstrated that levels of soluble (s)
© Copyright CLINICAL AND
drome is the prototype of hepatitis C CD138, k-free and λ-free chains were
EXPERIMENTAL RHEUMATOLOGY 2021.
virus (HCV)-driven autoimmune and significantly higher in HCV-non Hodg-
Key words: large-vessel vasculitis, lymphoproliferative disorders. The kin lymphoma (NHL) patients than in
cryoglobulinaemia, ANCA-associated HCV trigger effect leads to permanent healthy controls. However, free k and λ
vasculitis clones of B-lymphocytes producing and the k/λ ratio were inversely related
oligoclonal or monoclonal IgM with with sCD138; the authors suggest that
rheumatoid factor (RF) activity, en- sCD138 may reflect more closely the
coded by the VH1-69 heavy chain gene lymphoma risk of the disease while the
paired with VK3-20 light chain vari- prognostic value of the free light chains
able gene, thus representing the com- (FLC) remain uncertain being altered
mon link for inflammatory and lym- by the presence of a monoclonal IgM
phoproliferative alterations. Indeed, component.
HCV-MC patients display a 35-fold Regarding epigenetic biomarkers, it
higher risk of developing lymphoma was observed a downregulation of
Competing interests: none declared. than the general population, therefore miR-26b in HCV-CV and HCV-NHL
Clinical and Experimental Rheumatology 2021 S-3One year in review 2021: vasculitis / F. Ferro et al.
patients, and a restoration of micro- and a strong immunoregulatory mecha- glomerular filtration rate (GFR), pro-
RNAs (miRNAs) miR-26b levels in nism that delay the lymphomagenesis teinuria and age (13).
CV patients after treatment-induced process (9). On the contrary, old pSS Despite these comforting results, we
clinical remission of vasculitis. The lymphoma patients presented very know that cryoglobulins and RF can
functional effectors of miR-26b are the early lymphoma, suggesting an immu- be detected in most cases after DAAs
lymphoid enhancer-binding factor 1, nosenescence incapable to contrast the therapy, reflecting the persistence of
overexpressed in pre-lymphomatous lymphomagenesis (9). B-cells autoreactive clones. These
conditions, therefore the downregula- Finally, among recent literature con- “dormant” cells may be reactivated by
tion of miR-26b could be an indicator tributions on non-infectious MC cases events that perturb B-cell homeostasis,
of a molecular mechanism of tumor classified as idiopathic or essential MC therefore, even in the DAA era, relapses
progression (7). The first miRNA with (EMC), the study by Del Padre M et al. of MC or cases refractory to treatment
an accepted oncogenetic role was miR (10) is worth to be quoted. The authors are described. In these patients, rituxi-
17-92, known as oncomiR-1. Lorini et (10) showed that when compared to mab (RTX) might be used as additional
al. (7) analysed the expression levels of HCV-MC patients, EMC patients had therapy (14). The timing of anti-CD20
miR 17-92 in 20 CV patients pre- and lower circulating CD21low B-cells, treatment and dosages are still debated
post-antiviral therapy. A significant re- mainly naïve-like CD21lowCD27- in MC patients, and the identification
duction in the expression levels of miR cells. CD21low B-cells of EMC and of serological biomarkers of mini-
17-92 following viral eradication was HCV-MC shared functional features of mal residual disease (MRD) in RTX-
observed, even if they did not reach exhaustion and had defective prolifera- treated MC patients could improve
levels comparable to those pre-therapy tive responses to ligation of Toll-like the MC-management. High levels of
in the control group (HCV patients receptor 9 (TLR9), supporting a com- FLCs, heavy/light chains (HLCs), and
without CV) (7). mon pathogenetic mechanism with au- vascular growth factor (VEGF) allow
toantigen-driven clonal expansion and to recognise a MRD in RTX-treated
New insights in hepatitis C virus- exhaustion of selected RF producing patients, representing a possible sig-
negative cryoglobulinaemic vasculitis B-cells (10). nature of “dormant” B cell clones’
Concerning HCV-negative cryoglo- activity (14), and the re-treatment of
bulinemia, the vast majority of HCV- New insights in these patients could prevent a relapse.
negative CV cases has been described HCV-cryoglobulinaemic Despite the safety and effectiveness of
in primary Sjögren’s syndrome (pSS) vasculitis therapy RTX (15), a retrospective French study
(8) being the presence of cryoglobu- The introduction of DAAs has radi- revealed a low risk (3.4%) of CV exac-
linemia a well recognised risk factor cally transformed the management of erbation within two weeks after RTX.
for lymphoma development. Lately, HCV-CV and has changed the epide- These CV-flares have been reported
a multicentre study on 1997 consecu- miology of MC. A large observational more frequently in patients with renal
tive pSS patients explored lymphoma longitudinal French cohort study (11) involvement, B-cell lymphoprolifera-
incidence and risk factors in individu- has shown a 1.5 fold decrease in inci- tion, a higher level of cryoglobulin and
als with early disease-onset (young dent MC cases between 2011-2014 and lower level of C4 (16).
≤35years) in comparison with patients 2015-2018 periods. Furthermore, in the Lastly, non-infectious RTX-refractory
with late disease-onset (old ≥65years). 2016-2018 period, HCV was no longer CV showed usually an overexpression
Cryoglobulinaemia remains an inde- the leading cause of MC whereas sys- of BAFF levels. Thus, several case se-
pendent lymphoma-associated factor temic autoimmune disease (i.e. sys- ries have further supported the efficacy
in younger pSS patients in addition to temic lupus erythematosus (SLE) and of sequential therapy by anti CD20
other traditional lymphoma risk factors pSS) represent the main causes of MC treatment and belimumab in the case of
such as: low C4, lymphadenopathy, and and CV (11). pSS-refractory CV (17-19).
SGE. By contrast, in older pSS patients Lately, DAAs have confirmed their ef- In the upcoming years, we speculate
SGE, low C4 and male gender but not ficacy in virological response achieve- that the incidence of HCV-MC will
cryoglobulinaemia were identified as ment (sustained virological response continue to decline along with its mor-
independent lymphoma-associated fac- [SVR] rates greater than 95%) and in tality, thus major interest could move
tors. Moreover, young pSS lymphoma the reduction of the mean cryocrit level on different clinical phenotypes of non-
patients presented two different peaks and RF level in MC patients at the end infectious MC and their risk of NHL
of incidence for lymphoma: the first of treatment (EOT) (12). Importantly, development and mortality (20), estab-
one within 3 years from pSS onset and results from the RENALCRYOGLOB- lishing an era of precision medicine.
the second one after 10 years of disease ULINEMIC study indicated that DAA
duration. The first peak was explained treatment improves also kidney surviv- Take home messages
by a strong B cell response along with al and reduces mortality in HCV-MC • Novel genetic and epigenetic bio-
classical risk factor for lymphoma, compared with control patients treated markers that can be useful to predict
while the second one was assigned to with pegylated interferon-ribavirin lymphoma risk in HCV-CV have
a longstanding stimulation of B-cells (IFN±RBV), regardless of the initial been identified;
S-4 Clinical and Experimental Rheumatology 2021One year in review 2021: vasculitis / F. Ferro et al.
• The value of cryoglobulinaemia as improving the early diagnosis and arterial wall whereas positron emission
an independent lymphoma risk fac- treatment of GCA. These guidelines tomography (PET) shows an increased
tor has been demonstrated in young- recommends either temporal artery uptake of fluorodeoxyglucose (FDG)
er pSS patients with HCV-negative biopsy (TAB) or ultrasound of tempo- in active vasculitis. A whole-body ex-
CV but not in the older ones; ral artery as confirmatory diagnostic amination is suggested with particu-
• Important progresses have been test for cranial GCA. Indeed, a diag- lar attention to aorta and aortic main
made to speculate on the positioning nostic approach has been proposed to branches and extracranial cephalic
of DAA and RTX, alone or in com- perform either one or both these tests, arteries. The homogeneous segmental
bination, in therapeutic algorithms depending on the estimated probability FDG uptake of those vessels higher
in HCV-CV. of GCA diagnosis. In the absence of than liver uptake indicates LVV; but
clinical features of cranial GCA, imag- lower uptake intensity and non-homo-
Large-vessel vasculitis ing of the extracranial vessels should geneous distribution patterns should
Pathophysiology advances in be considered in order to evaluate the be suspicious of an alternative diagno-
large-vessel vasculitis involvement of aorta and its proximal sis (31). High-resolution ultrasound is
During the last twelve months, interest- branches (24). important to identify smaller arteries
ing efforts have been made towards the Moreover, the recognition of GCA has while MRI and PET/CT display bet-
identification of molecular biomarkers been further improved by highlighting ter extracranial arteries. Unfortunately,
involved in the pathogenesis of LVV. possible unusual manifestation at the imaging sensitivity decreases with
In particular, both angiogenic induc- onset of the disease such as concomi- treatment so an important issue affect-
ers (VEGF, FGF-2, angiopoietin 1, -2, tant pericardial disease (25). Patients ing all these tools is represented by a
soluble VCAM-1) and inhibitors (an- developing pericardial effusion as ini- corrected timing (32).
giostatin, endostatin, pentraxin-3) have tial disease manifestation might repre- As well known, another main issue,
been implied in LVV angiogenesis dys- sent a clinical phenotype of GCA with particularly related to CDU is the inter-
regulation. When analysed in peripher- less cranial symptoms and a better prog- operator reproducibility; nevertheless,
al blood samples, only VEGF was sig- nosis, but more studies are required to the introduction of artificial intelligence
nificantly higher in Takayasu’s arteritis confirm this hypothesis. In the frame- algorithms improved the detection of
(TAK) patients compared to healthy work of outcome for GCA, Hočevar et the halo sign on CDU images. Data
controls (no difference was found in gi- al. identified jaw claudication, smoking from 137 patients were retrospectively
ant cell arteritis (GCA) patients), while and increasing age as factors most sig- collected and analysed using the VIA
angiostatin, endostatin and PTX3 were nificantly predictive of cranial ischae- software. A sensitivity of 60% and a
significantly higher in both GCA and mic complications in GCA (26). specificity of 95% was reached after the
TAK patients. These biomarkers also definition of an image positivity thresh-
correlated with disease activity evalu- New insights in LVV imaging old. The main confounding factors
ated by using PET scan and clinical Temporal artery biopsy (TAB) repre- identified were the presence of a throm-
indices (21). sents the gold standard for GCA diag- bus and the acquisition modalities and
In addition to angiogenic biomarkes, nosis. Recently, however, ultrasonog- even if further validation is needed, the
the role of inflammatory cells in patho- raphy (US) has been recognised at least approach seems promising (33).
genesis of TAK has been also the ob- equivalent to histology in confirming Other imaging techniques have been
jective of several studies (22, 23). TAK the diagnosis of LVV (27). Moreover, evaluated for diagnosis of GCA such
patients showed a decreased number the sensitivity and specificity of color as 3T-MRI with 2D sequences and full-
of peripheral blood natural killer (NK) duplex ultrasonography (CDU) highly field optical coherence tomography
cells, as well as a reduced production increases when considering also axil- (FF-OCT). Rodriguez-Régent et al.
of granzyme B and perforin compared lary artery (28). Notably, even not well evaluated the diagnostic performance
to control group. More specifically, predictive of future ischaemic events, of fat-suppressed 3D T1-weighted
granzyme B-expressing NK cells were US findings seems to strongly correlate black-blood MRI (CUBE T1) with 3D
lower in active TAK compared to inac- to the clinical features, final diagnosis TOF coregistration. The examination
tive TAK. On the other hand, T helper- and outcome of GCA (29). Ultrasound was performed in 32 patients with clin-
like Treg cells were lower in peripheral may also be important during follow- ically suspected GCA and 10 patients
blood of TAK patients with respect to up to evaluate the effect of steroids with diagnosis of GCA. CUBE showed
healthy controls, suggesting these cells treatment; major findings displayed a sensitivity of 80% and a specificity
might play a role in TAK pathogenesis. a change along temporal circulation of 100%, suggesting a reproducible use
with reduction of the hyperechoic wall of MRI along the diagnostic process of
New insights in LVV clinical features thickening than in axillary arteries (30). GCA (34).
The guidelines on diagnosis and treat- Specifically, ultrasonography (US), FF-OCT uses white light interference
ment of GCA from the British Society magnetic resonance imaging (MRI) microscopy to obtain high resolution
for Rheumatology have lately repre- and computed tomography (CT) dem- images of biological structures and also
sented an important step forward in onstrate a concentric thickening of the of subcellular metabolic contrast in the
Clinical and Experimental Rheumatology 2021 S-5One year in review 2021: vasculitis / F. Ferro et al.
tissue depth. Maldiney et al. reported guidelines on diagnosis and treatment were observed in 75% and 66% of
their experience applying high defini- of GCA (24) confirming the important GCA and TAK patients, respectively.
tion interference microscopy for path- evidence-based advances to support No significant increase of relapse risk
ological diagnosis of GCA. FF-OCT the management of LVV. in the year following tocilizumab dis-
revealed its potential for qualitative In a recent meta-analysis of 34 studies continuation was observed.
and quantitative evaluation of arterial (8 RCTs), including 2505 GCA patients Given the suppression of inflammatory
wall identifying architectural change treated with glucocorticoids (GC) markers provoked by the inhibition of
and fibrous tissue formation. This pre- alone, about half of the patients expe- the interleukin (IL)-6 pathway, imag-
liminary report encourages further re- rienced one or more than one relapses ing modalities, such as CDU of tem-
searches to confirm the role of this de- during follow-up. Notably, relapse rate poral arteries/large vessels and 18FDG
vice, especially using a handheld acqui- was significantly higher for patients PET-CT, may play a crucial role in the
sition probe to image the artery directly enrolled in RCTs compared to patients follow-up of patients receiving tocili-
(transcutaneous approach), rapidly and from observational studies (65.8% vs. zumab. In a recent study enrolling 22
with a non-invasive examination (35). 41.7%), mainly due to a shorter dura- consecutive GCA patients, tocilizumab
The role of imaging in Takayasu arteri- tion of GC therapy (39). induced remission in 91% of patients,
tis (TAK) has been widely recognised In order to decrease the risk of relapse confirming its effective GC-sparing
especially regarding management, nev- during GC tapering and minimise role, as well as a significant reduction
ertheless diagnosis remains difficult chronic GC exposure, several studies of quantitative assessment of both CDU
and delayed. In this regard, Kenar et have focused on maintenance treat- halo thickness of TA/large vessels and
al. defined disease activity according to ment strategies and GC-sparing regi- 18FDG PET-CT vascular uptake (44).
vascular imaging (Rad-Active) and ver- mens in GCA. Song et al. performed A recent multicentre, randomised, dou-
ified its agreement with other disease a meta-analysis of 6 RCTs assessing ble-blind, placebo-controlled trial evalu-
activity indexes; 76% of agreement was the efficacy and safety of tocilizumab, ated the efficacy of different therapeutic
observed with physician global assess- tumor necrosis factor (TNF)-inhibitors schedules of sirukumab, a selective,
ment and 83% with with Kerr’s criteria, and abatacept for the treatment of GCA high-affinity human anti-IL-6 mono-
confirming the key role of imaging in (40). Relapse rate and risk of serious clonal antibody, in patients with active
TAK to detect disease activity (36). adverse events (AE) was significantly GCA (45). Despite early study termina-
Finally, Goel et al. explored the pos- lower with tocilizumab than with pla- tion resulting in short treatment duration,
sibility of an angiographic-based dis- cebo, whereas no significant benefit in the proportion of patients with relapses
ease classification, potentially helpful terms of remission rate was observed at 52 weeks was significantly lower with
in identifying three novel cluster of between groups receiving TNF-inhibi- sirukumab than with placebo.
patients based on arterial damage. Pa- tors, abatacept, and placebo. Despite some initial promising results
tients in cluster one presented more dis- To determine if the results of the Gi- on the effectiveness of ustekinumab
ease in the abdominal aorta, renal and ACTA study (41) could be rationally (46), a recent open-label trial was pre-
mesenteric arteries; patients in cluster extended to real-world clinical practice, maturely interrupted, as 7 out of the ini-
two had more bilateral disease and the Calderón-Goercke et al. conducted a tial 10 patients relapsed soon after GC
carotids and subclavian arteries are comparative study between the GiAC- discontinuation (47).
more involved. Finally, patients in clus- TA trial (251 patients) and a multicentre In a multicentre retrospective case-con-
ter three had asymmetric disease with series of GCA patients treated with to- trol study, Quartuccio et al. analysed the
less territories involved. These three cilizumab in a real-world scenario (134 rate of GC-related AE in 114 GCA pa-
clusters still require validation and patients)(42). Sustained remission rate tients treated with an immunosuppres-
their aetiological and prognostic value did not differ between the two groups sant within 3 months from diagnosis,
need to be confirmed through further (54.6% in the GiACTA trial vs. 70.4% compared to 51 GCA patients who re-
research but it is surely an interesting in clinical practice group). Neverthe- ceived GC monotherapy or an immuno-
topic to be explored (37). Globally, all less, a higher cumulative GC dose and suppressant after at least 3 months high-
these data further confirmed how the a higher proportion of patients treated lighting the significantly higher rate of
role of imaging in LVV is of undoubt- with a conventional immunosuppres- GC-related AE and relapses in patients
ful importance in order to confirm the sive agent was observed in the clinical treated with monotherapy (48).
diagnosis and avoid important delay in practice group, contributing to a higher A recent case series of 14 GCA patients
their management. risk of serious infections. suggested some benefits from adjunc-
In order to mitigate GC-related AE, tive treatment with leflunomide, with
New insights in LVV treatment tocilizumab monotherapy, adminis- 64% of patients achieving remission at
In 2020, the publication of the 2018 tered for 1 year without concomitant 6 month (49). In a retrospective study
update of the EULAR recommenda- GC, was tested in an open-label study including 37 patients with LV-GCA
tions for the management of LVV (38), including 12 patients with newly diag- followed for ≥2 years, the introduction
has been followed by the release of nosed LVV (8 GCA, 4 TAK), followed of mycophenolate mofetil at diagnosis
the British Society for Rheumatology for 2 years (43). Complete responses yielded a GC-sparing effect, with rela-
S-6 Clinical and Experimental Rheumatology 2021One year in review 2021: vasculitis / F. Ferro et al. tively low relapse rates (16.2 and 27% significantly higher rates of remission ent ANCA serotypes (i.e. proteinase 3 at 1 year and 2 years, respectively) (50). at 12 months in patients treated with (PR3)-ANCA and myeloperoxidase These promising results require confir- leflunomide (ranging 77.4–84.6% vs. (MPO)-ANCA) has been further under- mation in larger cohorts or clinical trials. 38.2–53.5%) (58, 59). lined by two recent original papers. The The evidence published during the last Finally, an observational study enroll- first one by Lee et al. (66) showed that 12 months regarding TAK confirmed ing 68 patients with TAK compared PR3 antibody production may even pre- the long-term efficacy and safety of to- the effectiveness of leflunomide (40 cede the development of vasculitis. The cilizumab. A 96-week extension of the patients) versus methotrexate (28 pa- second one by van Dam et al. (67) dem- TAK treated with tocilizumab (TAKT) tients). Prevalence of complete remis- onstrated that the increased production trial including 28 patients treated with sion at 6 months was achieved by a sig- of PR3 antibodies also predicts relapses weekly tocilizumab showed a steroid- nificantly higher proportion of patients in patients treated with rituximab pin sparing effect, improvement in imaging treated with leflunomide compared to pointing the crucial role of ANCA se- findings (17.9% of patients) or stable methotrexate (72.5% vs. 53.6%). How- rotypes in the pathogenesis of ANCA imaging findings (67.9% of patients) ever, the benefit was not confirmed and also their potential usefulness as compared to baseline (51). A French during longer follow-up, despite a therapeutic biomarkers in the manage- open-label trial in naïve patients with lower frequency of relapses in patients ment of AAV patients. Besides ANCA, TAK assessed the chances of glucocor- treated with leflunomide (60). great attention has been paid to neutro- ticoids discontinuation after 7 infusions phils and to the alternative complement of tocilizumab which was achieved by Take home messages pathway. Moiseev et al. (68) evaluated 54% of patients. However, after dis- • Angiogenic inducers (VEGF, FGF-2, complement components in 59 AAV continuation of tocilizumab, approxi- angiopoietin 1, -2, soluble VCAM-1) patients and performed a meta-analysis mately half of the patients relapsed and inhibitors (angiostatin, endosta- on the topic highlighting that plasma suggesting that long-term maintenance tin, pentraxin-3) have been implied MAC, C5a and factor B were increased treatment is necessary (52). in LVV angiogenesis dysregulation in patients with active AAV compared Newer therapeutic options are desir- opening new avenues for targeted to patients in remission thus support- able in the treatment of TAK. Indeed, therapies; ing the role of the alternative pathway the drug retention rate in patients with • Ultrasonography (US) has been rec- of the complement system in AAV TAK is relatively low, with 43% of ognised at least equivalent to histol- patients. Activation of the alternative treatment courses being stopped by 24 ogy in confirming the diagnosis of complement pathway results in gen- months. In this scenario, TNF inhibi- LVV and crucial in the follow-up to eration of C5a, which in turn can prime tors have been reported to have a longer monitor disease activity; moreover, neutrophils through the C5a receptor. retention rate compared to tocilizumab other imaging techniques such as The potential of C5aR antagonism as (53). Infliximab has been confirmed to 3T-MRI with 2D sequences and full- a therapeutic option for vasculitis has ensure a glucocorticoid sparing effect field optical coherence tomography been largely explored recently with the in an open-label study including 23 pa- (FF-OCT) have been evaluated for avacopan, an orally administered C5a tients with TAK (54). diagnosis of GCA; receptor inhibitor (69). Noteworthy, Recently, small case reports are report- • Therapeutic goals have shifted from novel therapies may also be identified ing the potential effectiveness of to- symptom control towards GC-spar- exploring neutrophils and other im- facitinib in the management of TAK. ing regimens in GCA. mune cells immunemetabolisms. Ac- These interesting findings warrant fur- cording to the study by Leacy et al. ther confirmation in larger studies (55, ANCA vasculitis (70) priming events may alter the me- 56). A number of studies published in Pathophysiology advances in tabolism of immune cells (i.e. increased the past 12 months have assessed the AAV vasculitis glycolysis), fostering the inflammatory role of conventional immunosuppres- ANCA vasculitis (AAV) are complex immune response and the interaction sants, especially leflunomide in the potentially life-threatening systemic between ANCA and neutrophils; pre- management of TAK. In a case series autoimmune diseases that have recent- liminary data suggest that inflammation of 56 patients with TAK, leflunomide ly been subject of considerable immu- can be therefore modulated through a treatment was associated with com- nologic and clinical research (61-64). metabolic inhibition. plete remission in approximately 70% New insights into AAV pathogenesis of patients at 12 months, including a are on the rise, paving new avenues for New insights into AAV clinical good response rate in patients refrac- targeted therapies. As highlighted in a features and treatment tory to previous lines of treatment, comprehensive review by Kronbichler Recent literature widely underlines that including cyclophosphamide (57). et al. (65) a variety of different genetic AAV are disabling disorders leading to Two observational studies conducted and environmental factors have been severe disease-related and treatment in China compared the effectiveness implicated in the pathogenesis of AAV. related organ-damage with important of leflunomide versus cyclophospha- Lately, the importance of recognising long term sequelae (71). During the past mide in patients with TAK reporting the specific pathogenetic role of differ- few months it has been generally em- Clinical and Experimental Rheumatology 2021 S-7
One year in review 2021: vasculitis / F. Ferro et al. phasised that the clinical presentation provement of current therapeutic strat- sustained remission at week 52. and the outcome of the patients more egies to optimise remission induction Avacopan improved eGFR and al- closely reflect the ANCA serotype rath- and maintenance therapeutic strate- buminuria in vasculitis probably by er than the traditional definition GPA or gies. In this regard, during the last few preventing the chemoattraction, ac- MPA (72). Still, there is an unmet need months, a number of important studies tivation of neutrophils and the con- for phenotype identification in order to have been carried out (74, 75) to pave sequent damaging of the glomeruli. ameliorate the management of AAV. new ways for lesser toxic induction A better quality of life was observed From this perspective, this year great regimens based on low-dose glucocor- in both treatment groups. The mean efforts have been made and two studies ticoids (Table I). daily glucocorticoid dose in the Ava- specifically deserve to be mentioned. a. PEXIVAS (76). A recent large mul- copan group was one third of that Wojcik et al. (62) applied latent class ticentre study primarily aimed at in the prednisone and Avacopan re- analysis (LCA) to subcategorise GPA defining the role of plasmapheresis duced the incidence of glucocorti- and MPA AAV patients included in the in patients with severe AAV, has re- coid-related toxicities from 80.5% to multicentre POLVAS registry. The au- cently shown that plasma exchange 63.5%. thors identified four different subgroups do not benefit in patients with glo- c. RITAZAREM (77). In this trial pa- of patients potentially candidate to dif- merulonephritis or pulmonary haem- tients with relapsing GPA and MPA ferent therapeutic approaches: a group orrhage. However, indeed PEXI- were prospectively randomised to presenting anti-MPO autoantibod- VAS has addressed the question of receive remission-induction therapy ies positivity (defined as severe MPO glucocorticoid dose for induction of with rituximab and a higher or lower AAV) and three different subgroups remission in AAV. Patients were ran- dose of glucocorticoids. A proportion among anti-PR3 positive patients that domly assigned or to a standard or to of patients around 90% achieved re- differ in renal involvement severity an accelerated prednisone-tapering mission at the fourth month. Notably, (no renal, mild renal and severe renal schedule defined as around 50% of 71% of them received the lower dose involvement) and number of organs in- standard dose over 3 months and of glucocorticoids regimen. Smith et volved (less or more than 3). Particu- around 60% over 6 months. The au- al. concluded that rituximab, in con- larly the authors identified a subgroup thors observed a significative reduc- junction with relatively lower doses of young GPA patients characterised by tion in severe infections in the low- of glucocorticoids, was effective at multiorgan involvement, high relapse dose glucocorticoid group during the reinducing remission also in patients rate, relatively high risk of death, but first year. Noteworthy, lower doses with AAV relapsing disease. no end-stage kidney disease that may of prednisone were as effective as the Overall, these data encourage the use require prompt diagnosis and aggres- higher dose regimens in preventing of lower doses of prednisone to foster sive treatment. Similarly, Matsumoto et death or end stage renal disease in better long-term outcomes for patients. al. (73) investigated the association be- AAV patients. Likewise, during the last few months tween AAV patients’ clinical character- b. ADVOCATE (69). Activation of less toxic drugs such as mycophenolate istics and immune cell profiles in AAV. the alternative complement pathway mofetil (MMF) have been evaluated as Cluster analysis according to peripheral has been identified as a key mecha- alternative options to CYC as remis- immune cell populations (i.e. plasma nism in the pathogenesis of AAV sion-inducing therapy. From this per- cells, plasmablasts, activated T cells, vasculitis; preclinical data as well spective Kuzuya et al. (78) performed CD14++ CD16+ monocytes, eosinophils as CLEAR and CLASSIC phase II a meta-analysis of four randomised and neutrophils) indicated three sub- trial data have shown that AVACO- controlled trials (RCTs) with mycophe- groups: antibody production-related, PAN (68) a selective oral inhibitor of nolate mofetil (MMF). In these studies cytotoxic activity-related and neutrocy- C5a receptor may replace glucocor- patients with a newly diagnosed disease tosis/lymphocytopenia-related. The an- ticoids in the control of AAV-related (79), relapsing disease(80) and an early tibody production-related or cytotoxic renal involvement thus reducing onset of disease (81) were enrolled. Pa- activity-related group was associated glucocorticoid toxicity. The ADVO- tients with life-threatening AAV were with CNS involvement, and the neutro- CATE trial, a randomised, double- excluded MMF was compared with in- cytosis/lymphocytopenia-related group blind, phase 3 trial has evaluated travenous (79, 81) and oral CYC (80). was associated with high incidence of the efficacy of Avacopan in patients Data showed that remission rates were kidney involvement and severe infec- with AAV treated with rituximab or similar between CYC and MMF groups. tions. Incidence of disease relapse was cyclophosphamide. Patients were However, Jones et al. (79) found that comparable among the three groups. randomised to receive Avacopan or patients in the MMF treatment group, The authors concluded that immuno- standard glucocorticoids in addition particularly PR3-ANCA-positive pa- profiles may help to stratify homogene- to standard immunosuppression. The tients, were more likely to relapse than ous subsets of AAV patients useful to authors demonstrated that Avacopan ones in the CYC. In conclusion, ac- select more appropriate treatment. was not inferior to glucocorticoids cording to this meta-analysis, MMF Indeed, one of the most relevant unmet in obtaining remission at week 26 was suggested as an alternative drug need in AAV is represented by the im- and superior to glucocorticoids for for non-life-threatening MPO positive S-8 Clinical and Experimental Rheumatology 2021
One year in review 2021: vasculitis / F. Ferro et al.
Table I. Low-dose glucocorticoids regimes in clinical trials.
Trial Eligibility criteria Study design First outcome: results Second outcome: results
Pexivas 704 patients All: CYC or RTX plus: Death/ESKD Death from any cause
ANCA vasculitis ESKD
(new or relapse) PLEX + standard GC Sustained remission
PLEX + reduced GC Serious adverse events (SAEs)
eGFR GC reduce
Advocate 331 patients All: CYC or RTX plus Remission (week 26): GC-induced toxic effects:
Avacopan = PDN Avacopan < PDN
ANCA vasculitis Avacopan (30 mg twice daily) +
PDN-matching PBO Sustained remission (week 52) GC Toxicity index aggregate
eGFR ≥15 ml/min Avacopan >PDN Improvement score:
PDN + avacopan-matching PBO Avacopan < PDN
Effects on eGFR (change from baseline):
Avacopan > PDN
Ritazarem 188 patients All: RTX Remission (month 4th): • SAEs:
(induction phase) Schedule IA:18,5%; IB: 12,7%
ANCA vasculitis Schedule 1A: GC cumulative dose • Serious infections:
(relapse) GC starting dose: 1 mg/kg/day (patients remission) Schedule IA:0%; IB:3,7%
GC cumulative dose: 3010 mg = • Non-serious infections:
GC cumulative dose Schedule IA: 22%; IB:35.1%
Schedule 1B: (patients not remission) • IgG 60 years, ANCA positivity,
strategies, RTX still retains a central treatment for 18 months, were ran- previous relapse, ENT involvement,
role within the AAV therapeutic arma- domly assigned to receive an extra 18 lower prednisolone dose and absence
mentarium (77, 82, 83). A significant months RTX maintenance course with of concomitant immunosuppression.
effort has been made during the past the MAINRITSAN regimen (fixed 500 For infection risk, five predictors were
twelve months in order to better define mg dose on D0, D14, M6, M12, M18) retained in the model: male sex, pres-
RTX regimens for induction and main- or placebo. Relapse-free survival at 28 ence of structural lung disease, diabetes
tenance of AAV. Indeed, RTX indica- months (the primary endpoint) was sig- mellitus, occurrence of infections dur-
tions have been addressed by the most nificantly higher in the extended treat- ing rituximab treatment and lower IgG
recently published recommendations ment group, moving the authors to pro- level. These models could guide the cli-
on AAV management (84-87), which pose extending maintenance duration nician decision making, by separating
take into account the experience of the in patients at high risk for relapses (i.e. patients into low- and high- risk groups
last trials and are briefly summarised in with PR3 ANCAs, and patients with for relapse and infection respectively.
Table II. Nevertheless, despite the most previous relapse). The second open question is related to
recent advances, several issues about These results have been acknowledged the most appropriate dosing intervals
RTX use remain a matter of debate. by the main study groups on AAV, who for RTX.
The first open question is related to unanimously suggest prolonging the The MAINRITSAN2 trial explored
how long clinicians should push main- maintenance treatment with RTX in pa- the potentialities of an individually tai-
tenance immunosuppressive treatment tients considered at high risk for relapse lored RTX-infusion schedule based on
with RTX. (Table II) (84-87). From this perspec- ANCA positivity and CD19+B-cell lev-
Long-term follow-up data from the tive, McClure et al. (89) generated a els, suggesting that in the near future a
MAINRITSAN trial showed a progres- risk prediction models to identify those single-patient individualised treatment
sive reduction in relapse-free survival patients who were at higher risk of re- approach could be guided by serum bio-
after RTX cessation, with around 60% lapses when stopping maintenance im- markers (90). In a recent post hoc anal-
relapse-free survival rate 32 months munosuppression, taking into account ysis of the MAINRITSAN2, Charles et
Clinical and Experimental Rheumatology 2021 S-9One year in review 2021: vasculitis / F. Ferro et al.
Table II. Recommendations for the use of rituximab (RTX) in ANCA-associated vasculitis.
Recommendations RTX for induction RTX for maintenance RTX duration
BSR consensus guidelines (84) No specific regimen 500 mg or 1000 mg 5 yrs
every 6 months for 2 years
French recommendations (85) 375 mg/m2/week 500 mg 4 years
(4 infusions 1-week intervals). D0, D14, M6, M12, M18 (PR3-AAV severe or relapsing MPO-AAV)
(MAINRITSAN regimen) 2 years
(newly severe MPO-AAV)
CanVasc 2020 (86)] No specific regimen no specific dose recommended 2 years
every 4-6 months 2 years (plus additional 18 months):
(patients with previous relapse(s), pre-existing
organ damage, PR3-ANCA and/or persistent ANCA)
FVSG recommendations (87) 375 mg/m2/week 500 mg 18 months: patients in first remission.
(4 infusions 1-week intervals). D0, D14, M6, M12, M18 Beyond 18 months: patients with previous
(MAINRITSAN regimen) relapse(s)
al. (91) suggested that omitting the D14 with the depth of B cells depletion. of the available data. On the other hand
rituximab remission-maintenance dose More in detail, they individuated a cut- the BSR GL for maintenance of remis-
may not modify the short-term relapse- off value of 550 ng/mL above which sion with RTX recommend employing
free rate of ANCA vasculitis. 100% of patients displayed B-cell de- B-cells ablation therapy with the same
However, a clear and solid correla- pletion in contrast with 51% of patients modalities as in GPA and MPA.Cur-
tion between ANCA titres, circulating with RTX levels below 550 ng/mL. rently there are two ongoing RCTs on
CD19+ B-cell and relapse risk has not The third open question is related to the the use of RTX respectively for induc-
been proved yet. As a result of this, the use of RTX in EGPA. Currently there tion (REOVAS) and remission mainte-
last recommendations do not support are no available prospective controlled nance (MAINRITSEG) of EGPA. Their
the use of tailored-administration strat- trial on RTX use for induction or remis- results are impatiently awaited to better
egy as a first-line maintenance treat- sion maintenance in EGPA patients. define the role of anti-CD20 therapy in
ment, suggesting that more data on this After performing a systematic literature such a complex disease.
field are needed. review, Akiyama et al. analysed the re-
On this respect, van Dam et al. em- sults of seven studies (mainly retrospec- Take home messages
ployed highly-sensitive flow cytom- tive) for a total of 171 EGPA patients • PR3-ANCA and MPO-ANCA have
etry (HSFC), traditionally used to detect treated with RTX (94). Patients were different roles in the pathogenesis of
minimal residual disease in haemato- mostly refractory to the standard ther- AAV;
logic neoplasia, to perform a phenotypic apy or had relapsing disease, although • C5aR antagonism represents a valid
analysis of the B-cell compartment in 14 of them had newly diagnosed EGPA. therapeutic option for AAV;
patients undergoing RTX treatment for RTX was used for induction of remis- • Induction regimens based on low-
either induction or remission mainte- sion with the RAVE trial regimen (375 dose glucocorticoids seem to be asso-
nance (92). They showed that RTX in- mg/m2 x 4/weekly), or the RA regimen ciate with a significative reduction in
duced strong reductions in circulating B- (1000 mg x 2 biweekly). The remission severe infections and adverse events;
cells, but never resulted in complete B- rates were 36 to 100%, a result that is • Plasma exchange do not benefit in
cell depletion when the serum samples similar to that observed for the use of patients with glomerulonephritis or
were analysed by HSFC, in contrast to RTX in GPA and MPO patients induc- pulmonary haemorrhage;
conventional low-sensitive flow cytom- tion. A trend for higher remission rates • RTX regimens for induction and
etry. This “minimal residual autoimmun- in ANCA positive patients was noted, a maintenance of AAV should be better
ity”, driven mainly by memory B-cells difference that reached statistical sig- defined in the near future in terms of
and plasma cells, may explain some in- nificance in one of the studies included maintenance duration, dosing inter-
stances of relapse where conventional in the review. Moreover all the studies vals, and use in EGPA.
flow cytometry would mistakenly indi- reported a successful reduction of the
cate a complete B-cell depletion. GC dose, namely from a median dose References
Another study that is worth mentioning of 12.5–60 mg/day to a median dose of 1. ELEFANTE E, BOND M, MONTI S et al.:
One year in review 2018: systemic vasculitis.
was performed by Springer et al., who 0–8.5 mg after RTX treatment. In spite Clin Exp Rheumatol 2018; 36 (Suppl. 111);
measured RTX concentrations in the of these results the French Vasculitis S12-32.
sera of 30 AAV patients treated for in- Study Group does not recommend to 2. FELICETTI M, TREPPO E, POSARELLI C et al.:
One year in review 2020: vasculitis. Clin Exp
duction or remission maintenance (93). use RTX as a first line agent for neither Rheumatol 2020; 38 (Suppl. 124) S3-14.
The authors noticed that RTX concen- induction nor remission maintenance of 3. MONTI S, BOND M, FELICETTI M et al.:
trations were significantly associated EGPA patients, because of the weakness One year in review 2019: vasculitis. Clin Exp
S-10 Clinical and Experimental Rheumatology 2021One year in review 2021: vasculitis / F. Ferro et al.
Rheumatol 2019; 37 (Suppl. 117): S3-19. 18. SAADOUN D, GHEMBAZA A, RIVIERE S et arteries for the diagnosis of giant cell arteritis:
4. DE RE V, TORNESELLO ML, DE ZORZI et al., Rituximab plus belimumab in non-in- a multicentre deep learning study. Clin Exp
al.: PDCD1 and IFNL4 genetic variants and fectious refractory cryoglobulinemia vascu- Rheumatol 2020; 38 (Suppl. 124): S120-25.
risk of developing hepatitis C virus-related litis: A pilot study. J Autoimmun 2021; 116: 34. RODRIGUEZ-RÉGENT C, BEN HASSEN W,
diseases. Liver Int 2021; 41: 133-49. 102577. SENERS P, OPPENHEIM C, RÉGENT A: 3D T1-
5. BASILE U, MARINO M, GRAGNANI L et al.: 19. CHEVALIER K, BELKHIR R, SEROR R, MARI- weighted black-blood magnetic resonance im-
Sentinel biomarkers in HCV positive pa- ETTE X, NOCTURNE G: Efficacity of a se- aging for the diagnosis of giant cell arteritis.
tients with mixed cryoglobulinemia. J Immu- quential treatment by anti-CD 20 monoclonal Clin Exp Rheumatol 2020; 38 (Suppl. 124):
nol Methods 2020; 476: 112687. antibody and belimumab in type II cryoglo- S95-8.
6. GULLI F, MARINO M, NAPODANO C et al.: Bio- bulinaemia associated with primary Sjögren 35. MALDINEY T, GREIGERT H, MARTIN L et al.:
markers in HCV-related mixed cryoglobuline- syndrome refractory to rituximab alone. Ann Full-field optical coherence tomography for
mia patients withnon-Hodgkin lymphoma. Eur Rheum Dis 2020; 79: 1257-9. the diagnosis of giant cell arteritis. PLoS One
Rev Med Pharmacol Sci 2020; 24: 8067-74. 20. RETAMOZO S, GHEITASI H, QUARTUCCIO L 2020; 15: e0234165.
7. LORINI S, GRAGNANI L, ZIGNEGO AL: et al.: Cryoglobulinaemic vasculitis at diag- 36. KENAR G, KARAMAN S, ÇETIN P et al.:
The relevance of microRNAs in the patho- nosis predicts mortality in primary Sjögren Imaging is the major determinant in the as-
genesis and prognosis of HCV-disease: the syndrome: analysis of 515 patients. Rheuma- sessment of disease activity in Takayasu’s ar-
emergent role of miR-17-92 in cryoglobu- tology (Oxford) 2016; 55: 1443-51. teritis. Clin Exp Rheumatol 2020; 38 (Suppl.
linemic vasculitis. Viruses 2020; 12: 1364. 21. PULSATELLI L, BOIARDI L, ASSIRELLI E et 124): S55-60.
8. QUARTUCCIO L, ISOLA M, CORAZZA L et al.: al.: Imbalance between angiogenic and anti- 37. GOEL R, GRIBBONS KB, CARETTE S et al.:
Performance of the preliminary classification angiogenic factors in sera from patients with Derivation of an angiographically based clas-
criteria for cryoglobulinaemic vasculitis and large-vessel vasculitis. Clin Exp Rheumatol sification system in Takayasu’s arteritis: an ob-
clinical manifestations in hepatitis C virus- 2020; 38 (Suppl. 124): S23-30. servational study from India and North Ameri-
unrelated cryoglobulinaemic vasculitis. Clin 22. LI T, GAO N, CUI W, ZHAO L, PAN L: Natural ca. Rheumatology (Oxford) 2020; 59: 1118-27.
Exp Rheumatol 2012; 30 (Suppl. 70): S48-52. killer cells and their function in Takayasu’s 38. HELLMICH B, AGUEDA A, MONTI S et al.:
9. GOULES AV, ARGYROPOULOU OD, PEZOU- arteritis. Clin Exp Rheumatol 2020; 38 (Sup- 2018 Update of the EULAR recommenda-
LAS VC et al.: Primary Sjögren’s syndrome pl. 124): S84-90. tions for the management of large vessel vas-
of early and late onset: distinct clinical phe- 23. GAO N, CUI W, ZHAO LM et al.: Contribution culitis. Ann Rheum Dis 2020; 79: 19-30.
notypes and lymphoma development. Front of Th2-like Treg cells to the pathogenesis 39. MAINBOURG S, ADDARIO A, SAMSON M et
Immunol 2020; 11, 594096. of Takayasu’s arteritis. Clin Exp Rheumatol al.: Prevalence of giant cell arteritis relapse
10. DEL PADRE M, MINAFÒ YA, MARRAPODI et 2020; 38 (Suppl. 124): S48-54. in patients treated with glucocorticoids: a
al.: Rheumatoid factor-producing CD21low 24. MACKIE SL, DEJACO C, APPENZELLER S et meta-analysis. Arthritis Care Res (Hoboken)
anergic clonal B-cells in essential mixed al.: British Society for Rheumatology guide- 2020; 72: 838-49.
cryoglobulinaemia: a model for autoantigen- line on diagnosis and treatment of giant cell 40. SONG GG, LEE YH: Efficacy and safety of
driven pathogenesis of infectious and non-in- arteritis: executive summary. Rheumatology biological agents in patients with giant cell
fectious cryoglobulinaemias. Clin Exp Rheu- (Oxford) 2020; 59: 487-94. arteritis: A meta-analysis of randomized trials.
matol 2020; 38 (Suppl. 124): S139-47. 25. FAYYAZ B, REHMAN HJ: The spectrum of Int J Clin Pharmacol Ther 2020; 58: 504-10.
11. BOLETO G, GHILLANI-DALBIN P, MUSSET et pericardial involvement in giant cell arteritis 41. STONE JH, TUCKWELL K, DIMONACO S et
al.: Cryoglobulinemia after the era of chronic and polymyalgia rheumatica: a systematic al.: Trial of tocilizumab in giant-cell arteritis.
hepatitis C infection. Semin Arthritis Rheum review of literature. J Clin Rheumatol 2021; N Engl J Med 2017; 377: 317-28.
2020; 50: 695-700. 27: 5-10. 42. CALDERÓN-GOERCKE M, CASTAÑEDA S,
12. POZZATO G, MAZZARO C, ARTEMOVA M et 26. HOČEVAR A, JEŠE R, TOMŠIČ M, ROTAR Ž: ALDASORO V et al.: Tocilizumab in giant
al.: Direct-acting antiviral agents for hepa- Risk factors for severe cranial ischaemic cell arteritis: differences between the GiAC-
titis C virus-mixed cryoglobulinaemia: dis- complications in giant cell arteritis. Rheuma- TA trial and a multicentre series of patients
sociated virological and haematological re- tology (Oxford) 2020; 59: 2953-9. from the clinical practice. Clin Exp Rheuma-
sponses. Br J Haematol 2020; 191: 775-83. 27. DEYHOLOS C, SYTEK MC, SMITH S, CAR- tol 2020; 38 (Suppl. 124): S112-9.
13. PÉREZ DE JOSÉ A, CARBAYO J, POCURULL DELLA J, ORION KC: Impact of temporal 43. SAITO S, OKUYAMA A, OKADA Y et al.:
A et al.: Direct-acting antiviral therapy im- artery biopsy on clinical management of Tocilizumab monotherapy for large vessel
proves kidney survival in hepatitis C virus- suspected giant cell arteritis. Ann Vasc Surg vasculitis: results of 104-week treatment of a
associated cryoglobulinaemia: the RENAL- 2020; 69: 254-60. prospective, single-centre, open study. Rheu-
CRYOGLOBULINEMIC study. Clin Kidney 28. HOP H, MULDER DJ, SANDOVICI M et al.: matology (Oxford) 2020; 59: 1617-21.
J 2021; 14: 586-92. Diagnostic value of axillary artery ultra- 44. SEBASTIAN A, KAYANI A, PRIETO-PENA D et
14. BASILE U, GULLI F, NAPODANO C et al.: sound in patients with suspected giant cell al.: Efficacy and safety of tocilizumab in gi-
Biomarkers of minimal residual disease in arteritis. Rheumatology (Oxford) 2020; 59: ant cell arteritis: a single centre NHS experi-
rituximab-treated patients with mixed cryo- 3676-84. ence using imaging (ultrasound and PET-CT)
globulinemia. Biotechnol Appl Biochem 29. PONTE C, SERAFIM AS, MONTI S et al.: Early as a diagnostic and monitoring tool. RMD
2021; 68: 319-29. variation of ultrasound halo sign with treat- Open 2020; 6: e001417.
15. VACCHI C, VISENTINI M, GRAGNANI L et ment and relation with clinical features in pa- 45. SCHMIDT WA, DASGUPTA B, LUQMANI R
al.: Safety and effectiveness of biosimilar of tients with giant cell arteritis. Rheumatology et al.: A Multicentre, Randomised, Double-
Rituximab CT-P10 in the treatment of cryo- (Oxford) 2020; 59: 3717-26. Blind, Placebo-Controlled, Parallel-Group
globulinemic vasculitis: the MARBLe study 30. FORD JA, DIIORIO MA, HUANG W et al.: Study to Evaluate the Efficacy and Safety
(Mixed cryoglobulinemiA Rituximab Biosim- Follow-up vascular ultrasounds in patients of Sirukumab in the Treatment of Giant Cell
iLar). Intern Emerg Med 2021; 16: 149-56. with giant cell arteritis. Clin Exp Rheumatol Arteritis. Rheumatol Ther 2020; 7: 793-810.
16. DESBOIS AC, BIARD L, SÈNE D et al.: Ritux- 2020; 38 (Suppl. 124): S107-11. 46. CONWAY R, MOLLOY ES: Ustekinumab in gi-
imab-associated vasculitis flare: incidence, 31. NIELSEN BD, GORMSEN LC: 18F-Fluorode- ant cell arteritis. Comment on the article by
predictors, and outcome. J Rheumatol 2020; oxyglucose PET/computed tomography in Matza et al. Arthritis Care Res (Hoboken)
47: 896-902. the diagnosis and monitoring of giant cell 2020 Sep 22 [Online ahead of print].
17. DE VITA S, QUARTUCCIO L, SALVIN S et al.: arteritis. PET Clin 2020; 15: 135-45. 47. MATZA MA, FERNANDES AD, STONE JH, UNI-
Sequential therapy with belimumab followed 32. SCHMIDT WA, NIELSEN BD: Imaging in ZONY SH: Ustekinumab for the treatment of
by rituximab in Sjögren’s syndrome associat- large-vessel vasculitis. Best Pract Res Clin giant cell arteritis. Arthritis Care Res (Hobo-
ed with B-cell lymphoproliferation and over- Rheumatol 2020; 34; 101589. ken) 2020 Jul 23 [Online ahead of print].
expression of BAFF: evidence for long-term 33. RONCATO C, PEREZ L, BROCHET-GUÉGAN A 48. QUARTUCCIO L, ISOLA M, BRUNO D et al.:
efficacy. Clin Exp Rheumatol 2014; 32: 490-4. et al.: Colour Doppler ultrasound of temporal Treatment strategy introducing immunosup-
Clinical and Experimental Rheumatology 2021 S-11One year in review 2021: vasculitis / F. Ferro et al.
pressive drugs with glucocorticoids ab initio vasculitis: Long-term outcome and mortality cytoplasmic antibody-associated vasculitis:
or very early in giant cell arteritis: A multi- predictors. J Autoimmun 2020; 108: 102397. randomized, controlled trial. Clin J Am Soc
center retrospective controlled study. J Transl 65. KRONBICHLER A, LEE KH, DENICOLÒ S et Nephrol 2019; 14: 1021-8.
Autoimmun 2020; 3: 100072. al.: Immunopathogenesis of ANCA-Associ- 81. HAN F, LIU G, ZHANG X et al.: Effects of my-
49. MUSTAPHA N, BARRA L, CARETTE S et al.: ated Vasculitis. Int J Mol Sci 2020; 21: 7319. cophenolate mofetil combined with corticos-
Efficacy of leflunomide in the treatment of 66. LEE A, NISSEN MJ, BEROUKAS D, AHERN MJ, teroids for induction therapy of microscopic
vasculitis. Clin Exp Rheumatol 2021; 39 BARBARA JA: Detectable anti-proteinase-3 polyangiitis. Am J Nephrol 2011; 33: 185-92.
(Suppl. 129): S00-00. antibodies precede clinical manifestations 82. CHEUNG CK, MCADOO SP: Maintenance
50. KARABAYAS M, DOSPINESCU P, FLUCK N et in a case of anti-neutrophil cytoplasmic anti- rituximab treatment for ANCA-associated
al.: Evaluation of adjunctive mycophenolate body-associated vasculitis. Scand J Rheuma- vasculitis: to be continued? Rheumatology
for large vessel giant cell arteritis. Rheumatol tol 2021; 50: 76-7. (Oxford) 2021; 60: 1010-2.
Adv Pract 2020; 4: rkaa069. 67. VAN DAM LS, DIRIKGIL E, BREDEWOLD EW 83. CHARLES P, GUILLEVIN L: Long-term rituxi-
51. NAKAOKA Y, ISOBE M, TANAKA Y et al.: Long- et al.: Proteinase-3-anti-neutrophil cytoplas- mab use to maintain remission of antineutro-
term efficacy and safety of tocilizumab in re- mic antibodies (PR3-ANCAs) predict relaps- phil cytoplasmic antibody-associated vascu-
fractory Takayasu arteritis: final results of the es in ANCA-associated vasculitis patients af- litis. Ann Intern Med 2020; 173: 948.
randomized controlled phase 3 TAKT study. ter rituximab. Nephrol Dial Transplant 2020 84. TIEU J, SMITH R, BASU N et al.: Rituximab for
Rheumatology (Oxford) 2020; 59: 2427-34. Jun 30 [Online ahead of print]. maintenance of remission in ANCA-associ-
52. MEKINIAN A, SAADOUN D, VICAUT E et 68. MOISEEV S, LEE JM, ZYKOVA A et al.: The ated vasculitis: expert consensus guidelines.
al.: Tocilizumab in treatment-naïve patients alternative complement pathway in ANCA- Rheumatology (Oxford) 2020; 59: e24-e32.
with Takayasu arteritis: TOCITAKA French associated vasculitis: further evidence and a 85. TERRIER B, DARBON R, DUREL CA et al.:
prospective multicenter open-labeled trial. meta-analysis. Clin Exp Immunol 2020; 202: French recommendations for the management
Arthritis Res Ther 2020; 22: 218. 394-402. of systemic necrotizing vasculitides (polyarte-
53. CAMPOCHIARO C, TOMELLERI A, SARTO- 69. JAYNE DRW, MERKEL PA, SCHALL TJ et al.: ritis nodosa and ANCA-associated vascu-
RELLI S et al.: Drug retention and discon- Avacopan for the treatment of ANCA-asso- litides). Orphanet J Rare Dis 2020; 15: 351.
tinuation reasons between seven biologics ciated vasculitis. N Engl J Med 2021; 384: 86. MENDEL A, ENNIS D, GO E et al.: CanVasc
in patients with Takayasu arteritis. Semin 599-609. consensus recommendations for the manage-
Arthritis Rheum 2020; 50: 509-14. 70. LEACY E, BRADY G, LITTLE MA: Pathogene- ment of antineutrophil cytoplasm antibody-
54. MERTZ P, KLEINMANN JF, LAMBERT et al.: sis of ANCA-associated vasculitis: an emerg- associated vasculitis: 2020 Update. J Rheu-
Infliximab is an effective glucocorticoid- ing role for immunometabolism. Rheumatol- matol 2020 Sep 15 [Online ahead of print].
sparing treatment for Takayasu arteritis: re- ogy (Oxford) 2020; 59: iii33-iii41. 87. TERRIER B, CHARLES P, AUMAÎTRE O et al.:
sults of a multicenter open-label prospective 71. SMITH R: Complications of therapy for ANCA-associated vasculitides: Recommen-
study. Autoimmun Rev 2020; 19: 102634. ANCA-associated vasculitis. Rheumatology dations of the French Vasculitis Study Group
55. PALERMO A, MARVISI C, CASALI M et al.: (Oxford) 2020; 59: iii74-iii78. on the use of immunosuppressants and bio-
Tofacitinib for the treatment of refractory Taka- 72. HUNTER RW, WELSH N, FARRAH TE, GAL- therapies for remission induction and main-
yasu’s arteritis: description of 2 cases. Clin LACHER PJ, DHAUN N: ANCA associated tenance. Presse Med 2020; 49: 104031.
Exp Rheumatol 2020; 38 (Suppl. 124): S234-5. vasculitis. BMJ 2020; 369: m1070. 88. CHARLES P, PERRODEAU É, SAMSON M et
56. LI J, LI M, TIAN X, ZENG X: Tofacitinib in 73. MATSUMOTO K, SUZUKI K, YOSHIMOTO K al.: Long-term rituximab use to maintain
patients with refractory Takayasu’s arteritis. et al.: Significant association between clini- remission of antineutrophil cytoplasmic
Rheumatology (Oxford) 2020; 59: e95-e98. cal characteristics and immuno-phenotypes antibody-associated vasculitis: a randomized
57. CUI X, DAI X, MA L et al.: Efficacy and safety in patients with ANCA-associated vasculitis. trial. Ann Intern Med 2020; 173: 179-87.
of leflunomide treatment in Takayasu arteri- Rheumatology (Oxford) 2020; 59: 545-53. 89. MCCLURE ME, ZHU Y, SMITH RM et al.:
tis: Case series from the East China cohort. 74. ROSSI GM, PEYRONEL F, FENAROLI P, MARI- Long-term maintenance rituximab for ANCA-
Semin Arthritis Rheum 2020; 50: 59-65. TATI F, VAGLIO A: New therapeutics for AN- associated vasculitis: relapse and infection
58. YING S, XIAOMENG C, XIAOMIN D et CA-associated vasculitis: 10 years devoted prediction models. Rheumatology (Oxford)
al.: Efficacy and safety of leflunomide. to lessen toxicity. Clin Exp Rheumatol 2020; 2021; 60: 1491-501.
Ther Adv Musculoskelet Dis 2020; 12: 38 (Suppl. 124): S18-22. 90. CHARLES P, TERRIER B, PERRODEAU É et al.:
1759720X20930114. 75. SARICA SH, GALLACHER PJ, DHAUN N et al.: Comparison of individually tailored versus
59. DAI X, CUI X. SUN Y, MA L, JIANG L: Multimorbidity in antineutrophil cytoplas- fixed-schedule rituximab regimen to maintain
Effectiveness and safety of leflunomide com- mic antibody-associated vasculitis: results ANCA-associated vasculitis remission: re-
pared with cyclophosphamide as induction from a longitudinal, multicenter data linkage sults of a multicentre, randomised controlled,
therapy in Takayasu’s arteritis: an observa- study. Arthritis Rheumatol 2021; 73: 651-9. phase III trial (MAINRITSAN2). Ann Rheum
tional study. Ther Adv Chronic Dis 2020; 11: 76. WALSH M, MERKEL PA, PEH CA et al.: Dis 2018; 77: 1143-9.
2040622320922019. Plasma exchange and glucocorticoids in se- 91. CHARLES P, DECHARTRES A, TERRIER B et
60. WU C, SUN Y, CUI X et al.: Effectiveness and vere ANCA-associated vasculitis. N Engl J al.: Reducing the initial number of rituximab
safety of methotrexate. Ther Adv Chronic Med 2020; 382: 622-31. maintenance-therapy infusions for ANCA-as-
Dis 2020; 11: 2040622320975233. 77. SMITH RM, JONES RB, SPECKS U et al., sociated vasculitides: randomized-trial post-
61. WALLACE ZS, FU X, HARKNESS T et al.: Rituximab as therapy to induce remission hoc analysis. Rheumatology (Oxford) 2020;
All-cause and cause-specific mortality in after relapse in ANCA-associated vasculitis. 59: 2970-5.
ANCA-associated vasculitis: overall and ac- Ann Rheum Dis 2020; 79: 1243-9. 92. VAN DAM LS, OSKAM JM, KAMERLING SWA
cording to ANCA type. Rheumatology (Ox- 78. KUZUYA K, MORITA T, KUMANOGOH A: et al.: Highly sensitive flow cytometric detec-
ford) 2020; 59: 2308-15. Efficacy of mycophenolate mofetil as a re- tion of residual B-cells after rituximab in anti-
62. WÓJCIK K, BIEDROŃ G, WAWRZYCKA- mission induction therapy in antineutrophil neutrophil cytoplasmic antibodies-associated
ADAMCZYK K et al.: Subphenotypes of cytoplasmic antibody: associated vasculitis-a vasculitis patients. Front Immunol 2020; 11:
ANCA-associated vasculitis identified by la- meta-analysis. RMD Open 2020; 6: e001195. 566732.
tent class analysis. Clin Exp Rheumatol 2021; 79. JONES RB, HIEMSTRA TF, BALLARIN J et al.: 93. SPRINGER JM, FUNK RS: Defining a thera-
39 (Suppl. 129): S62-8. Mycophenolate mofetil versus cyclophospha- peutic window for rituximab maintenance
63. HOUBEN E, MENDEL A, CARETTE S et al.: mide for remission induction in ANCA-asso- therapy in ANCA-associated vasculitis: a lon-
Predictors of fatal and non-fatal cardiovas- ciated vasculitis: a randomised, non-inferiori- gitudinal observational study. J Clin Rheuma-
cular events in ANCA-associated vasculitis: ty trial. Ann Rheum Dis 2019; 78: 399-405. tol 2020 Dec 15 [Online ahead of print].
Data from the Toronto CanVasc cohort. Joint 80. TUIN J, STASSEN PM, BOGDAN DI et al.: 94. AKIYAMA M, KANEKO Y, TAKEUCHI T: Rituxi-
Bone Spine 2020; 87: 221-4. Mycophenolate mofetil versus cyclophos- mab for the treatment of eosinophilic granulo-
64. QUARTUCCIO L, BOND M, ISOLA M et al., phamide for the induction of remission in matosis with polyangiitis: A systematic litera-
Alveolar haemorrhage in ANCA-associated nonlife-threatening relapses of antineutrophil ture review. Autoimmun Rev 2021; 20: 102737.
S-12 Clinical and Experimental Rheumatology 2021You can also read
