Large vessel involvement in giant cell arteritis has long been described, although its right frequency and potential prognostic value have only been highlighted for two decades. Large vessel ...involvement not only is associated with a high incidence of late aortic aneurysms, but also might cause greater resistance to glucocorticoids and longer treatment duration, as well as worse late cardiovascular outcomes. These data were brought to our attention, thanks to substantial progress recently made in large vessel imaging. This relies on four single, often complementary, approaches of varying availability: colour Doppler ultrasound, contrast-enhanced computed tomography with angiography and, magnetic resonance imaging, which all demonstrate homogeneous circumferential wall thickening and describe structural changes; 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET/CT), which depicts wall inflammation and assesses many vascular territories in the same examination. In addition, integrated head-and-neck PET/CT can accurately and reliably diagnose cranial arteritis. All four procedures exhibit high diagnostic performance for a large vessel arteritis diagnosis so that the choice is left to the physician, depending on local practices and accessibility; the most important is to carry out the chosen modality without delay to avoid false or equivocal results, due to early vascular oedema changes as a result of high dose glucocorticoid treatment. Yet, ultrasound study of the superficial cranial and subclavian/axillary arteries remains a first line assessment aimed at strengthening and expediting the clinical diagnosis as well as raising suspicion of large-vessel involvement. In treated patients, vascular imaging results are poorly correlated with clinical-biological controlled disease so that it is strongly recommended not to renew imaging studies unless a large vessel relapse or complication is suspected. On the other hand, a structural monitoring of aorta following giant cell arteritis is mandatory, but uncertainties remain regarding the best procedural approach, timing of first control and spacing between controls. Individuals at greater risk of developing aortic complication, e.g. those with classic risk factors for aneurysm and/or visualised aortitis, should be monitored more closely.
Summary
Background
A new autoinflammatory syndrome related to somatic mutations of UBA1 was recently described and called VEXAS syndrome (‘Vacuoles, E1 Enzyme, X‐linked, Autoinflammatory, Somatic ...syndrome’).
Objectives
To describe clinical characteristics, laboratory findings and outcomes of VEXAS syndrome.
Methods
One hundred and sixteen patients with VEXAS syndrome were referred to a French multicentre registry between November 2020 and May 2021. The frequency and median of parameters and vital status, from diagnosis to the end of the follow‐up, were recorded.
Results
The main clinical features of VEXAS syndrome were found to be skin lesions (83%), noninfectious fever (64%), weight loss (62%), lung involvement (50%), ocular symptoms (39%), relapsing chondritis (36%), venous thrombosis (35%), lymph nodes (34%) and arthralgia (27%). Haematological disease was present in 58 cases (50%): myelodysplastic syndrome (MDS; n = 58) and monoclonal gammopathy of unknown significance (n = 12; all patients with MGUS also have a MDS). UBA1 mutations included p.M41T (45%), p.M41V (30%), p.M41L (18%) and splice mutations (7%). After a median follow‐up of 3 years, 18 patients died (15·5%; nine of infection and three due to MDS progression). Unsupervised analysis identified three clusters: cluster 1 (47%; mild‐to‐moderate disease); cluster 2 (16%; underlying MDS and higher mortality rates); and cluster 3 (37%; constitutional manifestations, higher C‐reactive protein levels and less frequent chondritis). The 5‐year probability of survival was 84·2% in cluster 1, 50·5% in cluster 2 and 89·6% in cluster 3. The UBA1 p.Met41Leu mutation was associated with a better prognosis.
Conclusions
VEXAS syndrome has a large spectrum of organ manifestations and shows different clinical and prognostic profiles. It also raises a potential impact of the identified UBA1 mutation.
What is already known about this topic?
VEXAS syndrome is a recently described autoinflammatory disease related to UBA1 mutation. The clinical phenotype includes patients with thrombosis, fever, chondritis, neutrophilic dermatosis and MDS.
What does this study add?
The main clinical features of VEXAS patients remain recurrent fever (64.7% vs. 72%, in original description by Beck et al.), skin lesions (83.6% vs. 88%), lung infiltrates (49.1% vs. 72%), unprovoked thrombosis (35.5% vs. 44%), with new features such as arthralgia (28.4%), ocular involvement (40.5%) or lymph node enlargement (34.5%), expanding the previous clinical phenotype of VEXAS syndrome.
We identified 3 clusters of VEXAS syndrome, including an MDS‐related phenotype; mild‐to‐moderate disease with less fever, chondritis and thromboembolism, and one with more ‘inflammatory' profile characterized by cutaneous vasculitis lesions and relapsing profile.
A phenotype–genotype association was observed for UBA1 p.Met41Leu which was associated with less ‘inflammatory' and mild‐to‐moderate phenotype and better overall prognosis.
Linked Comment: L.T. Nicholson and L.M. Madigan. Br J Dermatol 2022; 186:392–393.
Plain language summary available online
Acquired hemophilia A (AHA) is a rare autoimmune disorder due to autoantibodies against Factor VIII, with a high mortality risk. Treatments aim to control bleeding and eradicate antibodies by ...immunosuppression. International recommendations rely on registers and international expert panels.
CREHA, an open-label randomized trial, compared the efficacy and safety of cyclophosphamide and rituximab in association with steroids in patients with newly diagnosed AHA. Participants were treated with 1 mg/kg prednisone daily and randomly assigned to receive either 1.5–2 mg/kg/day cyclophosphamide orally for 6 weeks, or 375 mg/m2 rituximab once weekly for 4 weeks. The primary endpoint was complete remission over 18 months. Secondary endpoints included time to achieve complete remission, relapse occurrence, mortality, infections and bleeding, and severe adverse events.
Recruitment was interrupted because of new treatment recommendations after 108 patients included (58 cyclophosphamide, 50 rituximab). After 18 months, 39 cyclophosphamide patients (67.2 %) and 31 rituximab patients (62.0 %) were in complete remission (OR 1.26; 95 % CI, 0.57 to 2.78). In the poor prognosis group (FVIII < 1 IU/dL, inhibitor titer > 20 BU mL−1), significantly more remissions were observed with cyclophosphamide (22 patients, 78.6 %) than with rituximab (12 patients, 48.0 %; p = 0.02). Relapse rates, deaths, severe infections, and bleeding were similar in the 2 groups. In patients with severe infection, cumulative doses of steroids were significantly higher than in patients without infection (p = 0.03).
Cyclophosphamide and rituximab showed similar efficacy and safety. As first line, cyclophosphamide seems preferable, especially in poor prognosis patients, as administered orally and less expensive.
French Ministry of Health.
ClinicalTrials.gov number: NCT01808911.
•Cyclophosphamide and rituximab have similar efficacy and safety in AHA.•Cyclophosphamide seems preferable in patients with low FVIII and high inhibitor titer.•If immunosuppressant is added to steroids, cyclophosphamide should be preferred.•It is crucial to reduce total steroid intake in AHA as much as possible.•Cumulative dose and duration of steroid are correlated with the risk of serious sepsis.
Management of giant cell arteritis (GCA, Horton's disease) involves many uncertainties. This work was undertaken to establish French recommendations for GCA management.
Recommendations were developed ...by a multidisciplinary panel of 33 physicians, members of the French Study Group for Large Vessel Vasculitis (Groupe d’étude français des artérites des gros vaisseaux GEFA). The topics to be addressed, selected from proposals by group members, were assigned to subgroups to summarize the available literature and draft recommendations. Following an iterative consensus-seeking process that yielded consensus recommendations, the degree of agreement among panel members was evaluated with a 5-point Likert scale. A recommendation was approved when ≥ 80% of the voters agreed or strongly agreed.
The 15 retained topics resulted in 31 consensus recommendations focusing on GCA nomenclature and classification, the role of temporal artery biopsy and medical imaging in the diagnosis, indications and search modalities for involvement of the aorta and its branches, the glucocorticoid regimen to prescribe, treatment of complicated GCA, indications for use of immunosuppressants or targeted biologic therapies, adjunctive treatment measures, and management of relapse and recurrence.
The recommendations, which will be updated regularly, are intended to guide and harmonize the standards of GCA management.
Recurrent FUO (fever of unknown origin) is a rare subtype of FUO for which diagnostic procedures are ill-defined and outcome data are lacking.
We performed a retrospective multicentre study of ...patients with recurrent FUO between 1995 and 2018. By multivariate analysis, we identified epidemiological, clinical and prognostic variables independently associated with final diagnosis and mortality.
Of 170 patients, 74 (44%) had a final diagnosis. Being ≥ 65 years of age (OR = 5.2; p < 0.001), contributory history (OR = 10.4; p < 0.001), and abnormal clinical examination (OR = 4.0; p = 0.015) independently increased the likelihood of reaching a diagnosis, whereas lymph node and/or spleen enlargement decreased it (OR = 0.2; p = 0.004). The overall prognosis was good; 58% of patients recovered (70% of those with a diagnosis). Twelve (7%) patients died; patients without a diagnosis had a fatality rate of 2%. Being ≥ 65 years of age (OR = 41.3; p < 0.001) and presence of skin signs (OR = 9.5; p = 0.005) significantly increased the risk of death.
This study extends the known yield of recurrent FUO and highlights the importance of repeated complete clinical examinations to discover potential diagnostic clues during follow-up. Moreover, their overall prognosis is excellent.
Si l'atteinte des gros troncs artériels au cours de l'artérite à cellules géantes est. connue de longue date, son importance, en termes de fréquence et de possible incidence pronostique, n'est. mise ...en exergue que depuis deux décades. Outre un risque élevé d'anévrisme aortique retardé, l'atteinte des gros troncs artériels pourrait conférer une plus grande résistance aux traitements et grever le pronostic cardio-vasculaire lointain. Ces notions sont apparues grâce à des travaux permis par les progrès spectaculaires de l'imagerie artérielle. Celle-ci repose sur quatre techniques d'accessibilité inégale et volontiers complémentaires: l'écho-doppler, la tomodensitométrie et l'imagerie par résonance magnétique, qui objectivent un épaississement vasculaire pariétal concentrique homogène et apprécient les modifications structurales; la tomographie par émission de positrons au 18F-fluorodeoxyglucose couplée au scanner, qui démontre l'inflammation pariétale des gros vaisseaux et en donne une bonne cartographie, qui peut même intégrer, avec un protocole approprié, l'atteinte des artères vertébrales, temporales, faciales et maxillaires. Les quatre procédures obtiennent de hautes sensibilités et spécificités pour le diagnostic d'artérite et le choix est. laissé à la discrétion du clinicien, en fonction des moyens à sa disposition, l'essentiel étant d'obtenir au plus tôt les images, compte tenu des modifications rapides de l'inflammation pariétale induites par la corticothérapie. Cependant, l'écho-doppler des artères crâniennes et sous-clavières/axillaires est. la procédure de première intention, à effectuer devant toute suspicion d'artérite à cellules géantes, car permettant d'orienter plus rapidement le diagnostic d'ACG et celui d'atteinte des gros vaisseaux. Les corrélations entre le contrôle clinique, les signes inflammatoires biologiques et les résultats de l'imagerie vasculaire sont mauvaises chez un patient traité, si bien qu'il est. recommandé de ne pas multiplier celle-ci à titre de monitorage thérapeutique, en l'absence de suspicion de complication ou de rechute macro-artérielle. En revanche, une surveillance structurale de l'aorte est. nécessaire, mais la date de début, les modalités et la fréquence de cette surveillance restent discutés cas par cas, en l'absence de guide précis. Les patients avec aortite démontrée au diagnostic et/ou facteurs de risque additionnel d'anévrisme seront à surveiller de plus près.
Large vessel involvement in giant cell arteritis has long been described, although its right frequency and potential prognostic value have only been highlighted for two decades. Large vessel involvement not only is associated with a high incidence of late aortic aneurysms, but also might cause greater resistance to glucocorticoids and longer treatment duration, as well as worse late cardiovascular outcomes. These data were brought to our attention, thanks to substantial progress recently made in large vessel imaging. This relies on four single, often complementary, approaches of varying availability: colour Doppler ultrasound, contrast-enhanced computed tomography with angiography and, magnetic resonance imaging, which all demonstrate homogeneous circumferential wall thickening and describe structural changes; 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET/CT), which depicts wall inflammation and assesses many vascular territories in the same examination. In addition, integrated head-and-neck PET/CT can accurately and reliably diagnose cranial arteritis. All four procedures exhibit high diagnostic performance for a large vessel arteritis diagnosis so that the choice is left to the physician, depending on local practices and accessibility; the most important is to carry out the chosen modality without delay to avoid false or equivocal results, due to early vascular oedema changes as a result of high dose glucocorticoid treatment. Yet, ultrasound study of the superficial cranial and subclavian/axillary arteries remains a first line assessment aimed at strengthening and expediting the clinical diagnosis as well as raising suspicion of large-vessel involvement. In treated patients, vascular imaging results are poorly correlated with clinical-biological controlled disease so that it is strongly recommended not to renew imaging studies unless a large vessel relapse or complication is suspected. On the other hand, a structural monitoring of aorta following giant cell arteritis is mandatory, but uncertainties remain regarding the best procedural approach, timing of first control and spacing between controls. Individuals at greater risk of developing aortic complication, e.g. those with classic risk factors for aneurysm and/or visualised aortitis, should be monitored more closely.
Introduction
Some studies suggest that there is an increased risk of malignancies in giant cell arteritis (GCA). We aimed to describe the clinical characteristics and outcomes of GCA patients with ...concomitant malignancy and compare them to a GCA control group.
Method
Patients with a diagnosis of GCA and malignancy and with a maximal delay of 12 months between both diagnoses were retrospectively included in this study and compared to a control group of age-matched (3:1) patients from a multicenter cohort of GCA patients.
Results
Forty-nine observations were collected (median age 76 years). Malignancies comprised 33 (67%) solid neoplasms and 16 (33%) clonal hematologic disorders. No over-representation of a particular type of malignancy was observed. Diagnosis of GCA and malignancy was synchronous in 7 (14%) patients, while malignancy succeeded GCA in 29 (59%) patients. Malignancy was fortuitously diagnosed based on abnormalities observed in laboratory tests in 26 patients, based on imaging in 14 patients, and based on symptoms or clinical examination in the nine remaining patients. Two patients had a concomitant relapse of both conditions. When compared to the control group, patients with concomitant GCA and malignancy were more frequently male (
p
< 0.001), with an altered general state (
p
< 0.001), and polymyalgia rheumatica (
p
< 0.01).
Conclusions
This study does not indicate an over-representation of any particular type of malignancy in GCA patients. Initial follow-up dictated by vasculitis may have led to an early identification of malignancy. Nevertheless, GCA male patients with an altered general state and polymyalgia rheumatica might more frequently show concomitant malignancies.
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