A study of HBV infection and reactivation in patients with rheumatic diseases on immunosuppressive treatment

Introduction: Hepatitis B Virus (HBV) is unique due to the complexity of the interaction between its viral replication and the host’s immune defense. In patients with rheumatic disease and chronic or resolved HBV infection who receive immunosuppressive therapy, HBV reactivation (HBVr) is a complication with potentially severe morbidity and mortality. In order to study the effect of biologic treatment in the course of HBV infection and the appearance of HBVr, we followed up a cohort of rheumatic patients with comorbid HBV infection and examined the kinetics of quantitative HBsAg (qHBsAg) in patient with chronic hepatitis B (CHB) or chronic HBV infection (CHI) as well as the kinetics of anti-HBs in patients with resolved HBV infection or immunization. Patients and Methods: In a single-center observational cohort study we identified patients with rheumatic diseases and comorbid HBV infection and studied hepatitis B epidemiology and the incidence of HBVr. HBsAg-positive rheumatic patients on biologic treatment (cases) were divided into two groups, depending on whether they suffered with CHB (group A) or CHI (group B) and were appropriately matched with non-rheumatic patients (controls) who were not receiving immunosuppressives. qHBsAg was measured in regular annual intervals and cases and controls were compared with regards to the changes in qHBsAg from baseline, the annual changes in qHBsAg, the probabilities of annual “rapid qHBsAg” (i.e. a drop in qHBsAg > 0.5 log10 iu/mL in any annual interval) and the rates of HBsAg loss. In patients with rheumatoid arthritis (RA) and evidence of resolved infection or immunization (anti-HBs-positive) who were receiving treatment with non-TNFi biologics, we compared anti-HBs serum titers at the start and the end of the treatment courses. Results:Among 852 patients with rheumatic disease who received at least one dose of biologic immunosuppressive therapy in our cohort, 38 (5.7%) had CHB or CHI, while evidence of resolved infection were identified in 119 (18%). 28 HBsAg-positive patients were divided in patients with CHB (group A, n=13) and patients with CHI (group B, n=15) and were matched to appropriate non-rheumatic controls. During their prospective follow up period (3.86 ± 2.8 years), none of the patients developed HBVr or hepatitis flare. For the patients in group A (CHB), there were no statistically significant differences in the change of qHBsAg from baseline or in the annual change between cases and controls. Similarly, the cumulative incidence of annual rapid qHBsAg decline (32.7% versus 28.4% at 4 years respectively, log-rank p = 0.726) and the probability of HBsAg loss (1/13 versus 2/26 at years respectively) did not differ significantly in survival analysis. On the contrary, in group B (CHI), the change in qHBsAg from baseline and the annual rates of qHBsAg decline were lower in rheumatic patients receiving immunosuppressive treatment and antiviral prophylaxis in comparison with non-rheumatic controls receiving no treatment. Furthermore, there was statistically significant difference in the cumulative incidence of annual rapid qHBsAg decline and HBsAg loss between cases and controls in survival analysis (0% and 0% versus 24% and 20% in 4 years, respectively). We also identified 36 rheumatoid arthritis patients with either resolved HBV infection (n=25) or immunization (n=11) who received 48 treatment courses with non-TNFi agents (female sex 89%, mean age 63.6 ±18 years, seropositive 58.3%) and had a mean follow up of 2.41 ±2 years. During follow up no cases of HBVr or biochemical hepatitis flare were identified, even though the anti-HBs titers dropped below 10 iu/mL in three patients. Serum anti-HBs titers were statistically significantly lower at the end of treatment courses (343 ±182 iu/mL) compared to their start (405 ±383 iu/mL) (p=0.004). With regards to different non-TNFi treatments, the change in anti-HBs titers was not significant for RTX and ABA, but the titers differed significantly for TCZ (start: 437 ±388 iu/mL versus end: 323 ±368 iu/mL, p=0.027).Conclusions:In patients with rheumatic disease on immunosuppressive treatment, the strategy of offering prophylactic antiviral therapy in patients with moderate/high risk for HBVr (HBsAg-positive) and careful monitoring in patients with low relevant risk (HBsAg-negative, anti-HBs-positive) was efficacious in preventing any cases of HBVr or hepatitis flares after a follow up of such patient in our cohort for approximately 4 and 2 years respectively. The annual qHBsAg decline, the annual rate of rapid qHBsAg decline and the probability of HBsAg loss were significantly lower in rheumatic patients with CHI, but not CHB, when compared to appropriate non-rheumatic controls. This may indicate that the combination of immunosuppressive treatment and antiviral prophylaxis that is recommended for those patients may alter the natural course of HBeAg-negative CHI and reduce the probability of “functional cure”. Finally, in patients with resolved HBV infection or immunization (anti-HBs-positive) and RA, treatment with non-TNFi agents caused small drops in anti-HBs titers between start and end of treatments which were not deemed clinically significant. Interestingly, between the non-TNFi agents, it was anti-IL6 inhibition with TCZ that correlated with the most pronounced drop in anti-HBs titers.Εισαγωγή: Ο ιός της ηπατίτιδας Β είναι μοναδικός για την πολυπλοκότητα της αλληλεπίδρασής του με το ανοσιακό σύστημα του ανθρώπινου ξενιστή. Σε ασθενείς με ρευματικές παθήσεις που έχουν χρόνια ή παρελθούσα λοίμωξη από τον ιό της ηπατίτιδας Β και πρόκειται να λάβουν προχωρημένη ανοσοκατασταλτική θεραπεία η εμφάνισης επανενεργοποίησης της HBV λοίμωξης είναι μια επιπλοκή με ενδεχόμενη σοβαρή νοσηρότητα και θνητότητα. Για να διευκρινίσουμε την επίδραση της βιολογικής θεραπείας στην πορεία της HBV λοίμωξης και την εμφάνιση επανενεργοποίησής (HBVr) της, μελετήσαμε μια κοορτή ασθενών ρευματικές παθήσεις και HBV λοίμωξη και εξετάσαμε την κινητική του ποσοτικού HBsAg σε πάσχοντες από χρόνια ηπατίτιδα Β ή χρόνια HBV λοίμωξη και την κινητική του anti-HBs σε ασθενείς με παρελθούσα HBV λοίμωξη ή εμβολιασμό. Ασθενείς και μέθοδοι: Σε μια μονοκεντρική μελέτη παρατήρησης αναζητήθηκαν ασθενείς με ρευματικές παθήσεις και ηπατίτιδα Β που ήταν υπό αγωγή με βιολογικές θεραπείες και μελετήθηκε η επιδημιολογία της HBV λοίμωξης και η επίπτωση της HBVr. Οι HBsAg-θετικοί ρευματικοί ασθενείς υπό βιολογική θεραπεία χωρίστηκαν σε δύο ομάδες, ανάλογα με το αν έπασχαν από χρόνια («ενεργό») ηπατίτιδα Β (ΧΗΒ, ομάδα Α) ή χρόνια HBV λοίμωξη (ΧΒΛ, «ανενεργοί φορείς») (ομάδα Β) και εξομοιώθηκαν με μη ρευματικούς ασθενείς που δεν ελάμβαναν ανοσοκατασταλτική θεραπεία. Έγινε μέτρηση των επιπέδων του qHBsAg στον ορό σε ετήσια χρονικά διαστήματα και σύγκριση μεταξύ των ασθενών-περιπτώσεων και των ασθενών-ελέγχου όσον αφορά την αλλαγή του qHBsAg από την αρχική τιμή, την πιθανότητα ετήσιας ταχείας πτώσης qHBsAg (δηλαδή πτώση στο qHBsAg > 0,5 log10 iu/mL/έτος) και την πιθανότητα κάθαρσης του HBsAg. Σε ασθενείς με ρευματοειδή αρθρίτιδα και ευρήματα παρελθούσας λοίμωξης ή εμβολιασμού (anti-HBs-θετικοί) που έλαβαν θεραπεία με μη-TNFi παράγοντες συγκρίθηκαν τα επίπεδα anti-HBs στον ορό στην αρχή και το τέλος του κύκλου θεραπείας. Αποτελέσματα:Μεταξύ 852 ασθενών με ρευματικές παθήσεις που έλαβαν βιολογική θεραπεία στην κοορτή μας, ΧΗΒ ή ΧΒΛ είχαν 38 ασθενείς (5,7%), ενώ παρελθούσα λοίμωξη 119 (18%). 28 HBsAg-θετικοί ασθενείς χωρίστηκαν σε ασθενείς με ΧΗΒ (ομάδα Α, n=13) και ασθενείς με ΧΒΛ (ομάδα Β, n=15) και εξομοιώθηκαν με μη ρευματικούς ασθενείς με αντίστοιχες διαγνώσεις. Στη διάρκεια της παρακολούθησης (3,86 ± 2,8 έτη) κανείς από τους ρευματικούς ασθενείς δεν ανέπτυξε HBVr ή βιοχημική έξαρση της ηπατίτιδας Β. Για τους ασθενείς της ομάδας Α (ΧΗΒ), δεν υπήρχαν στατιστικά σημαντικές διαφορές στην αλλαγή του qHBsAg από την αρχική τιμή ούτε στον ρυθμό πτώσης του qHBsAg ανά ετήσιο διάστημα μεταξύ των ρευματικών και μη ρευματικών ασθενών. Παρομοίως, η αθροιστική επίπτωση της ταχείας ετήσια πτώσης του qHBsAg (32,7% έναντι 28,4% στα 4 χρόνια αντίστοιχα, log-rank p = 0,726) και η πιθανότητα κάθαρσης του HBsAg (1/13 έναντι 2/26 στα 4 χρόνια αντίστοιχα) δε διέφερε σημαντικά στην ανάλυση επιβίωσης μεταξύ των δύο ομάδων. Στους ασθενείς της ομάδας Β (ΧΒΛ), η αλλαγή στα επίπεδα του qHBsAg από την αρχική τιμή και οι τιμές του ρυθμού της ετήσιας πτώσης του qHBsAg ήταν χαμηλότερες στους ρευματικούς ασθενείς που λάμβαναν ανοσοκαταστολή και αντιιική προφύλαξη σε σχέση με τους ασθενείς ελέγχου που δεν λάμβαναν θεραπεία. Επιπλέον, υπήρχε σημαντική διαφορά στην αθροιστική επίπτωση ταχείας ετήσιας πτώσης qHBsAg και κάθαρσης του HBsAg μεταξύ των δύο ομάδων στην ανάλυση επιβίωσης (0% και 0% έναντι 24% και 20% αντίστοιχα στα 4 έτη). Εντοπίστηκαν 36 ασθενείς με παρελθούσα HBV λοίμωξη (n=25) ή εμβολιασμό (n=11) που έπασχαν από ΡΑ, έλαβαν 48 κύκλους θεραπείας με μη-TNFi βιολογικούς παράγοντες (γυναίκες 89%, μέση ηλικία 63,6 ±18 έτη, οροθετικοί 58,3%) και είχαν μέση διάρκεια παρακολούθησης 2,41 ±2 έτη. Κατά τη διάρκεια της παρακολούθησης δεν παρατηρήθηκαν περιπτώσεις HBVr ή βιοχημική έξαρση της ηπατίτιδας Β, παρότι σε τρεις ασθενείς ο τίτλος των anti-HBs έπεσε κάτω των 10 iu/mL. Τα επίπεδα των anti-HBs στον ορό διέφεραν στατιστικά σημαντικά μεταξύ της έναρξης (405 ±383 iu/mL) και του τέλους της θεραπείας (343 ±182 iu/mL) (p=0.004). Οι διαφορές στα anti-HBs έναρξης και τέλους θεραπείας μεταξύ διαφορετικών μη-TNFi θεραπειών δε διέφεραν για το RTX και το ABA, αλλά είχαν στατιστικά σημαντική διαφορά για το TCZ (έναρξη: 437 ±388 iu/mL έναντι τέλος: 323 ±368 iu/mL, p=0.027).Συμπεράσματα:Σε ασθενείς με ρευματικές παθήσεις υπό ανοσοκατασταλτική θεραπεία, η στρατηγική της χορήγησης προφυλακτικής αντιιικής αγωγής σε ασθενείς μέτριου-υψηλού κινδύνου για HBVr (HBsAg-θετικοί) και της στενής παρακολούθησης σε ασθενείς χαμηλού κινδύνου (HBsAg-αρνητικοί, anti-HBc-θετικοί) είναι ασφαλής στην πρόληψη εμφάνισης HBV επανενεργοποίησης μετά από ένα διάστημα παρακολούθησης κοντά στα 4 και 2 έτη αντίστοιχα. Η ετήσια πτώση του qHBsAg, ο ρυθμός ταχείας πτώσης qHBsAg και η πιθανότητα κάθαρσης του HbsAg διέφεραν σημαντικά μεταξύ ρευματικών και μη ρευματικών ασθενών στην περίπτωση των ασθενών με ΧΒΛ, αλλά όχι σε ασθενείς με ΧΗΒ. Αυτό σημαίνει ότι ο συνδυασμός ανοσοκατασταλτικής και αντιιικής αγωγής που ενδείκνυται να χορηγηθεί σε αυτή την ομάδα ασθενών πιθανώς τροποποιεί τη φυσική ιστορία στους HBeAg-αρνητικής ΧΒΛ και επηρεάζει την πιθανότητα «λειτουργικής ίασης» στους ηπατίτιδας Β. Τέλος, σε ασθενείς με παρελθούσα HBV λοίμωξη και ΡΑ, η χορήγηση μη-TNFi παραγόντων προκάλεσε μικρές πτώσεις στον τίτλο του anti-HBs αντισώματος μεταξύ έναρξης και τέλους του κύκλου θεραπείας που δε συνδυάστηκαν με κλινική σημαντικότητα. Μεταξύ των διαφόρων μη-TNFi, το TCZ συσχετίστηκε με μεγαλύτερη πτώση στους τίτλους του anti-HBs

Increased Frequency of Peripheral B and T Cells Expressing Granulocyte Monocyte Colony-Stimulating Factor in Rheumatoid Arthritis Patients

ObjectivesGranulocyte monocyte colony-stimulating factor (GM-CSF) is currently considered a crucial inflammatory mediator and a novel therapeutic target in rheumatoid arthritis (RA), despite the fact that its precise cellular sources remain uncertain. We studied the expression of GM-CSF in peripheral lymphocytes from RA patients and its change with antirheumatic therapies.MethodsIntracellular GM-CSF expression was assessed by flow cytometry in stimulated peripheral B (CD19+) and T (CD3+) cells from RA patients (n = 40), disease (n = 31 including osteoarthritis n = 15, psoriatic arthritis n = 10, and systemic rheumatic diseases n = 6) and healthy (n = 16) controls. The phenotype of GM-CSF+ B cells was assessed as well as longitudinal changes in GM-CSF+ lymphocytes during methotrexate (MTX, n = 10) or anti-tumor necrosis factor (anti-TNF, n = 10) therapy.ResultsAmong untreated RA patients with active disease (Disease Activity Score 28-C-reactive protein = 5.6 ± 0.89) an expanded population of peripheral GM-CSF+ B (4.1 ± 2.2%) and T (3.4 ± 1.6%) cells was detected compared with both disease (1.7 ± 0.9%, p < 0.0001 and 1.7 ± 1.3%, p < 0.0001, respectively) and healthy (0.3 ± 0.2%, p < 0.0001 and 0.6 ± 0.6%, p < 0.0001) controls. RA GM-CSF+ B cells displayed more commonly a plasmablast or transitional phenotype (37.12 ± 18.34% vs. 14.26 ± 9.46%, p = 0.001 and 30.49 ± 15.04% vs. 2.45 ± 1.84%, p < 0.0001, respectively) and less a memory phenotype (21.46 ± 20.71% vs. 66.99 ± 16.63%, p < 0.0001) compared to GM-CSF− cells. GM-CSF expression in RA patients did not correlate to disease duration, activity or serological status. Anti-TNF treatment led to a statistically significant decrease in GM-CSF+ B and T cells while MTX had no significant effect.DiscussionThis is the first study showing an expanded population of GM-CSF+ B and T lymphocytes in patients with active RA which declined after anti-TNF therapy

Better outcomes of COVID-19 in vaccinated compared to unvaccinated patients with systemic rheumatic diseases

Objective tau o report outcomes of breakthrough COVID-19 in comparison with COVID-19 in unvaccinated patients with systemic rheumatic diseases (SRDs). Methods Patients with SRD with COVID-19 (vaccinated and unvaccinated) were included by their rheumatologists in a registry operated by the Greek Rheumatology Society in a voluntarily basis. Type, date and doses of SARS-CoV-2 vaccines were recorded, and demographics, type of SRD, concurrent treatment, comorbidities and COVID-19 outcomes (hospitalisation, need for oxygen supplementation and death) were compared between vaccinated and unvaccinated patients. Results Between 1 March 2020 and 31 August 2021, 195 patients with SRD with COVID-19 were included; 147 unvaccinated and 48 vaccinated with at least one dose of a SARS-CoV-2 vaccine (Pfizer n=38 or AstraZeneca n=10). Among vaccinated patients, 29 developed breakthrough COVID-19 >14 days after the second vaccine dose (fully vaccinated), while 19 between the first and <14 days after the second vaccine dose (partially vaccinated). Despite no differences in demographics, SRD type, treatment or comorbidities between unvaccinated and vaccinated patients, hospitalisation and mortality rates were higher in unvaccinated (29.3% and 4.1%, respectively) compared with partially vaccinated (21% and 0%) or fully vaccinated (10.3% and 0%) patients. Conclusions Vaccinated patients with SRD with breakthrough COVID-19 have better outcomes compared with unvaccinated counterparts with similar disease/treatment characteristics

Validation Study Of The International Classification Criteria For The Cryoglobulinemic Vasculitis

Background/Purpose: preliminary Classification Criteria for cryoglobulinemic vasculitis (CV) have been developed in 2011 by an European cooperative study, with an adequate methodology in a large number of real cases and controls (1). The aim of this study is to validate these classification criteria for CV. Methods: Centres from Europe, United States, Japan and Egypt, were involved. A dedicated chart included: l) a validated questionnaire for CV (1); 2) the pattern of organ involvement (4 items: constitutional, articular, vascular and neurologic involvement); 3) laboratory tests (3 items: rheumatoid factor, complement C4 and serum monoclonal component), according to the preliminary criteria (1). New patients with CV (Group A) and controls (Group B), i.e., subjects with cryoglobulins but lacking CV based on the golden standard clinical judgment, were studied. A sample size of at least 140 patients for each group was estimated in order to obtain a sensitivity and a specificity of at least 90.5%, based on the previous results (1). Sensitivity and specificity were calculated by comparing Group A versus Group B. Finally, not for classification purposes, but to disclose whether the Criteria may be also clinically helpful in patients lacking serum cryoglobulins, but where CV is suspected (1), Group A was also compared with Group C, including patients with diseases mimicking CV, but without serum cryoglobulins. Results: Six hundred forty-three patients were enrolled in 22 Centres (from Italy, Spain, France, Greece, Slovenia, Japan and Egypt). MajorA comprised 268 patients with CV, Group B 182 controls with serum cryoglobulins without CV, and Group C 193 controls without serum cryoglobulins. Notably, 20 patients showed type I cryoglobulinemia, 13 in Group A, and 7 in Group B. Group C included 108/193 (55.9%) systemic vasculitides, 100/108 (92.6%) were small vessel vasculitides. The classification criteria [positivity of at least 2/3 items among questionnaire (2/3 positive questions), clinical item (3/4 clinical manifestations), laboratory (2/3 tests)] showed 89.9% (95% CI 86.1–93.6) of sensitivity and 93.5% (95% CI 89.7–97.2) of specificity, replicating previous results (1). Sensitivity of 91.7% and specificity of 100% were observed in the subgroup of type I cryoglobulinemia. By the comparison of Group A vs. Group C, the Criteria showed a specificity 92.6% (88.8–96.5) and a sensitivity of 77.8% (72.6–83.0) when the laboratory item was positive (questionnairelaboratory item; or clinical laboratory item). Conclusion: the International Classification Criteria for the CV have been validated in a new real cohort. High specificity and sensitivity were confirmed. Notably, in patients where CV is suspected on clinical grounds, but where cryoglobulins are negative by initial testing, or not yet available (patients who cannot be classified as CV, as positive serum cryoglobulinemia is a conditio sine qua non for classification) (1), the Criteria appear relevant to strengthen the suspicion for CV, and to optimize the follow-up