Increased activity of T follicular helper (Tfh) cells plays a major pathogenic role in systemic lupus erythematosus (SLE). However, the mechanisms that cause aberrant Tfh cell responses in SLE remain ...elusive. Here we showed the OX40 ligand (OX40L)-OX40 axis contributes to the aberrant Tfh response in SLE. OX40L was expressed by myeloid antigen-presenting cells (APCs), but not B cells, in blood and in inflamed tissues in adult and pediatric SLE patients. The frequency of circulating OX40L-expressing myeloid APCs positively correlated with disease activity and the frequency of ICOS+ blood Tfh cells in SLE. OX40 signals promoted naive and memory CD4+ T cells to express multiple Tfh cell molecules and were sufficient to induce them to become functional B cell helpers. Immune complexes containing RNA induced OX40L expression on myeloid APCs via TLR7 activation. Our study provides a rationale to target the OX40L-OX40 axis as a therapeutic modality for SLE.
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•OX40L is expressed by myeloid antigen-presenting cells in patients with active SLE•OX40 signals promote the differentiation of human Th cells toward the Tfh lineage•Strong TCR signals promote the expression of Tfh molecules by human Th cells•RNP-Anti-RNP immune complexes induce monocytes to express OX40L via TLR7
Although increased activity of T follicular helper (Tfh) cells plays a pathogenic role in systemic lupus erythematosus (SLE), the mechanism has been unclear. Ueno and colleagues show that exaggerated OX40 signals promote the generation of Tfh cells in SLE.
Purpose
About 25% of patients with common variable immunodeficiency disease (CVID) have splenomegaly, necessitating sometimes splenectomy whom consequences on the immunological profile of CVID ...patients have never been studied. We analyzed 11 CVID patients’ comprehensive blood immune cell phenotypes pre- and post-splenectomy.
Methods
Flow cytometry analyses of immune cell populations.
Results
Among 89 CVID cohort patients, 41 with splenomegaly, splenomegaly was strongly associated with granulomatous disease, autoimmune disorders, lymphoid hyperplasia, and/or portal hypertension. CVID patients with splenomegaly have significant peripheral lymphopenia (
p
= 0.001), and significantly fewer peripheral class-switched memory B cells (smBs) (
p
= 0.001), CD4
+
T lymphocytes (
p
= 0.001), NK (
p
= 0.0001) and dendritic cells (
p
≤ 0.01), and significantly more circulating CD4
+
and CD8
+
(
p
= 0.00001) T cell subset activation (
p
= 0.00005), than CVID patients without splenomegaly. Examination of splenectomy impact on circulating lymphocyte subset distributions demonstrated the drastically enhanced total circulating lymphocyte count post-splenectomy, predominantly B lymphocytes and CD8
+
T cells. However, splenectomy did not change B cell distribution, with smBs remaining persistently low, in contrast to complete inversion of the circulating T cell composition, with reversal of the CD4
+
/CD8
+
ratio suggesting that amplification of the CD8
+
T cell compartment is a CVID characteristic in patients with splenomegaly. Our results highlight this CD8
+
amplification in CVID–splenomegaly patients that might be explained by a homing effect to the spleen and/or possible chronic virus replication, which in turn could induce T cell expansions.
Conclusion
Splenectomizing CVID patients with splenomegaly restores the absolute circulating lymphocyte count, suggesting that the decreased T cell count in the presence of splenomegaly cannot be used as an exclusive criterion for combined immunodeficiency.
Objective
Earlier studies of eosinophilic granulomatosis with polyangiitis (Churg‐Strauss) (EGPA), with limited patient numbers and followup durations, demonstrated that clinical presentation at ...diagnosis, but not outcome, differed according to antineutrophil cytoplasmic antibody (ANCA) status. This study was undertaken to describe the main characteristics of a larger patient cohort and their long‐term outcomes.
Methods
A retrospective study of EGPA patients in the French Vasculitis Study Group cohort who satisfied the American College of Rheumatology criteria and/or Chapel Hill definitions was conducted. Patient characteristics and outcomes were compared according to ANCA status and year of diagnosis.
Results
We identified 383 patients diagnosed between 1957 and June 2009 (128 33.4% before 1997 or earlier) and followed up for a mean ± SD of 66.8 ± 62.5 months. At diagnosis, their mean ± SD age was 50.3 ± 15.7 years, and 91.1% had asthma (duration 9.3 ± 10.8 years). Main manifestations included peripheral neuropathy (51.4%); ear, nose, and throat (ENT) signs (48.0%); skin lesions (39.7%); lung infiltrates (38.6%); and cardiomyopathy (16.4%). Among the 348 patients tested at diagnosis for ANCA, the 108 ANCA‐positive patients (31.0%) had significantly more frequent ENT manifestations, peripheral neuropathy, and/or renal involvement, but less frequent cardiac manifestations, than the ANCA‐negative patients. Vasculitis relapses occurred in 35.2% of the ANCA‐positive versus 22.5% of the ANCA‐negative patients (P = 0.01), and 5.6% versus 12.5%, respectively, died (P < 0.05). The 5‐year relapse‐free survival rate was 58.1% (95% confidence interval 95% CI 45.6–68.6) for ANCA‐positive and 67.8% (95% CI 59.8–74.5) for ANCA‐negative patients (P = 0.35). Multivariable analysis identified cardiomyopathy, older age, and diagnosis during or prior to 1996 as independent risk factors for death and lower eosinophil count at diagnosis as predictive of relapse.
Conclusion
The characteristics and long‐term outcomes of EGPA patients differ according to their ANCA status. Although EGPA relapses remain frequent, mortality has declined, at least since 1996.
Summary
The aim of this study was to assess the prevalence and the burden of difficult‐to‐treat primary ITP (pITP), defined by the need for another ITP treatment after romiplostim and eltrombopag. ...Adult patients were selected in the prospective, real‐world CARMEN‐France registry up to December 2021. Out of 821 adult patients with pITP, 29 had difficult‐to‐treat ITP (3.5%; 95% confidence interval CI: 2.3%–4.8% in total; 7.6%; 95% CI: 4.9%–10.2% of patients needing ≥2nd line treatment). The 3‐year cumulative incidence of bleeding, infection and thrombosis was 100%, 24.1% and 13.8% respectively. The median cumulative duration of hospital stays was 31 days (median follow‐up: 30.3 months).
To compare individually tailored, based on trimestrial biological parameter monitoring, to fixed-schedule rituximab reinfusion for remission maintenance of antineutrophil cytoplasm antibody ...(ANCA)-associated vasculitides (AAVs).
Patients with newly diagnosed or relapsing granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in complete remission after induction therapy were included in an open-label, multicentre, randomised controlled trial. All tailored-arm patients received a 500 mg rituximab infusion at randomisation, with rituximab reinfusion only when CD19+B lymphocytes or ANCA had reappeared or ANCA titre rose markedly based on trimestrial testing until month 18. Controls received a fixed 500 mg rituximab infusion on days 0 and 14 postrandomisation, then 6, 12 and 18 months after the first infusion. The primary endpoint was the number of relapses (new or reappearing symptom(s) or worsening disease with Birmingham Vasculitis Activity Score (BVAS)>0) at month 28 evaluated by an independent Adjudication Committee blinded to treatment group.
Among the 162 patients (mean age: 60 years; 42% women) included, 117 (72.2%) had GPA and 45 (27.8%) had MPA. Preinclusion induction therapy included cyclophosphamide for 100 (61.7%), rituximab for 61 (37.6%) and methotrexate for 1 (0.6%). At month 28, 21 patients had suffered 22 relapses: 14/81 (17.3%) in 13 tailored-infusion recipients and 8/81 (9.9%) in 8 fixed-schedule patients (p=0.22). The tailored-infusion versus fixed-schedule group, respectively, received 248 vs 381 infusions, with medians (IQR) of 3 (2-4) vs 5 (5-5) administrations.
AAV relapse rates did not differ significantly between individually tailored and fixed-schedule rituximab regimens. Individually tailored-arm patients received fewer rituximab infusions.
NCT01731561; Results.
Romiplostim and eltrombopag, the first thrombopoietic receptor-agonists with demonstrated efficacy against immune thrombocytopenia in prospective controlled studies, were recently authorized in most ...countries for adults with chronic immune thrombocytopenia. So far, no data are available about the potential contribution of switching from romiplostim to eltrombopag or vice versa in terms of efficacy or tolerance. Efficacies and tolerance profiles were evaluated for 46 patients who sequentially received both drugs, switching from one to the other. The reasons for switching were: lack of efficacy for 23 patients, platelet-count fluctuations for 11, side effects for 4, and 8 patients' preferences. For 50-80% of the patients, switching from romiplostim to eltrombopag or eltrombopag to romiplostim effectively impacted the platelet count, with fluctuations disappearing in 54% and side effects resolved in 100%. In 80% of the patients, the 2 thrombopoietic receptor-agonists achieved similar response patterns. Our results confirmed that switching from one thrombopoietic receptor-agonist to the other could be beneficial in clinical practice for patients with severe chronic immune thrombopenia who failed to respond or experienced adverse events to the first. (Clinical Trials.gov identifier: NCT01618734).
Although splenectomy is still considered the most effective curative treatment for immune thrombocytopenia (ITP), its use has significantly declined in the last decade, especially since the approval ...of thrombopoietin receptor agonists (TPO‐RAs). The main objective of the study was to determine whether splenectomy was still as effective nowadays, particularly for patients with failure to respond to TPO‐RAs. Our secondary objective was to assess, among patients who relapsed after splenectomy, the pattern of response to treatments used before splenectomy. This multicenter retrospective study involved adults who underwent splenectomy for ITP in France from 2011 to 2020. Response status was defined according to international criteria. We included 185 patients, 100 (54.1%) and 135 (73.0%) patients had received TPO‐RAs and/or rituximab before the splenectomy. The median follow‐up after splenectomy was 39.2 months 16.5–63.0. Overall, 144 (77.8%) patients had an initial response and 23 (12.4%) experienced relapse during follow‐up, for an overall sustained response of 65.4%, similar to that observed in the pre‐TPO‐RA era. Among patients who received at least one TPO‐RA or rituximab before splenectomy, 92/151 (60.9%) had a sustained response. Six of 13 (46%) patients with previous lack of response to both TPO‐RAs and rituximab had a sustained response to splenectomy. Among patients with relapse after splenectomy, 13/21 (61.2%) patients responded to one TPO‐RAs that failed before splenectomy. In conclusion, splenectomy is still a relevant option for treating adult primary ITP not responding to TPO‐RAs and rituximab. Patients with lack of response or with relapse after splenectomy should be re‐challenged with TPO‐RAs.
Biannual rituximab infusions over 18 months effectively maintain remission after a "standard" remission induction regimen for patients with antineutrophil cytoplasmic antibody-associated vasculitis ...(AAV).
To evaluate the efficacy of prolonged rituximab therapy in preventing AAV relapses in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who have achieved complete remission after completing an 18-month maintenance regimen.
Randomized controlled trial. (ClinicalTrials.gov: NCT02433522).
39 clinical centers in France.
68 patients with GPA and 29 with MPA who achieved complete remission after the first phase of maintenance therapy.
Rituximab or placebo infusion every 6 months for 18 months (4 infusions).
The primary end point was relapse-free survival at month 28. Relapse was defined as new or reappearing symptoms or worsening disease, with a Birmingham Vasculitis Activity Score greater than 0.
From March 2015 to April 2016, 97 patients (mean age, 63.9 years; 35% women) were randomly assigned, 50 to the rituximab and 47 to the placebo group. Relapse-free survival estimates at month 28 were 96% (95% CI, 91% to 100%) and 74% (CI, 63% to 88%) in the rituximab and placebo groups, respectively, an absolute difference of 22% (CI, 9% to 36%) with a hazard ratio of 7.5 (CI, 1.67 to 33.7) (
= 0.008). Major relapse-free survival estimates at month 28 were 100% (CI, 93% to 100%) versus 87% (CI, 78% to 97%) (
= 0.009), respectively. At least 1 serious adverse event developed in 12 patients (24%) in the rituximab group (with 9 infectious serious adverse events occurring among 6 patients 12%) versus 14 patients (30%) in the placebo group (with 6 infectious serious adverse events developing among 4 patients 9%). No deaths occurred in either group.
Potential selection bias based on previous rituximab response and tolerance.
Extended therapy with biannual rituximab infusions over 18 months was associated with a lower incidence of AAV relapse compared with standard maintenance therapy.
French Ministry of Health and Hoffmann-La Roche.
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