Sophie Candon

Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass

Aims/hypothesisThe aim of the study was to examine the 48xa0month outcome of treating recent-onset type 1 diabetic patients for 6xa0days with humanised CD3-antibody, ChAglyCD3.MethodsEighty patients, aged 12–39xa0years, were recruited for a phase 2 multicentre trial and randomised to placebo (nu2009=u200940) or ChAglyCD3 (nu2009=u200940) treatment by a third party member; participants and care-givers were blinded. The change in insulin dose (Uxa0kg−1u2009day−1) over 48xa0months was chosen as primary endpoint and compared in 31 placebo- and 33 ChAglyCD3-treated patients. Adverse events were followed in 35 and 38 patients, respectively.ResultsTreatment with ChAglyCD3 delayed the rise in insulin requirements of patients with recent-onset diabetes and reduced its amplitude over 48xa0months (+0.09 vs +0.32xa0Uu2009kg−1u2009day−1 in the placebo group). Using multivariate analysis this effect was correlated with higher baseline residual beta cell function and a younger age. It was associated with better outcome variables in subgroups selected according to these variables. In the ChAglyCD3 subgroup with higher initial beta cell function, 0/11 patients became C-peptide-negative over 48xa0months vs 4/9 in the corresponding placebo subgroup. In the subgroup aged <27xa0years old, antibody treatment preserved initial beta cell function for 36xa0months (vs >80% decline within 24xa0months in the placebo subgroup <27xa0years old), resulted in lower HbA1c concentrations and tended to reduce glycaemic variability (pu2009=u20090.08). No long-term adverse events were observed.Conclusions/interpretationA 6xa0day ChAglyCD3 treatment can suppress the rise in insulin requirements of recent-onset type 1 diabetic patients over 48xa0months, depending on their age and initial residual beta cell function. In younger patients this effect is associated with reduced deterioration of metabolic variables. These observations help to define inclusion criteria for prevention trials.Trial registration:ClinicalTrials.gov NCT00627146Funding:Center grants from the Juvenile Diabetes Research Foundation (4-2001-434, 4-2005-1327) and grants from the Belgian Fund for Scientific Research-Flanders and from Brussels Free University-VUB.

Rituximab in Severe Lupus Nephritis: Early B-Cell Depletion Affects Long-Term Renal Outcome

BACKGROUND AND OBJECTIVESnStandard treatment for lupus nephritis, including corticosteroids and cyclophosphamide, is efficient but is still associated with refractory or relapsing disease, or severe deleterious effects. Rituximab, a monoclonal chimeric anti-B cell antibody, is increasingly used in patients with lupus nephritis, but reported series were small and had a short follow-up.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnThe authors analyzed clinical and histologic data of 20 patients who were treated with rituximab for lupus nephritis and followed up for at least 12 mo.nnnRESULTSnNineteen women and one man received rituximab as induction treatment for an active class IV (15 cases) or class V (5 cases) lupus nephritis. Rituximab was given for lupus nephritis refractory to standard treatment (12 cases), for relapsing disease (6 cases), or as first-line treatment (2 cases). Three patients received cyclophosphamide concomitantly with rituximab. Ten received new injections of rituximab as maintenance therapy. Side effects included mainly five infections and four moderate neutropenias. After a median follow-up of 22 mo, complete or partial renal remission was obtained in 12 patients (60%). Lupus nephritis relapsed in one patient, who responded to a new course of rituximab. The achievement of B cell depletion 1 mo after rituximab, which negatively correlated with black ethnicity and hypoalbuminemia, was strongly associated with renal response. Rapidly progressive glomerulonephritis did not respond to rituximab.nnnCONCLUSIONnRituximab is an interesting therapeutic option in relapsing or refractory lupus nephritis when early B cell depletion is obtained.

Rationale and efficacy of interleukin-1 targeting in Erdheim–Chester disease

Erdheim-Chester disease (ECD) pathophysiology remains largely unknown. Its treatment is not codified and usually disappointing. Interferon (IFN)-α therapy lacks efficacy for some life-threatening manifestations and has a poor tolerance profile. Because interleukin (IL)-1Ra synthesis is naturally induced after stimulation by IFN-α, we hypothesized that recombinant IL-1Ra (anakinra) might have some efficacy in ECD. We treated 2 patients who had poor tolerance or contraindication to IFN-α with anakinra as a rescue therapy and measured their serum C-reactive protein, IL-1β, IL-6, and monocytic membranous IL-1α (mIL-1α) levels before, under, and after therapy. Another untreated ECD patient and 5 healthy subjects were enrolled as controls. After treatment, fever and bone pains rapidly disappeared in both patients, as well as eyelid involvement in one patient. In addition, retroperitoneal fibrosis completely or partially regressed, and C-reactive protein, IL-6, and mIL-1α levels decreased to within the normal and control range. Beside injection-site reactions, no adverse event was reported. Therefore, our results support a central role of the IL-1 network, which seemed to be overstimulated in ECD. Its specific blockade using anakinra thereby opens new pathophysiology and therapeutic perspectives in ECD.

Bortezomib as the Sole Post‐Renal Transplantation Desensitization Agent Does Not Decrease Donor‐Specific Anti‐HLA Antibodies

Persistence of donor‐specific anti‐HLA antibodies (DSA) associated with antibody‐mediated graft injuries following kidney transplantation predicts evolution toward chronic humoral rejection and reduced graft survival. Targeting plasma cells, the main antibody‐producing cells, with the proteasome inhibitor bortezomib may be a promising desensitization strategy. We evaluated the in vivo efficacy of one cycle of bortezomib (1.3 mg/m2× 4 doses), used as the sole desensitization therapy, in four renal transplant recipients experiencing subacute antibody‐mediated rejection with persisting DSA (>2000 [Mean Fluorescence Intensity] MFI). Bortezomib treatment did not significantly decrease DSA MFI within the 150‐day posttreatment period in any patient. In addition, antivirus (HBV, VZV and HSV) antibody levels remained stable following treatment suggesting a lack of efficacy on long‐lived plasma cells. In conclusion, one cycle of bortezomib alone does not decrease DSA levels in sensitized kidney transplant recipients in the time period studied. These results underscore the need to evaluate this new desensitization agent properly in prospective, randomized and well‐controlled studies.

Humoral and cellular immune responses after influenza vaccination in kidney transplant recipients.

It has been speculated that influenza vaccination of renal allograft recipients could be associated with de novo production and/or increased titers of anti‐HLA antibodies (HLA‐Ab). To directly address this issue, we recruited 66 stable renal transplant recipients and 19 healthy volunteers during the 2005–2006 vaccination campaign. At day 0 and day 30 following vaccination, HLA‐Ab were screened and in parallel influenza‐specific antibody and T‐cell responses were assessed. Humoral postvaccinal responses to A/H1N1 and A/H3N2 strains, but not B strain, were less frequent in transplanted patients than in control subjects. Significant expansion of influenza‐specific IFN‐γ‐producing T cells was observed at similar frequencies in patients and controls. There was no correlation between cellular and humoral postvaccinal responses. No impact of sex, age or immunosuppressive regimen could be evidenced. Vaccination was not associated with any significant change in preexisting or de novo anti‐HLA sensitization. No episode of allograft rejection was recorded in any of the patients. Our results suggest that flu vaccination is safe in stable renal transplanted patients. Larger studies are needed for definitive statistical proof of the safety and effectiveness, with regard to the quality of the immune response, of yearly influenza vaccination in immunosuppressed patients.

Antibiotics in Early Life Alter the Gut Microbiome and Increase Disease Incidence in a Spontaneous Mouse Model of Autoimmune Insulin-Dependent Diabetes

Insulin-dependent or type 1 diabetes is a prototypic autoimmune disease whose incidence steadily increased over the past decades in industrialized countries. Recent evidence suggests the importance of the gut microbiota to explain this trend. Here, non-obese diabetic (NOD) mice that spontaneously develop autoimmune type 1 diabetes were treated with different antibiotics to explore the influence of a targeted intestinal dysbiosis in the progression of the disease. A mixture of wide spectrum antibiotics (i.e. streptomycin, colistin and ampicillin) or vancomycin alone were administered orally from the moment of conception, treating breeding pairs, and during the postnatal and adult life until the end of follow-up at 40 weeks. Diabetes incidence significantly and similarly increased in male mice following treatment with these two antibiotic regimens. In NOD females a slight yet not significant trend towards an increase in disease incidence was observed. Changes in gut microbiota composition were assessed by sequencing the V3 region of bacterial 16S rRNA genes. Administration of the antibiotic mixture resulted in near complete ablation of the gut microbiota. Vancomycin treatment led to increased Escherichia, Lactobacillus and Sutterella genera and decreased members of the Clostridiales order and Lachnospiraceae, Prevotellaceae and Rikenellaceae families, as compared to control mice. Massive elimination of IL-17-producing cells, both CD4+TCRαβ+ and TCRγδ+ T cells was observed in the lamina propria of the ileum and the colon of vancomycin-treated mice. These results show that a directed even partial ablation of the gut microbiota, as induced by vancomycin, significantly increases type 1 diabetes incidence in male NOD mice thus prompting for caution in the use of antibiotics in pregnant women and newborns.

Transient Epstein-Barr virus reactivation in CD3 monoclonal antibody-treated patients

Here we report a unique situation in which an early and synchronized Epstein-Barr virus (EBV) reactivation was induced by a 6-day course of treatment with a humanized CD3-specific monoclonal antibody in patients with recent onset of type 1 diabetes. The virologic and immunologic analysis demonstrated that this reactivation was transient, self-limited, and isolated, associated with the rapid advent of an EBV-specific T-cell response. The anti-CD3 antibody administration induced short-lasting immunosuppression and minor yet clear-cut signs of T-cell activation that preceded viral reactivation. Early posttransplant monitoring of renal and islet allograft recipients showed that no comparable phenomenon was observed after the administration of full-dose immunosuppressive therapy. This EBV reactivation remains of no apparent clinical concern over the long term and should not preclude further development of therapeutic anti-CD3 antibodies. This phenomenon may also direct new research avenues to understand the still ill-defined nature of stimuli triggering EBV reactivation in vivo.

12-month follow-up after successful infliximab therapy in pediatric crohn disease.

Aim: Infliximab (IFX) therapy is highly efficacious for the induction and maintenance of remission in pediatric Crohn disease (CD). However, to date it is unclear how long patients should be given IFX. Given the increasing safety concerns about the concomitant and prolonged use of IFX and azathioprine in CD, we wanted to address the clinical outcome in pediatric CD patients who responded to IFX medication, once IFX was stopped. Patients and Methods: Upon induction therapy with 3 IFX infusions, 36 of 38 patients with CD were in clinical remission at 3 months. These 36 responders were separated into 2 groups: 16 patients received no further IFX infusions, whereas 20 patients received scheduled maintenance therapy with IFX for 12 months. Results: Among the 16 patients who received no further IFX infusions, 12 experienced relapse during the 12-month follow-up interval after IFX was stopped. In the group receiving maintenance therapy, 11 of 20 patients remained in clinical remission at 12 months of therapy, whereas 8 patients required adjustment of IFX doses or intervals. Among the 11 children who were in clinical remission and receiving maintenance therapy without dose adjustment, 8 experienced relapse within 12 months after IFX maintenance therapy was stopped. Overall, the relapse rates after IFX induction or maintenance therapy was stopped were 75% and 72%, respectively. Conclusions: These data indicate that IFX is efficacious in controlling severe pediatric CD; however, to induce and maintain clinical remission, repeated IFX infusions are required, with a need for dose adjustment in a substantial number of patients.

Non–TNF-Targeted Biologic vs a Second Anti-TNF Drug to Treat Rheumatoid Arthritis in Patients With Insufficient Response to a First Anti-TNF Drug: A Randomized Clinical Trial

ImportancenOne-third of patients with rheumatoid arthritis show inadequate response to tumor necrosis factor α (TNF-α) inhibitors; little guidance on choosing the next treatment exists.nnnObjectivenTo compare the efficacy of a non-TNF-targeted biologic (non-TNF) vs a second anti-TNF drug for patients with insufficient response to a TNF inhibitor.nnnDesign, Setting, and ParticipantsnA total of 300 patients (conducted between 2009-2012) with rheumatoid arthritis, with persistent disease activity (disease activity score in 28 joints-erythrocyte sedimentation rate [DAS28-ESR] u2009≥u20093.2 [range, 0-9.3]) and an insufficient response to anti-TNF therapy were included in a 52-week multicenter, pragmatic, open-label randomized clinical trial. The final follow-up date was in August 2013.nnnInterventionsnPatients were randomly assigned (1:1) to receive a non-TNF-targeted biologic agent or an anti-TNF that differed from their previous treatment. The choice of the biologic prescribed within each randomized group was left to the treating clinician.nnnMain Outcomes and MeasuresnThe primary outcome was the proportion of patients with good or moderate response according to the European League Against Rheumatism (EULAR) scale at week 24. Secondary outcomes included the EULAR response at weeks 12 and 52; at weeks 12, 24, and 52; DAS28ESR, low disease activity (DAS28 ≤3.2), remission (DAS28 ≤2.6); serious adverse events; and serious infections.nnnResultsnOf the 300 randomized patients (243 [83.2%] women; mean [SD] age, 57.1 [12.2] years; baseline DAS28-ESR, 5.1 [1.1]), 269 (89.7%) completed the study. At week 24, 101 of 146 patients (69%) in the non-TNF group and 76 (52%) in the second anti-TNF group achieved a good or moderate EULAR response (OR, 2.06; 95% CI, 1.27-3.37; Pu2009=u2009.004, with imputation of missing data; absolute difference, 17.2%; 95% CI, 6.2% to 28.2%). The DAS28-ESR was lower in the non-TNF group than in the second anti-TNF group (mean difference adjusted for baseline differences, -0.43; 95% CI, -0.72 to -0.14; Pu2009=u2009.004). At weeks 24 and 52, more patients in the non-TNF group vs the second anti-TNF group showed low disease activity (45% vs 28% at week 24; OR, 2.09; 95% CI, 1.27 to 3.43; Pu2009=u2009.004 and 41% vs 23% at week 52; OR, 2.26; 95% CI, 1.33 to 3.86; Pu2009=u2009.003).nnnConclusions and RelevancenAmong patients with rheumatoid arthritis previously treated with anti-TNF drugs but with inadequate primary response, a non-TNF biologic agent was more effective in achieving a good or moderate disease activity response at 24 weeks than was the second anti-TNF medication.nnnTrial Registrationnclinicaltrials.gov Identifier: NCT01000441.

Outcome of kidney transplantations performed with preformed donor-specific antibodies of unknown etiology.

The detection of preformed donor‐specific alloantibodies (DSA) with multiplex‐bead arrays has led to the common observation that individuals without a history of pregnancy, transfusion or transplantation can have circulating anti‐HLA antibodies of unknown etiology. We retrospectively analyzed the risk of antibody‐mediated rejection (AMR) and graft outcome in 41 kidney transplant recipients with DSA of unknown etiology (DSA cause‐unk) at the time of transplantation. Twenty‐one patients received a posttransplantation desensitization protocol, and 20 received standard immunosuppressive therapy. The mean number of DSA was 1.4u2009±u20090.8, ranging from 1 to 5. Complement‐dependent cytotoxicity crossmatches were negative for all the patients. Flow cytometry crossmatches were positive in 47.6% of cases. The incidence of acute AMR was 14.6% at 1 year, regardless of the immunosuppressive regimen. No patients experienced graft loss following AMR. At month 12, across the entire population of patients with DSA cause‐unk, the outcomes were favorable: the measured glomerular filtration rate was 63.8u2009±u200916.4u2009mL/min/1.73u2009m2, the screening biopsies showed low frequencies of microvascular inflammation and no transplant glomerulopathy, and graft and patient survival were 100%. In conclusion, patients with DSA cause‐unk are able to mount AMR but have favorable 1‐year outcomes.