Search

Background Chronic active antibody-mediated rejection (AMR) is a major cause of graft loss with no approved drugs for its treatment. Currently, off-label regimens are used, reflecting the high unmet need for effective therapies based on well-controlled trials. Clazakizumab is a high-affinity, humanized monoclonal antibody that binds interleukin-6 and decreases donor-specific antibody (DSA) production and inflammation. Phase 2 pilot studies of clazakizumab in kidney transplant recipients with chronic active AMR suggest modulation of DSA, stabilization of glomerular filtration rate (GFR), and a manageable safety profile. We report the design of the Phase 3 IMAGINE study (NCT03744910) to evaluate the safety and efficacy of clazakizumab for the treatment of chronic active AMR. Methods IMAGINE is a multicenter, double-blind trial of approximately 350 kidney transplant recipients with chronic active AMR (Banff chronic glomerulopathy [cg] >0 with concurrent positive human leukocyte antigen DSA) randomized 1:1 to receive clazakizumab or placebo (12.5 mg subcutaneous once every 4 weeks). The event-driven trial design will follow patients until 221 occurrences of all-cause graft loss are observed, defined as return to dialysis, graft nephrectomy, re-transplantation, estimated GFR (eGFR) 2, or death from any cause. A surrogate for graft loss (eGFR slope) will be assessed at 1 year based on prior modeling validation. Secondary endpoints will include measures of pharmacokinetics/pharmacodynamics. Recruitment is ongoing across North America, Europe, Asia, and Australia. Discussion IMAGINE represents the first Phase 3 clinical trial investigating the safety and efficacy of clazakizumab in kidney transplant recipients with chronic active AMR, and the largest placebo-controlled trial in this patient population. This trial includes prognostic biomarker enrichment and uniquely utilizes the eGFR slope at 1 year as a surrogate endpoint for graft loss, which may accelerate the approval of a novel therapy for patients at risk of graft loss. The findings of this study will be fundamental in helping to address the unmet need for novel therapies for chronic active AMR. Trial registration ClinicalTrials.govNCT03744910. Registered on November 19, 2018.

Summary Targeting interleukin‐6 (IL‐6) is a promising strategy to counteract antibody‐mediated rejection (ABMR). In inflammatory states, IL‐6 antagonism was shown to modulate cytochrome P450 (CYP), but its impact on drug metabolism in ABMR treatment was not addressed so far. We report a sub‐study of a phase 2 trial of anti‐IL‐6 antibody clazakizumab in late ABMR (ClinicalTrials.gov, NCT03444103). Twenty kidney transplant recipients were randomized to clazakizumab versus placebo (4‐weekly doses; 12 weeks), followed by a 9‐month extension where all recipients received clazakizumab. To study CYP2C19/CYP3A4 metabolism, we administered pantoprazole (20 mg intravenously) at prespecified time points. Dose‐adjusted C0 levels (C0/D ratio) of tacrolimus (n = 13) and cyclosporin A (CyA, n = 6) were monitored at 4‐weekly intervals. IL‐6 and C‐reactive protein were not elevated at baseline, the latter was then suppressed to undetectable levels under clazakizumab. IL‐6 blockade had no clinically meaningful impact on pantoprazole pharmacokinetics (area under the curve; baseline versus week 52: 3.16 [2.21–7.84] versus 4.22 [1.99–8.18] μg/ml*h, P = 0.36) or calcineurin inhibitor C0/D ratios (tacrolimus: 1.49 [1.17–3.20] versus 1.37 [0.98–2.42] ng/ml/mg, P = 0.21; CyA: 0.69 [0.57–0.85] versus 1.08 [0.52–1.38] ng/ml/mg, P = 0.47). We conclude that IL‐6 blockade in ABMR – in absence of systemic inflammation – may have no meaningful effect on CYP metabolism., In inflammatory disease states, interleukin‐6 antagonism was shown to interfere with CYP450 metabolism. In this phase 2 pilot trial of anti‐interleukin‐6 antibody clazakizumab in late antibody‐mediated rejection ‐ in absence of systemic inflammation ‐ we found no significant effect of treatment on the pharmacokinetics of CYP substrate pantoprazole and dose‐adjusted calcineurin inhibitor levels. Abbreviations: ABMR, antibody‐mediated rejection; CYP, cytochrome P450; DSA, donor‐specific antibodies; eGFR, estimated glomerular filtration rate; EP, endpoint; IL‐6, interleukin‐6, PK, pharmacokinetics.

PURPOSE OF REVIEW Chronic antibody-mediated rejection (AMR) is a cardinal cause of transplant failure, with currently no proven effective prevention or treatment. The present review will focus on new therapeutic concepts currently under clinical evaluation. RECENT FINDINGS One interesting treatment approach may be interference with interleukin-6 (IL-6) signaling to modulate B-cell immunity and donor-specific antibody (DSA) production. Currently, a large phase III randomized controlled trial is underway to clarify the safety and efficacy of clazakizumab, a high-affinity anti-IL-6 antibody, in chronic AMR. A prevention/treatment strategy may be costimulation blockade using belatacept to interfere with germinal center responses and DSA formation. In a recent uncontrolled study, belatacept conversion was shown to stabilize renal function and dampen AMR activity. Moreover, preliminary clinical results suggest efficacy of CD38 antibodies to deplete plasma and natural killer cells to treat AMR, with anecdotal reports demonstrating at least transient resolution of active rejection. SUMMARY There are promising concepts on the horizon for the prevention and treatment of chronic AMR. The design of adequately powered placebo-controlled trials to clarify the safety and efficacy of such new therapies, however, remains a big challenge, and will rely on the definition of precise surrogate endpoints predicting long-term allograft survival. Mapping the natural history of AMR would greatly help the understanding of who would derive benefits from treatment.

Background Late antibody-mediated rejection (ABMR) triggered by donor-specific antibodies (DSA) is a cardinal cause of kidney allograft dysfunction and loss. Diagnostic criteria for this rejection type are well established, but effective treatment remains a major challenge. Recent randomized controlled trials (RCT) have failed to demonstrate the efficacy of widely used therapies, such as rituximab plus intravenous immunoglobulin or proteasome inhibition (bortezomib), reinforcing a great need for new therapeutic concepts. One promising target in this context may be interleukin-6 (IL-6), a pleiotropic cytokine known to play an important role in inflammation and adaptive immunity. Methods This investigator-driven RCT was designed to assess the safety and efficacy of clazakizumab, a genetically engineered humanized monoclonal antibody directed against IL-6. The study will include 20 DSA-positive kidney allograft recipients diagnosed with ABMR ≥ 365 days after transplantation. Participants will be recruited at two study sites in Austria and Germany (Medical University of Vienna; Charité University Medicine Berlin). First, patients will enter a three-month double-blind RCT (1,1 randomization, stratification according to ABMR phenotype and study site) and will receive either clazakizumab (subcutaneous administration of 25 mg in monthly intervals) or placebo. In a second open-label part of the trial (months 4–12), all patients will receive clazakizumab at 25 mg every month. The primary endpoint is safety and tolerability. Secondary endpoints are the pharmacokinetics and pharmacodynamics of clazakizumab, its effect on drug metabolism in the liver, DSA characteristics, morphological ABMR lesions and molecular gene expression patterns in three- and 12-month protocol biopsies, serum/urinary biomarkers of inflammation and endothelial activation/injury, Torque Teno viral load as a measure of overall immunosuppression, kidney function, urinary protein excretion, as well as transplant and patient survival. Discussion Currently, there is no treatment proven to be effective in halting the progression of late ABMR. Based on the hypothesis that antagonizing the effects of IL-6 improves the outcome of DSA-positive late ABMR by counteracting DSA-triggered inflammation and B cell/plasma cell-driven alloimmunity, we suggest that our trial has the potential to provide proof of concept of a novel treatment of this type of rejection. Trial registration ClinicalTrials.gov, NCT03444103. Registered on 23 February 2018 (retrospective registration). Electronic supplementary material The online version of this article (10.1186/s13063-018-3158-6) contains supplementary material, which is available to authorized users.

Compounds that target interleukin (IL)−6 pathways include antibodies against the IL-6 receptor or ligand, and inhibitors of IL-6 signal transduction. The anti-IL-6 receptor (IL-6R) monoclonal antibody tocilizumab has been licensed for several years; data from multiple studies demonstrate its efficacy and tolerability in rheumatoid arthritis as monotherapy or in combination with methotrexate. In addition, another anti-IL-6R monoclonal antibody, sarilumab, has recently been approved in both the US and EU. Anti-IL-6 monoclonal antibodies include olokizumab and clazakizumab, which both have data from phase II studies, as well as sirukumab which has completed phase III trials but may not be brought to the market. Comparative data for olokizumab versus tocilizumab intervention in rheumatoid arthritis suggest no difference in efficacy between blocking the receptor or the ligand. Head-to-head studies are needed to determine whether inhibition of the Janus kinase pathway is similar in its overall efficacy to direct inhibition of IL-6 or its receptor. The IL-6 inhibitors appear to be more effective when combined with methotrexate. However, they have shown superiority to tumour necrosis factor inhibitors when used as monotherapy, and may have an advantage in patients who cannot use methotrexate or any other conventional synthetic disease modifying anti-rheumatic drug. Regarding disease activity assessment, CDAI is a more appropriate measure than DAS28 when looking at the effect of IL-6 inhibition, as these agents interfere with the acute phase response, which is heavily weighted in the formula of DAS28.

Interleukin (IL)−6 represents one of several possible targets for the treatment of rheumatoid arthritis. Drugs targeting IL-6 can be divided into monoclonal antibodies against IL-6 itself and monoclonal antibodies against the IL-6 receptor. Both types of agent inhibit both classical signalling through membrane­-bound IL-6 receptor, and trans-signalling via formation of a complex between IL-6 and soluble IL-6 receptor. The IL-6 receptor blockers tocilizumab and sarilumab inhibit the low affinity binding of IL-6 to its receptor. The anti-IL-6 agents clazakizumab and vobarilizumab also block binding of IL-6 to the receptor, while olokizumab blocks the higher affinity interaction of the IL-6-receptor complex with gp130. The doses and dosing intervals of the biologics targeting different elements vary, but no major differences in efficacy or safety have yet been seen between the two approaches, although more studies are needed in this area. In addition to the different blocking actions of monoclonal antibodies, we consider therapeutic strategies including the timing of IL-6 blockade and the use of monotherapy versus the addition of methotrexate.

In 1973, IL-6 was identified as a soluble factor that is secreted by T cells and is important for antibody production by B cells. Since its discovery more than 40 years ago, the IL-6 pathway has emerged as a pivotal pathway involved in immune regulation in health and dysregulation in many diseases. Targeting of the IL-6 pathway has led to innovative therapeutic approaches for various rheumatic diseases, such as rheumatoid arthritis, juvenile idiopathic arthritis, adult-onset Still's disease, giant cell arteritis and Takayasu arteritis, as well as other conditions such as Castleman disease and cytokine release syndrome. Targeting this pathway has also identified avenues for potential expansion into several other indications, such as uveitis, neuromyelitis optica and, most recently, COVID-19 pneumonia. To mark the tenth anniversary of anti-IL-6 receptor therapy worldwide, we discuss the history of research into IL-6 biology and the development of therapies that target IL-6 signalling, including the successes and challenges and with an emphasis on rheumatic diseases.

Background Severe Acute Respiratory Syndrome caused by coronavirus 2 (SARS-CoV-2) is characterized by an overwhelming cytokine response. Various treatment strategies have been attempted. Methods and Results A 61-year-old male with heart transplantation in 2017 presented with fever, cough, and dyspnea, and confirmed positive for the SARS-CoV-2 disease (COVID-19). Laboratory tests showed significant elevations in C-reactive protein and interleukin-6 (IL-6). Echocardiogram showed LVEF 58% (with EF 57% 6 months prior). Given the lack of clear management guidelines, the patient was initially managed symptomatically. However, the patient subsequently had a rapid respiratory deterioration with worsening inflammatory markers on day 5 of admission. Tocilizumab (anti-IL-6R) was in low supply in the hospital. The patient was offered clazakizumab (anti-IL-6) for compassionate use. Patient received 25 mg intravenously x1 dose. Within 24 hours, he noted significant improvement in symptoms, oxygen requirements, radiological findings and inflammatory markers. There was a transient leukopenia which improved in 4 days. He was discharged home on day 11, with negative nasopharyngeal SARS-CoV-2 PCR as an outpatient on day 35, development of positive serum COVID-19 IgG antibody, and he continued to do well on day 60, with no heart-related symptoms. Conclusion Clazakizumab is a monoclonal antibody against human IL-6, which may be helpful in inhibiting the cytokine response to SARS-CoV-2 in COVID-19. Although not yet FDA approved, it is being investigated for treatment of renal antibody-mediated rejection. Clinical trials of clazakizumab for treatment of COVID-19 are underway worldwide., Highlights • Severe Acute Respiratory Syndrome caused by coronavirus 2 (SARS-CoV-2) is characterized by an overwhelming cytokine response. • A 61-year-old male with heart transplantation in 2017 presented with fever, cough, and dyspnea, and confirmed positive for the SARS-CoV-2 disease (COVID-19). Laboratory tests showed significant elevations in C-reactive protein, interleukin-6 (IL-6), and other inflammatory markers. Echocardiogram showed normal LV function. • The patient received clazakizumab (anti-IL-6 monoclonal antibody) 25 mg as a single dose, with significant improvement in symptoms, oxygen requirements, radiological findings and inflammatory markers within 24 hours, and discharge to home on day 11. He had a negative nasopharyngeal SARS-CoV-2 PCR as an outpatient on day 35, developed a positive serum COVID-19 IgG antibody, and was continuing to do well clinically on day 60. • Clazakizumab is a monoclonal antibody against human IL-6, which may be helpful in inhibiting the cytokine response to SARS-CoV-2 in COVID-19.

Currently clinicians all around the world are experiencing a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The clinical presentation of this pathology includes fever, dry cough, fatigue and acute respiratory distress syndrome that can lead to death infected patients. Current studies on coronavirus disease 2019 (COVID-19) continue to highlight the urgent need for an effective therapy. Numerous therapeutic strategies have been used until now but, to date, there is no specific effective treatment for SARS-CoV-2 infection. Elevated inflammatory cytokines have been reported in patients with COVID-19. Evidence suggests that elevated cytokine levels, reflecting a hyperinflammatory response secondary to SARS-CoV-2 infection, are responsible for multi-organ damage in patients with COVID-19. For these reason, numerous randomized clinical trials are currently underway to explore the effectiveness of biopharmaceutical drugs, such as, interleukin-1 blockers, interleukin-6 inhibitors, Janus kinase inhibitors, in COVID-19. The aim of the present paper is to briefly summarize the pathogenetic rationale and the state of the art of therapeutic strategy blocking hyperinflammation.

The aim of this study was to systemically review the efficacy and safety of inhibitors of interleukin 6 (IL-6): clazakizumab, IL-12/23: ustekinumab, and IL-17A: secukinumab, brodalumab, and ixekizumab in psoriatic arthritis (PsA).The literature search was conducted using MEDLINE, EMBASE, Cochrane Library, Scopus, and Web of Science. We included randomized controlled trials that assessed the efficacy of IL inhibitors and reported American College of Rheumatology 20 response at 24 weeks. Meta-analysis was done using random-effects model utilizing the DerSimonian and Laird method. Quality assessment was done using RobotReviewer Cochrane Risk-of-Bias Assessment Tool. Heterogeneity was assessed with Q statistic and quantified with I. Publication bias was assessed with a funnel plot.Eight studies including 2722 subjects demonstrate the efficacy of IL inhibitors clazakizumab, secukinumab, ixekizumab, brodalumab, and ustekinumab in the treatment of PsA. The American College of Rheumatology 20/50/70 risk ratios were 2.02 (95% confidence interval [CI], 1.65-2.47; P = 0.000), 2.95 (95% CI, 2.32-3.73; P = 0.00), and 5.14 (95% CI, 3.28-8.06; P = 0.00), respectively, in favor of treatment versus placebo. There was no evidence of significant heterogeneity between trials. Subgroup analysis showed efficacy in patients who were tumor necrosis factor naive, as well as tumor necrosis factor nonresponders or inadequate responders. The number of adverse events was higher in the treatment groups versus placebo, the majority were mild and did not require treatment adjustment (risk ratio, 1.17; 95% CI, 1.06-1.28; P = 0.001). There was no significant difference in drug withdrawals.Our meta-analysis shows that the inhibitors of IL-6 (clazakizumab), IL-12/23 (ustekinumab), and IL-17A (secukinumab, brodalumab, ixekizumab) are efficacious and generally well tolerated when used to treat patients with PsA.

Objective To evaluate the efficacy of clazakizumab, a monoclonal antibody with high affinity and specificity for the interleukin-6 (IL-6) cytokine, in psoriatic arthritis (PsA). Methods In this randomized, double-blind, placebo-controlled, dose-ranging study (ClinicalTrials. gov identifier: NCT01490450), patients with active PsA and an inadequate response to nonsteroidal antiinflammatory drugs were randomized (1:1:1:1) to receive subcutaneous placebo or clazakizumab 25 mg, 100 mg, or 200 mg every 4 weeks, with or without methotrexate. The primary end point was the response rate according to the American College of Rheumatology 20% criteria for improvement (ACR20) at week 16, with secondary efficacy end points at weeks 16 and 24. Results A total of 165 patients were randomized. At week 16, the ACR20 response rate was significantly higher with clazakizumab 100 mg versus placebo (52.4% versus 29.3%; P = 0.039). ACR20 response rates at week 16 were 46.3% with clazakizumab 25 mg (P = 0.101 versus placebo) and 39.0% with clazakizumab 200 mg (P = 0.178 versus placebo). ACR50/ACR70 response rates were numerically higher with clazakizumab versus placebo at weeks 16 and 24. Compared with placebo, clazakizumab treatment significantly improved musculoskeletal manifestations (joint signs and symptoms, enthesitis, and dactylitis), with minimal improvements in skin disease, without clear evidence of a dose response. Clazakizumab was well tolerated. Conclusion This is the first clinical trial of an IL-6–targeted therapy in PsA. Clazakizumab may be an effective treatment option for musculoskeletal aspects of PsA, but because of the lack of a dose response in this study, further studies are required to confirm the appropriate dose. The safety profile is consistent with the pharmacology of IL-6 blockade and prior clinical experience with this antibody in rheumatoid arthritis.

Background:Biologic disease-modifying antirheumatic drugs (bDMARDs) extend the treatment choices for rheumatoid arthritis (RA) patients with suboptimal response or intolerance to conventional synthetic DMARDs (CsDMARDs). Currently, 9 biologic agents are approved in the RA treatment: and among them, three anti TNF agents are also approved in monotherapy (adalimumab, certolizumab and etanercept), but also abatacept, anakinra and tocilizumab. Registries of routine clinical practice treatment indicate that approximately one third of RA patients are being treated with a bDMARD in monotherapy and analyses from health care claims suggest that when methotrexate (MTX) is prescribed in combination with a bDMARD, more than half of the patients do not collect the MTX prescription and overall patients seem to taper MTX intake over time. So it is important to evaluate the benefit and harm associated with use of biological agents as monotherapy, and not only the traditional combination therapy strategies.Objectives:To compare the efficacy and safety of the individual biological agents used in monotherapy in patients with RA than the combination therapy strategy with CsDMARD + bDMARD.Methods:We used The Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, and MEDLINE in order to carry out our research, for published reports from inception of each database through December 2019. Search results were limited to randomised controlled trials (RCTs), with our two arms: biological agent in monotherapy and combination strategie (with any CsDMARDs). Major outcome was the ACR 20 reponse criteria at 24 week. The secondary outcomes were: the ACR 20 at 52 week, ACR 50, 70, 90 reponse criteria, the DAS 28 remission (with CRP and/or ESR), the score sharps modified non progressor, the proportion of patients who withdrawals the study due to adverse events, the proportion of patients who withdrawals the study due to lack of efficacy, the HAQ improvement > 0,22, CDAI and SDAI remission at week 24 and 52 if the data were available. The study of tolerance was also made. To estimate the relative efficacy of treatments whilst preserving the randomized comparisons within each trial, a Bayesian network meta-analysis was conducted in R (version 3.6.1) using fixed and random-effects.Results:The systematic review identified 2566 citations. The analysis comprises 22 trials (6358 patients), including six biological agents approved for RA (abatacept, adalimumab, etanercept, golimumab, rituximab and tocilizumab) as well as two other molecules: Clazakizumab, a humanized monoclonal antibody that binds to the interleukin-6 (IL-6) cytokine and Anbainuo, recombinant human TNFRII:Fc fusion protein. No study satisfyies our search criteria for anakinra, certolizumab and infliximab. Compared to combination therapy with CsDMARD+bDMARD, bDMARD monotherapy has less probability to give a ACR20 response at 24 weeks (RR: 0,92 [0,89 – 0,96]) in fixed or random effect model and this result is similar at 52 weeks (RR: 0,94 [0,89 – 0,99]). For all other outcome mesures, we can see an increased of ACR50–70 and 90 responses, an improve of the DAS 28 remission score, an increase of the proportion of sharp’s score non progressors (Conclusion:Evidence from this meta-analysis suggests that combinaison strategy with bDMARD+CsDMARD remains the most efficacious option, being more effective than the use of biologics in monotherapy. The interest from this point of view is to sensitize prescribers to the use of other CsDMARDs when there is a contraindication or intolerance to MTX, but also to make patients aware of the superiority of the association of biological agents with CsDMARDs.figureDisclosure of Interests:Célia DELPECH: None declared, François-Xavier LABORNE: None declared, Pascal Hilliquin Consultant of: BMS, MSD, Novartis, Roche-Shugai.

Rheumatoid arthritis (RA) is an immune-mediated condition which primarily affects the joints, but with critical extra-articular manifestations, including a significantly increased cardiovascular risk. Patients suffering from RA can develop deforming and disabling alterations of the affected joints. Their quality of life can be substantially affected, and their life expectancy is shorter compared to that of healthy subjects. Fortunately, several pathogenic mechanisms characterizing RA have been identified, leading to the development of targeted drugs. Inhibitors of tumor necrosis factor (TNF) were the first developed among biological medications and they dramatically changed the therapeutic perspectives of RA patients. Now, 20 years after the licensing of etanercept (the first anti-TNF drug), more than 10 different biological agents have been approved by the U.S. Food and Drug Administration (FDA). Additionally, more and more drugs are under investigation in clinical trials. This review will focus on the more recently approved monoclonal antibodies and the more promising antibodies under investigation.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by polyarthritis. Numerous agents with varying mechanisms are used in the treatment of RA, including non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, and some biological agents. Studies to uncover the cause of RA have recently ended up scrutinizing the importance of pro-inflammatory cytokine such as tumor necrosis factor α (TNF-α) and interleukin (IL)-6 in the pathogenesis of RA. TNF-α inhibitors are increasingly used to treat RA patients who are non-responsive to conventional anti-arthritis drugs. Despite its effectiveness in a large patient population, up to two thirds of RA patients are found to be partially responsive to anti-TNF therapy. Therefore, agents targeting IL-6 such as tocilizumab (TCZ) attracted significant attention as a promising agent in RA treatment. In this article, we review the mechanism of anti-IL-6 in the treatment of RA, provide the key efficacy and safety data from clinical trials of approved anti-IL-6, TCZ, as well as six candidate IL-6 blockers including sarilumab, ALX-0061, sirukumab, MEDI5117, clazakizumab, and olokizumab, and their future perspectives in the treatment of RA.

In recent years the use of biotechnological agents has drastically revolutionized the therapeutic approach and the progression of rheumatoid arthritis (RA). In particular, interleukin-6 (IL-6) has been demonstrated as a pivotal cytokine in the pathogenesis of the disease by contributing to both the innate and the adaptive immune system perturbation, and to the production of acute-phase proteins involved in the systemic expression of the disorder. The first marketed IL-6 blocker was tocilizumab, a humanized anti-IL-6 receptor (anti-IL-6R) monoclonal antibody. The successful use of tocilizumab in RA has encouraged the development of other biologic agents specifically targeting the IL-6 pathway, either directed against IL-6 cytokine (sirukumab, olokizumab, and clazakizumab) or IL-6 receptor (sarilumab). One Phase II and six Phase III randomized controlled trials demonstrated a broad efficacy of sarilumab across all RA patient subtypes, ranging from methotrexate (MTX) to tumor necrosis factor inhibitor insufficient responders. In particular, sarilumab as monotherapy demonstrated a clear head-to-head superiority over adalimumab in MTX-intolerant subjects. In addition, compared with tocilizumab, sarilumab showed a similar safety profile with significantly higher affinity and longer half-life, responsible for a reduction of the frequency of administration (every other week instead weekly). All these aspects may be important in defining the strategy for positioning sarilumab in the treatment algorithm of RA. Indeed, observational data coming from post-marketing real-life studies may provide crucial additional information for better understanding the role of sarilumab in the management of the disease. This review summarizes both the biological role of IL-6 in RA and the clinical data available on sarilumab as an alternative therapeutic option in RA patients.

Objective Clazakizumab is a humanized monoclonal antibody that binds to the interleukin-6 (IL-6) cytokine. This study was undertaken to evaluate the efficacy and safety of clazakizumab in combination with methotrexate (MTX) or clazakizumab monotherapy versus MTX alone in patients with rheumatoid arthritis (RA) and an inadequate response to MTX. Methods In this multinational, phase IIb, randomized, double-blind, placebo-controlled, dose-ranging study, patients were randomized to receive 1) once-monthly subcutaneous (SC) clazakizumab at 25, 100, or 200 mg plus MTX, 2) once-monthly SC clazakizumab at 100 mg or 200 mg as monotherapy, or 3) MTX plus placebo (i.e., MTX alone). Adalimumab (40 mg) plus MTX was included as an active reference. The primary end point was the American College of Rheumatology 20% (ACR20) improvement response rate at week 12. Secondary end points included ACR20, ACR50, and ACR70 response rates as well as protocol-defined remission rates and Health Assessment Questionnaire disability index scores at weeks 12 and 24. Results In total, 418 patients were randomized, and baseline characteristics were balanced across the treatment groups. Patients receving clazakizumab had significantly greater ACR20 response rates at week 12 compared with patients receiving MTX alone (76.3%, 73.3%, and 60.0% of patients in the clazakizumab 25, 100, and 200 mg plus MTX groups, respectively, and 55.0% and 61.0% of patients in the clazakizumab 100 and 200 mg monotherapy groups, respectively, versus 39.3% of patients receiving MTX alone; P < 0.05 for all comparisons). At week 24, all clazakizumab groups had higher ACR20, ACR50, and ACR70 response rates and higher remission rates compared with MTX alone. Rates of serious adverse events ranged from 8.3% to 13.6% in the clazakizumab treatment groups, compared with 3.3% in the MTX alone group. Changes in laboratory data were consistent with the pharmacologic effects of IL-6 blockade. Conclusion In patients with RA and an inadequate response to MTX, treatment with clazakizumab in combination with MTX or clazakizumab monotherapy was well tolerated, and patients achieved significant improvements in disease activity, including higher rates of remission, as compared with patients receiving MTX alone.

Clinical trial data suggest the IL-6-targeted drug clazakizumab ameliorates the symptoms of psoriatic arthritis (PsA), in particular the musculoskeletal manifestations of the disease. Could this new treatment hold promise for a certain subgroup of patients with PsA?

Mease PJ et al. The Efficacy and Safety of Clazakizumab, an Anti-Interleukin-6 Monoclonal Antibody, in a Phase IIb Study of Adults With Active Psoriatic Arthritis.

Background Clazakizumab (CLZ) is a potent, neutralizing anti-interleukin (IL)-6 monoclonal antibody that is being studied in RA. CLZ in combination with MTX (+ MTX) or as monotherapy demonstrated efficacy in controlling the signs and symptoms of RA in a recent Phase IIb study.1 In response to increasing interest in imaging techniques to supplement X-ray, magnetic resonance imaging (MRI) has emerged as a sensitive method of assessing treatment effect on joint damage in clinical trials of RA. MRI can demonstrate whether efficacy in improving signs and symptoms with treatment translates to tissue effects and non-progression in RA joints. Objectives To assess the progression of joint damage by MRI at 12 weeks and X-ray at 24 weeks in a Phase IIb study of subcutaneous (SC) CLZ + MTX or as monotherapy compared with placebo + MTX or SC adalimumab (ADA) + MTX in patients with RA and inadequate response to DMARDs including MTX. Methods Patients with moderate-to-severe RA and inadequate response to DMARDs, (including MTX) were randomized in a double-blind, double-dummy fashion to receive: placebo + MTX; CLZ 25, 100, or 200 mg + MTX; CLZ 100 or 200 mg monotherapy (every 4 weeks); or ADA 40 mg + MTX (every 2 weeks) for 24 weeks. The most swollen hand/wrist at baseline was imaged at both baseline and at Week 12 using 1.5T MRI with contrast enhancement and a phased-array knee coil. The MRI sequences were: 2D coronal short tau inversion recovery at pre-contrast, and 3D coronal isotropic T1 gradient-echo with fat suppression at pre- and post-contrast. MRI (n=322) was assessed using a modified version of the OMERACT RAMRIS criteria.2 X-rays (n=351) of both hands/wrists and both feet was performed at baseline and Week 24 and assessed by modified Sharp/van der Heijde score (mTSS). Non-progressors were defined as patients with a change from baseline ≤0. Results The proportion of MRI non-progressors at Week 12 was numerically greater in the CLZ + MTX groups vs MTX alone for all components (Table). At Week 24, the proportion of X-ray non-progressors was numerically higher for all CLZ arms compared with MTX by mTSS and its components. Favourable trends in the mean change from baseline in MRI components and X-ray mTSS scores and erosion were observed in the CLZ + MTX arms versus MTX alone. In a post hoc analysis, combining all CLZ + MTX treatment arms led to a mean change from baseline (95% CI) in mTSS of 0.2 (–0.3, 0.6) versus 1.8 (0.9, 2.6) in the MTX arm (p

Background Clazakizumab (CLZ) is a potent, neutralizing anti-interleukin-6 (IL-6) monoclonal antibody currently in development for RA. The Phase IIb study described herein evaluated the efficacy and safety of subcutaneous (SC) CLZ with or without MTX in patients with moderate-to-severe RA and an inadequate response to MTX in a randomized, comparator-controlled, double-blind study.1 Objectives To compare the change from baseline at Weeks 12 and 24, and the proportion of patients achieving minimal clinically important differences (MCID) at Week 24, in patient-reported outcomes (PROs) on treatment with CLZ with and without MTX vs MTX alone. Methods This was a post hoc analysis of data from the Phase IIb study. Patients were randomized equally to receive either CLZ 25, 100, or 200 mg with MTX, CLZ 100 or 200 mg monotherapy, or MTX alone every 4 weeks or adalimumab with MTX every 2 weeks. PROs assessed included the Health Assessment Questionnaire-Disability Index (HAQ-DI); fatigue (visual analogue scale [VAS]), pain (VAS), Patient Global Assessment (PGA) of disease activity (VAS); and the physical component summary (PCS) and mental component summary (MCS) of the Short Form 36-item questionnaire (SF-36). HAQ-DI was previously reported.1 Analyses were conducted on the modified intent-to-treat population comprising all randomized patients who received at least one dose of study medication. MCIDs for each PRO were based on criteria from the literature. An analysis of covariance was conducted with treatment as a factor and baseline scores as covariates. In cases where patients received rescue medication, or with missing data, a last observation carried forward approach was used. Results Overall, 418 patients were randomized. Compared with MTX alone, treatment with CLZ with or without MTX (at all doses) resulted in greater mean changes from baseline, and higher proportions of patients achieving an MCID on each of the PROs assessed at Week 24, except MCS (Table). ![Figure][1] Conclusions Treatment with clazakizumab with or without MTX resulted in improvements in multiple PROs and a greater proportion of patients achieved MCID on these PROs compared with MTX alone in patients with RA with an inadequate response to MTX. References 1. Weinblatt M et al. Arthritis Rheum 2013;65(10):S735–36. Disclosure of Interest E. Alemao Shareholder of: BMS, Employee of: BMS, S. Joo Shareholder of: BMS, Employee of: BMS, S. Banerjee Shareholder of: BMS, Employee of: BMS, P. Emery Grant/research support: AbbVie, BMS, Merck, Pfizer, Roche, Consultant for: AbbVie, BMS, Merck, Pfizer, Roche, Takeda, M. Weinblatt Grant/research support: BMS, Crescendo Bioscience, UCB, Consultant for: BMS, Crescendo Bioscience, UCB, AbbVie, Roche, Janssen, G. L'Italien Shareholder of: BMS, Employee of: BMS DOI 10.1136/annrheumdis-2014-eular.1515 [1]: pending:yes

Kidney transplantation is recognized as the best replacement therapy for end-stage renal disease. However, its access, already limited by the shortage of grafts, will be even more restricted for so-called "immunized" kidney transplant candidates (KTC), i.e. those who have developed anti-HLA antibodies after a past immunological event (transplantation, pregnancy, transfusion). Desensitization (DES) aims to remove these anti-HLA antibodies and block their production in order to increase the number of compatible grafts. The standard-of-care (SOC) of DES (apheresis, rituximab, +/- intravenous immunoglobulin) is based on a few small, non-randomized studies. The results of DES, mainly supported in the field of living donor transplantation, are encouraging but the search for new therapies remains an important issue. Tocilizumab (TCZ) (anti-IL-6R monoclonal antibody) is a candidate of choice because of the central role of IL-6 in the immune response (differentiation of plasmacells ; orientation of T helper lymphocytes towards a Th17 rather than a regulatory T profile, etc). To date, only one clinical study tested the efficacy of TCZ as a treatment for DES. It was used as a 2nd line treatment in subjects who were resistant to SOC. Therefore, we conducted a prospective, non-randomized, exploratory study to evaluate the efficacy and safety of a TCZ-only DES protocol to improve kidney transplantation access for hyperimmunized subjects. Fourteen patients were included between 2016 and 2020 and treated with tocilizumab alone (8mg/kg monthly, for at least 6 months). The primary endpoint was the evolution of MFI (mean fluorescent intensity) of the immunodominant anti-HLA antibody between the beginning and the end of the TCZ treatment. We observed a decrease in the MFI of the immunodominant antibody in class I (7780 vs 10548; p = 0.00085) and in class II (6267 vs 7191; p = 0.019). In addition, there was a significant decrease in the mean MFI of all anti-HLA antibodies (with an initial MFI > 2000) in class I (7102 vs 7999; p = 0.012), as well as in the number of anti-HLA antibodies with MFI ≥ 10,000 in class I (14 vs 18; p = 0.0059) and class II (13 vs 19; p = 0.021). Finally, the safety profile was favorable with only one serious adverse event (spondylodiscitis). However, if statistically significant, the effect of TCZ alone was not clinically relevant because more than half of the patients retained at least one anti-HLA antibody with an MFI ≥ 10,000, and more than 80% of them had the MFI of their immunodominant antibody remain above 3,000. Thus, only one patient (7%) could be transplanted without further DES therapy. In contrast, eleven patients (79%) subsequently received a standard DES protocol, and eight of these were able to be transplanted. Our study therefore suggests that TCZ alone is not sufficient to improve access to transplantation for hyperimmunized KTC. Its place could be in association with the standard DES protocol, in order to improve its short-term efficacy (reduction of immunization and obtaining a compatible graft) but also - and above all - its long-term efficacy (reduction of the rebound of anti-HLA antibodies, of the risk of humoral rejection). This last hypothesis is supported by the study of lymphocyte phenotypes under TCZ which shows a blockage of the maturation of the B lineage. It would be relevant to test this last hypothesis with further studies.; La transplantation rénale est reconnue comme le meilleur traitement de suppléance de l’insuffisance rénale terminale. Cependant, son accès, déjà limité par la pénurie de greffon, est d’autant plus restreint pour les patients dits « immunisés », c’est-à-dire ayant développé au décours d’un évènement immunologique passé (transplantation, grossesse, transfusion) des anticorps anti-HLA. La désimmunisation (DES) a pour but d’éliminer ces anticorps et d’en bloquer la production afin d’augmenter le nombre de greffons compatibles. Le « standard-of-care » (SOC) de la DES (aphérèse, rituximab, +/- immunoglobulines polyvalentes) repose sur quelques études non randomisées, de faible effectif. Les résultats de la DES, étayés principalement dans le domaine de la greffe donneur vivant, sont encourageants mais la quête de nouvelles thérapeutiques reste un enjeu important. Le tocilizumab (TCZ) (anticorps monoclonal anti-IL-6R) est un candidat de choix du fait de la place centrale qu’occupe l’IL-6 dans la réponse immunitaire (différenciation des plasmocytes ; orientation des lymphocytes T helper vers un profil Th17 plutôt que T régulateur etc). Jusqu’à maintenant, une seule étude clinique a testé l’efficacité du TCZ comme traitement de DES (en 2ème ligne après échec du SOC). Nous avons donc mené une étude prospective, non randomisée, exploratoire visant à évaluer l’efficacité et la sécurité d’un protocole de DES par TCZ seul pour améliorer l’accès à la greffe rénale de sujets hyperimmunisés. Quatorze patients ont ainsi été traités par tocilizumab (8mg/kg tous les mois, pendant au moins 6 mois). Le critère de jugement principal était l’évolution de MFI (mean fluorescent intensity) de l’anticorps anti-HLA immunodominant entre le début et la fin du traitement. Nous avons observé une baisse de la MFI de l’anticorps immunodominant en classe I (7780 vs 10548 ; p = 0.00085) et en classe II (6267 vs 7191 ; p = 0.019). De plus, il existait une diminution de la moyenne de MFI de tous les anticorps anti-HLA (ayant une MFI initiale > 2000) en classe I (7102 vs 7999 ; p = 0.012), ainsi que du nombre d’anticorps anti-HLA avec une MFI ≥ 10 000 en classe I (14 vs 18 ; p = 0.0059) et en classe II (13 vs 19 ; p = 0.021). Enfin, le profil de sécurité était favorable avec un seul évènement indésirable grave (spondylodiscite). Toutefois, s’il était statistiquement significatif, l’effet du TCZ seul n’était pas cliniquement pertinent car plus de la moitié des patients gardaient au moins un anticorps anti-HLA avec une MFI ≥ 10 000, et plus de 80% d’entre eux voyaient la MFI de leur anticorps immunodominant rester supérieure à 3000. Ainsi, seulement un patient (7%) a pu être greffé sans autre thérapie de DES. En revanche, onze patients (79%) ont ensuite bénéficié d’un protocole standard de DES et huit d’entre eux ont pu être greffés. Notre étude suggère donc que le TCZ en monothérapie n’est pas suffisant pour améliorer l’accès à la greffe des sujets hyperimmunisés. Sa place pourrait se trouver en association avec le protocole standard, afin d’en améliorer l’efficacité à court terme (diminution de l’immunisation et obtention d’un greffon compatible) mais aussi – et surtout – l’efficacité à long terme (diminution du rebond des anticorps anti-HLA, du risque de rejet humoral). Cette dernière hypothèse, qu’il serait pertinent de tester dans une étude complémentaire, est soutenue par l’étude des phénotypes lymphocytaires sous TCZ montrant un blocage de la maturation de la lignée B.