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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.In this Perspective article, the authors recount the earliest stages of translational research into IL-6 biology and the subsequent development of therapeutic IL-6 pathway inhibitors for the treatment of autoimmune rheumatic diseases and potentially numerous other indications.

In this review article, it is highlighted the implications of pleiotropic functions of interleukin-6 (IL-6) for one of the therapeutic options targeting for COVID-19. Moreover, it is discussed how real-world data and trials with IL-6 signaling blockade will be crucial in informing the development of new treatment for COVID-19 pneumonia. Given physiological roles of IL-6 in inflammatory conditions and the data from real world, IL-6 signal inhibitors, along with standard of care (SOC) treatment, might provide efficacy, offering the potential to treat COVID-19 in hospitalized populations more effectively than current SOC alone. Therefore, on-going and planned randomized placebo-controlled studies in combination with SOC and other therapeutics to assess safety and efficacy of IL-6 signal inhibitors in hospitalized patients with severe COVID-19 pneumonia will be warranted to address the high unmet need and burden of disease in this severely ill population.

Polatuzumab vedotin (pola) is a CD79b‐targeted antibody‐drug conjugate delivering a potent antimitotic agent (monomethyl auristatin E) to B cells. This was an open‐label, single‐arm study of pola 1.8 mg/kg, bendamustine 90 mg/m2, rituximab 375 mg/m2 (pola + BR) Q3W for up to six cycles in patients with relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL) who received ≥1 prior line of therapy and were ineligible for autologous stem cell transplantation (ASCT) or experienced treatment failure with prior ASCT. Primary endpoint was complete response rate (CRR) at the end of the treatment (EOT) by positron emission tomography–computed tomography (PET‐CT) using modified Lugano Response Criteria. Secondary endpoints included efficacy, safety, and pharmacokinetics. Thirty‐five patients (median age 71 [range 46‐86] years) were enrolled. Twenty‐three (66%) patients had refractory disease, and 23 (66%) had ≥2 prior lines of therapy. At a median follow‐up of 5.4 (0.7‐11.9) months, patients received a median of five treatment cycles. CRR was 34.3% (95% confidence interval [CI] 19.1‐52.2) at EOT. Overall response rate was 42.9% at EOT, and median progression‐free survival was 5.2 months (95% CI 3.6‐not evaluable). Median overall survival was not reached. No fatal adverse events (AEs) were observed. Grade 3‐4 AEs were mainly hematological: anemia (37%), neutropenia (31%), white blood cell count decreased (23%), thrombocytopenia/platelet count decreased/neutrophil count decreased (20% each), and febrile neutropenia (11%). Grade 1‐2 peripheral neuropathy (PN; sensory and/or motor) was reported in 14% of patients; there were no ≥grade 3 PN events. This study (JapicCTI‐184048) demonstrated the efficacy and safety of pola + BR in Japanese patients with R/R DLBCL who were ineligible for ASCT. We report the results of an open‐label, single‐arm study of polatuzumab vedotin 1.8 mg/kg, bendamustine 90 mg/m2, rituximab 375 mg/m2 in patients with transplant‐ineligible relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL). A complete response rate of 34.3% at the end of the treatment and consistent safety profile with previous studies with polatuzumab vedotin were observed.

To explore the baseline predictors of clinical effectiveness after tocilizumab or infliximab treatment in biologic-naïve rheumatoid arthritis patients. Consecutive biologic-naïve patients with rheumatoid arthritis initiating infliximab (n = 57) or tocilizumab (n = 70) treatment were included in our prospective cohort study. Our cohort started in February 2010, and the patients observed for at least 1 year as of April 2013 were analysed. We assessed baseline variables including patients' characteristics (age, sex, disease duration, prednisolone dose, methotrexate dose, other disease-modifying antirheumatic drug use, Clinical Disease Activity Index [CDAI]) and serum biomarker levels (C-reactive protein, immunoglobulin M-rheumatoid factor, anti-cyclic citrullinated protein/peptide antibodies, interferon-γ, interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, IL-17, tumor necrosis factor-α, soluble intercellular adhesion molecule-1, bone alkaline phosphatase, osteonectin, osteopontin) to extract factors associated with clinical remission (CDAI ≤ 2.8) at 1 year using univariate analyses, and the extracted factors were entered into a multivariate logistic regression model. Similar analyses were also performed for Simplified Disease Activity Index (SDAI) remission (≤ 3.3) and Disease Activity Score with 28 joint counts, erythrocyte sedimentation rate (DAS28-ESR) remission (< 2.6). There were no significant differences in the baseline characteristics except for methotrexate use between the groups. In the multivariate analyses, the low baseline osteopontin levels (OR 0.9145, 95% CI 0.8399-0.9857) were identified as predictors of CDAI remission in the tocilizumab group, whereas no predictors of CDAI remission were found in the infliximab group. Similar results were obtained when using SDAI and DAS28-ESR remission criteria. Baseline low serum osteopontin levels predict clinical remission 1 year after tocilizumab treatment and not infliximab treatment in biologic-naïve patients with rheumatoid arthritis. Our prediction model provided insights into how to optimize the choice of biologics and warrants external validation in other cohorts.

Background Clinical trials have shown combinations of anti–tumor necrosis factor biologicals plus methotrexate (MTX) are more effective treatments for rheumatoid arthritis than biological monotherapies, based, in part, on the assumption that MTX reduces the immunogenicity of biologicals. However, co-treatment with the anti–interleukin-6 receptor-alpha antibody tocilizumab (TCZ) and MTX does not demonstrate the same level of incremental benefit over TCZ monotherapy. Using the human primary cell based BioMAP phenotypic profiling platform, we investigated the impact of TCZ, adalimumab (ADA), and the small molecule drug tofacitinib (TOF), alone and in combination with MTX, on translational biomarkers that could indicate unique pharmacodynamic interactions outside those of reduced immunogenicity. Methods TCZ, ADA, and TOF, alone and in combination with MTX, were profiled in BioMAP systems at concentrations close to clinical exposure levels: TCZ, 200 μg/ml; TOF1, 1.1 μM; TOF2, 0.12 µM; MTX, 10 μM. Changes in biomarkers were evaluated by statistical methods to determine whether combinations differed from the individual agents. Results Although the BioMAP activity profile for TCZ + MTX was not significantly different from that for TCZ alone, profiles for ADA + MTX and TOF1 + MTX or TOF2 + MTX had a greater number of statistically significant different activities (P < 0.01) than did agents profiled individually. Conclusions These data support the comparable efficacy of TCZ as monotherapy and as combination therapy and suggest that TOF, like ADA, may be more beneficial in combination with MTX. Taking an orthogonal approach to directly compare monotherapy and combination therapies indicates that MTX contributes to the efficacy of some, but not all, RA therapies and can be affected by factors additional to reduced immunogenicity.

We studied the influence of IL-6 on chemokine production from peripheral blood mononuclear cells (PBMC), fibroblastic synovial cells and human umbilical vessel endothelial cells (HUVEC). Moreover, we examined the effect of IL-6 on the adhesion of U937 cells to HUVEC. For chemokine production, PBMC, fibroblastic synovial cells and HUVEC were cultured with IL-6 or IL-6 + soluble IL-6R (sIL-6R) for 24 h and then the production of MCP-1 and IL-8 were measured in supernatants. IL-6 and IL-6 + sIL-6R induced production of both MCP-1 and IL-8 in PBMC and synovial cells, respectively. In HUVEC, IL-6 + sIL-6R induced MCP-1 production, but inhibited IL-8 production. For adhesion molecule expression, the production of soluble form of adhesion molecules in HUVEC culture supernatant were measured by ELISA and the expression of adhesion molecules on cell surface were examined by flow cytometry analysis. Soluble ICAM-1 was detectable in IL-6 + sIL-6R-treated HUVEC and IL-6 + sIL-6R-induced ICAM-1 expression on cell membrane of HUVEC. In addition, U937 cells were added to HUVEC, which were pre-treated with IL-6 + sIL-6R for 24 h, and 3 h later attached U937 cells were counted. The adhesion of U937 cells to HUVEC was augmented when HUVEC was pretreated by IL-6 + sIL-6R. This adhesion was suppressed by anti-ICAM-1 antibody and anti-IL-6R antibody, but not by antibodies against VCAM-1 or E-selectin. In conclusion, IL-6 signaling plays an important role in inflammatory cell migration by increasing the rate of cell adhesion and by inducing chemokine production in inflamed joints.

We have reported that serum IL-6 level was related with the degree of anemia in monkey collagen-induced arthritis (CIA). In this study, we examined whether IL-6 blockade ameliorated an anemia in monkey CIA. CIA was induced by twice immunization of bovine type II collagen with adjuvant. When anemia became evident, anti-IL-6 receptor antibody, tocilizumab was intravenously injected once a week for 4 weeks. Controls received PBS in a same manner. Hematological and biochemical parameters were measured regularly and serum hepcidin-25 levels were measured by SELDI-TOF mass spectrometry. Moreover, hepcidin mRNA induction in Hep3B cells by serum from arthritic monkeys was examined by real-time PCR. Administration of tocilizumab rapidly decreased CRP levels and improved iron-deficient anemia within 1 week. Tocilizumab induced rapid but transient reduction in serum hepcidin-25. Hepcidin mRNA expression was more potently induced by serum from arthritic monkey and this was inhibited by the addition of tocilizumab. Blockade of IL-6 signaling rapidly improved anemia in monkey arthritis via the inhibition of IL-6-induced hepcidin production.

We examined the therapeutic effect of high molecular weight hyaluronic acid (HA) on the progression of joint pain and cartilage degeneration in a rabbit osteoarthritis (OA) model. The OA model was induced by partial meniscectomy. In the time course study, cartilage degeneration was assessed at 3, 7 and 14 days after operation. In the therapeutic study, HA or loxoprofen (LOX) was administered for 14 days beginning four days after operation (after the onset of knee pain and cartilage degeneration). Knee pain was assessed by weight distribution on the hind paw, and cartilage damage and MMP production in the joints were evaluated 18 days after surgery. In the time course study, severe cartilage damage was found three days after operation. In the treatment study, weight-bearing on the injured paw in the control group decreased with time from four days after the operation. However, HA or LOX treatment beginning four days after the operation normalized the reduced hind paw weight distribution, and PGE 2 production was inhibited by HA treatment and LOX treatment. HA significantly inhibited cartilage degeneration, whereas LOX did not. HA also suppressed the production of MMP in joints. Treatment of HA after the onset of cartilage destruction and pain showed a cartilage protective effect as well as an analgesic effect.

MR16-1 is a monoclonal antibody to mouse IL-6 receptor (IL-6R) and a good tool to investigate the involvement of IL-6 in mouse disease models. However, long-term administration of MR16-1 induced anti-MR16-1 antibody that inhibited IL-6 blocking activity of MR16-1. In this study, we treated NZB/NZW F1 (BWF1) mice with MR16-1 (0.5 mg, weekly) and tested for proteinuria (an indicator of autoimmune disease) after inducing tolerance by intraperitoneal injection of anti-CD4 mAb, or in an exploratory experiment, by prior intravenous injection of 2 mg MR16-1. Anti-CD4 mAb treatment inhibited anti-MR16-1 antibody production. And the appearance of proteinuria was significantly delayed. However, anti-CD4 mAb injection alone also significantly delayed the onset of nephritis compared with saline treatment. Intravenous MR16-1 (2 mg) followed by weekly MR16-1 injections inhibited the production of anti-MR16-1 antibody and consequently decreased the prevalence of proteinuria and the level of anti-DNA antibodies. These results established the viability of intravenous MR16-1 injection as a means of inducing tolerance. It is superior to the anti-CD4 mAb method because it enabled the effects of MR16-1 monotherapy to be evaluated without the confounding effects of anti-CD4 mAb.