Е. Л. Насонов

OBJECTIVE: To examine the efficacy and safety of the humanized anti-interleukin-6 receptor antibody tocilizumab combined with conventional disease-modifying antirheumatic drugs (DMARDs) in patients with active rheumatoid arthritis (RA). METHODS: A total of 1,220 patients were randomized (2:1 ratio) in the phase III, double-blind, placebo-controlled, multicenter TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy) study. Patients remained on stable doses of DMARDs and received tocilizumab 8 mg/kg or placebo (control group) every 4 weeks for 24 weeks. RESULTS: At week 24, the proportion of patients achieving a response according to the American College of Rheumatology criteria for 20% improvement (ACR20) was significantly greater in the tocilizumab plus DMARD group than in the control group (61% versus 25%; P<0.0001). Secondary end points including 50% or 70% improvement (ACR50/70), the Disease Activity Score in 28 joints (DAS28), DAS28 remission responses (DAS28<2.6), European League Against Rheumatism responses, and systemic markers such as the C-reactive protein and hemoglobin levels showed superiority of tocilizumab plus DMARDs over DMARDs alone. Seventy-three percent of patients in the tocilizumab group had >or=1 adverse event (AE), compared with 61% of patients in the control group. AEs leading to withdrawal from the study were infrequent (4% of patients in the tocilizumab group and 2% of those in the control group). Serious AEs occurred in 6.7% and 4.3% of patients in the tocilizumab and control groups, respectively, and serious infections occurred in 2.7% and 1.9%, respectively. Elevations in the alanine aminotransferase level, from normal at baseline to >3-fold the upper limit of normal, occurred in 4% of patients in the tocilizumab group and 1% of those in the control group, and elevated total cholesterol levels were observed in 23% and 6% of patients, respectively. Sixteen patients started lipid-lowering therapy during the study. Grade 3 neutropenia occurred in 3.7% of patients receiving tocilizumab and none of the patients in the control group, and no grade 4 neutropenia was reported. CONCLUSION: Tocilizumab combined with any of the DMARDs evaluated was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to these agents.

BACKGROUND: Strontium ranelate is currently used for osteoporosis. The international, double-blind, randomised, placebo-controlled Strontium ranelate Efficacy in Knee OsteoarthrItis triAl evaluated its effect on radiological progression of knee osteoarthritis. METHODS: Patients with knee osteoarthritis (Kellgren and Lawrence grade 2 or 3, and joint space width (JSW) 2.5-5 mm) were randomly allocated to strontium ranelate 1 g/day (n=558), 2 g/day (n=566) or placebo (n=559). The primary endpoint was radiographical change in JSW (medial tibiofemoral compartment) over 3 years versus placebo. Secondary endpoints included radiological progression, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and knee pain. The trial is registered (ISRCTN41323372). RESULTS: The intention-to-treat population included 1371 patients. Treatment with strontium ranelate was associated with smaller degradations in JSW than placebo (1 g/day: -0.23 (SD 0.56) mm; 2 g/day: -0.27 (SD 0.63) mm; placebo: -0.37 (SD 0.59) mm); treatment-placebo differences were 0.14 (SE 0.04), 95% CI 0.05 to 0.23, p<0.001 for 1 g/day and 0.10 (SE 0.04), 95% CI 0.02 to 0.19, p=0.018 for 2 g/day. Fewer radiological progressors were observed with strontium ranelate (p<0.001 and p=0.012 for 1 and 2 g/day). There were greater reductions in total WOMAC score (p=0.045), pain subscore (p=0.028), physical function subscore (p=0.099) and knee pain (p=0.065) with strontium ranelate 2 g/day. Strontium ranelate was well tolerated. CONCLUSIONS: Treatment with strontium ranelate 1 and 2 g/day is associated with a significant effect on structure in patients with knee osteoarthritis, and a beneficial effect on symptoms for strontium ranelate 2 g/day.

Cytokine storm syndrome (CSS) is a severe complication of inflammatory immune diseases or treatment of malignancies; it may also appear during the progression of COVID-19. CSS is caused by dysregulation of the synthesis of cytokines, including pro-inflammatory, regulatory, and anti-inflammatory cytokines and chemokines, leading to pathologic activation of innate and adaptive (Th1 and Th17 mediated) immunity. Interleukin-6 (IL-6) plays an important role in the pathogenesis of CSS. The significant role of IL-6 in pathogenesis of COVID-19 was confirmed in a range of studies, which showed that the plasma concentration of IL-6 was increased in patients with severe COVID-19. Currently, IL-6 inhibitor therapeutics are not yet approved for the treatment of COVID-19; however, these medicines, including tocilizumab (TCZ) are used off-label for the treatment of patients with severe COVID-19, including life-threatening conditions. The role of IL-6 in the pathogenesis of CSS during COVID-19 is important however, a number of related issues are not yet clear. These issues include the indications for treatment with IL-6 inhibitors, as well as the estimation of risk associated with the disease, outcomes, treatment options, and adverse drug reactions. The development of personalized immunomodulatory therapy, with respect to the role of cytokines in pathogenesis, requires the studies that aimed to find other relevant therapeutic targets for the treatment of CSS in patients with COVID-19. These therapeutic targets include inhibition of IL-1, IL-6, TNFα, GM-CSF, IFNγ, IL-17, IL-18, and also activation of the complement system. The challenge of CSS in patients with COVID-19 is identifying the correct scientific targets and developing clinical trials aimed to evaluate the pathogenesis and treat immune-mediated inflammatory diseases (IMIDs). Hopefully, the significant efforts of scientists and physicians across the globe will improve the prognosis in COVID-19 patients and provide useful information on IMIDs required to support the struggle for treating potential viral outbreaks, and treatment of well-known IMIDs.