Efficacy outcomes of clinical trials published from 2012 to 2020 investigating bDMARDs specifically inhibiting IL-6 receptor or ligand compared against placebo or control group, shown across other studied immune-mediated diseases
| Disease | Study | Target | Population | Intervention/ Control | Primary endpoint | Efficacy |
| Psoriatic arthritis | Mease et al6 (2016) phase IIb | IL-6 | NSAID-IR and/or csDMARD bDMARD naïve | CLZ vs PBO | ACR 20 response at week 16 | |
| Ankylosing spondylitis | Sieper et al7 (2014)(BUILDER) phase II/III | IL-6R | TNFi-naïve | TCZ vs PBO | ASAS 20 response at week 12 | |
| Sieper et al8 (2015) (ALIGN) phase II | NSAID-IR | SAR vs PBO | ASAS 20 response at week 12 | |||
| Osteoarthritis | Richette et al71 (2020) (TIDOA) phase III | IL-6R | Refractory to analgetics | TCZ vs PBO | ΔVAS pain at week 6 | |
| Systemic lupus erythematosus | Wallace et al9 (2017)(BUTTERFLY) phase II | IL-6 | Active disease (SLEDAI-2K/BILAG) | PF-04236921 vs PBO | SLE Responder Index (SRI-4) at week 24 | |
| Rovin et al10 (2016) phase II | Class III or class IV Lupus nephritis | SIR vs PBO | Reduction in proteinuria from baseline to week 24 | |||
| NCT02437890 phase II | IL-6R | Moderate to severe active SLE | ALX-0061 vs PBO | mBICLA response rate at week 24 | ||
| Myositis | NCT02043548 phase II | IL-6R | Refractory PM/DM | TCZ vs PBO | Mean total improvement scores at visits 2–7 | |
| Sjögren’s syndrome | Felten et al11 (2020) (ETAP) phase II/III | IL-6R | ESSDAI≥5 | TCZ vs PBO | Response to treatment at week 24* | |
| Multiple myeloma | San-Miguel et al75 (2014) phase II | IL-6 | Untreated MM and no candidate for stem cell transplantation | SIL+VMP vs VMP | Complete response rate† | |
| Brighton et al76 (2019) phase II | High-risk smouldering multiple myeloma | SIL vs PBO | 1-year progression-free survival rate | |||
| Systemic sclerosis associated ILD | Khanna et al74 (2020) (focuSSced) phase III | IL-6R | Diffuse cutaneous-SSc; mRSS 10–35; inflammatory status | TCZ vs PBO | ΔmRSS from baseline to week 48; secondary outcome: ΔFVC% predicted from baseline to week 48 | |
| Late antibody-mediated kidney transplant rejection | Doberer et al77 (2020) phase II | IL-6 | Kidney transplant recipients with donor-specific, antibody-positive ABMR | CLZ vs PBO | Safety and tolerability; secondary outcomes: course of eGFR, protein/creatinine ratio | |
| AA-amyloidosis | Okuda et al78 79 (2014/2016) retrospective analyses | IL-6R | Amyloid A (AA) amyloidosis complicating rheumatic diseases | TCZ vs TNFi | Outcomes: retention rate, median ΔSAA, median ΔeGFR, mean ΔCDAI, mean ΔGC dose | |
| Polymyalgia rheumatica | Lally et al80 (2016) open label, phase IIa | IL-6R | PMR treated with GCs for ≤4 weeks | TCZ+GC vs GC | Relapse-free remission without GC treatment at 6 months | |
| Devauchelle-Pensec et al81 (2016) (TENOR) open label, phase II | Active disease defined as PMR-AS >10 | TCZ mono no control group | PMR-AS ≤10 at week 12 | |||
| COVID-19 CRS/pneumonia | Hermine et al90 (2020) (CORIMUNO-TOCI 1),open-label | IL-6R | Moderate to severe pneumonia | TCZ+SOC vs SOC | (1) % patients dead or needing NIV or mechanic ventilation on day 4 (scores>5 on WHO-CPS) and (2) survival without need of ventilation at day 14 | |
| Salvarani et al93 (2020) (RCT-TCZ-COVID-19), open-label | Mild pneumonia | TCZ+SOC vs SOC | Clinical worsening within 14 days‡ | |||
| Stone et al92 (2020) (BACC Bay Tocilizumab Trial), phase III | Mild pneumonia | TCZ+SOC vs PBO+SOC | Mechanical ventilation or death (time frame: 28 days) | |||
| Salama et al91 (2020) (EMPACTA), phase III | Moderate to severe pneumonia | TCZ+SOC vs PBO+SOC | Mechanical ventilation or death by day 28 |
Red denotes no difference comparted to placebo/control group; orange denotes promising results or rather mixed results across groups/trials and green denotes statistically superior compared with placebo or control group. For colorblind readers, table 2 is provided in the online supplemental appendix (section 7: S7.2).
*Response defined by combination of (1) decrease of at least 3 points in ESSDAI, (2) no new moderate/severe activity in any ESSDAI domain and (3) no worsening in physician’s global assessment on a visual numeric scale ≥1/10.
†Complete response (CR) based on European Group for Blood and Marrow Transplantation (EBMT) criteria
‡Defined by occurrence of 1 of the following events (whichever came first): (a) admission to intensive care unit with mechanical ventilation; (b) death or (c) paO2/FIO2 ratio <150 mm Hg.
ABMR, antibody-mediated rejection; ACR20, American College of Rheumatology 20% improvement criteria; ASAS20, Assessment in Ankylosing Spondylitis 20% response criteria; bDMARD, biological DMARD; BILAG, British Isles Lupus Assessment Group; CLZ, clazakizumab; csDMARD, conventional synthetic DMARD; DM, dermatomyositis; eGFR, estimated glomerular filtration rate; ESSDAI, EULAR Sjögren’s syndrome disease activity index; GC, glucocorticoids; ILD, interstitial lung disease; IR, inadequate response; mBICLA, modified BILAG-based Composite Lupus Assessment; MM, multiple myeloma; mRSS, modified Rodnan skin score; NIV, noninvasive ventilation; NSAID, non-steroidal anti-inflammatory drugs; %patients, proportion of patients; PBO, placebo; PM, polymyositis; PMR-AS, Polymyalgia Rheumatica (PMR) Activity Score; SAR, sarilumab; SIL, siltuximab; SIR, sirukumab; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000; SOC, standard of care; SRI4, systemic lupus erythematosus (SLE) Responder Index (SRI); TCZ, tocilizumab; TNF-i, tumour necrosis factor inhibitor; VMP, bortezomib-melphalan-prednisone; WHO-CPS, World Health Organization-Clinical Progression Scale; ΔCDAI, change in Clinical Disease Activity Index; ΔFVC%, change in percentage of predicted forced vital capacity; ΔmRSS, change in modified Rodnan skin score; ΔSAA, change in serum amyloid A (SAA) levels; ΔVAS, change in visual analogue scale.