Table 2.

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.