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Treatment of Rheumatoid Arthritis with Biological Agents —As a Typical and Common Immune-Mediated Inflammatory Disease

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Treatment of Rheumatoid Arthritis with Biological Agents —As a Typical and Common Immune-Mediated Inflammatory Disease 56 Proc. Jpn. Acad., Ser. B 94 (2018) [Vol. 94, Addendum to “Treatment of rheumatoid arthritis with biological agents — as a typical and common immune-mediated inflammatory disease” [Proc. Jpn. Acad., Ser. B 93, No. 8, 600–608] By Tsutomu TAKEUCHI Table 1 was updated, because Sarilumab, anti-IL-6 receptor mAb has been approved for RA in Japan. doi: 10.2183/pjab.94.005 ©2018 The Japan Academy No. 1] Table 1. Target molecules in immune-mediated inflammatory diseases CAPS RA JIA CD UC AS SpA PS PsA SLE pSS BD SSc GCA TA AAV AOSD FMF target biologics joint joint intestine intestine spine spine skin skin&joint fever systemic eye&mouth mucosa skin large vessel large vessel small vessel fever&joint adalimumab 䖂 ◎◎◎◎ ◎◎ ◎ certolizumab ◎ ◯ ◎ trial ◎◎◯ ◎ Ligand pegol TNFα golimumab ◎ ◯ ◎◎ ◎ infliximab ◎ × ◎◎◎ ◎◎ △ ◎ Receptor etanercept ◎◎ ◎ ◯ ◎◎ sirukumab ◯ clazakizumab ◯ × △ Ligand olokizumab ◯ × IL-6 Addendum to vobarilizumab ◯ trial tocilizumab ◎◎ × × × △ ◎ ◎ trial Receptor sarilumab ◎ × Ligand namilumab trial △ GM-CSF Receptor mavrilimumab ◯ “ Treatment of rheumatoid arthritis canakinumab × ◎ ◎ ◎ Ligand IL-1β rilonacept △△ ◎ Receptor anakinra ◎◎ trial ◎ IL-12/23 (p40) ustekinumab △ ◎ ◯ ◯ ◎◎ trial guselkumab △ ◯ △ risankizumab ◯ △ ◯◯ IL-23 (p19) tildrakizumab ◯ brazikumab △ ixekizumab △ ◯◯◎◎ Ligand IL-17 secukinumab △ × ◎ ◯ ◎◎ Receptor brodalumab × × ◯ ◎◎ ” belimumab △ ◎△ ◯ BAFF blisibimod × Ligand sifalimumab △ IFNα Receptor anifrolumab ◯ CD80/86 abatacept ◎◎△△ × trial ◎ × trial CD20 rituximab ◎△ △△◎ Integrin α4/β1 natalizumab × ◎△ vedolizumab ◎◎ Integrin α4/β7 etrolizumab ◯◯ approved, primarily in Japan, except for anakinra and rituximab for RA and abatacept for PsA (September 11, 2017). positive results in Phase 2 or 3 trial, proof of concept obtained, # no positive results in Phase 2 or 3, RA: rheumatoid arthritis, JIA: juvenile idiopathic arthritis, CD: crohn’s disease, UC: ulcerative colitis, AS: ankylosing spondylitis, SpA: spondyloathritis, PS: psoriasis, PsA: psoriatic arthritis, CAPS: cryopyrin associated periodic syndrome, FMF: familial medetrian fever, SLE: systemic lupus erythematosus, pSS: primary sjogren’s syndrome, SSc: 57 systemic sclerosis, GCA: giant cell arthritis, TA: Takayasu arteritis, AAV: ANCA associated vasculitis, AOSD: adult-onset Still’s disease 600 Proc. Jpn. Acad., Ser. B 93 (2017) [Vol. 93, Review Treatment of rheumatoid arthritis with biological agents — as a typical and common immune-mediated inflammatory disease † By Tsutomu TAKEUCHI*1, (Communicated by Tadamitsu KISHIMOTO, M.J.A.) Abstract: Molecules involved in the disease process facilitated our understanding of pathogenesis of the disease with unknown etiology such as immune-mediated and inflammatory diseases. Moreover, the targeted therapies against the proposed molecular targets by biological agents provide enormous benefits to the patients and societies. Here, I will review recent progress of the biological treatment in the immune-inflammatory diseases by focusing on the rheumatoid arthritis, the disease characterized by persistent polyarthritis leading to joint destruction and disability with autoimmune features, as a role model. Keywords: immune-mediated inflammatory diseases, rheumatoid arthritis, biologics, cytokines, therapy “biological agents” or “biologics”, those are bioengi- Introduction neered to target specific proteins or nucleic acids. Molecular and cellular understanding of human For instance, a common target of the inflammatory diseases is critical for dissecting the mechanisms of process is tumor necrosis factor (TNF), which is an pathogenesis and may provide a clue for developing inflammatory cytokine implicated in the pathogene- innovative treatment. Among human diseases such sis of rheumatoid arthritis. Monoclonal antibodies as cancers, infections, and metabolic disease, there against single cytokine, TNF alpha (TNF,), have is a group of inflammatory diseases mediated by made revolutionary changes in treatment for a range immunological mechanisms without apparent etiol- of conditions such as rheumatoid arthritis (RA), ogies, called immune-mediated inflammatory diseases inflammatory bowel disease, ankylosing spondyritis, (IMIDs) including rheumatoid arthritis, inflamma- and psoriasis (Table 1). The miracle achieved in the tory bowel diseases, and psoriasis.1),2) While the treatment of the IMIDs is reviewed here with a focus human immune system involves highly complex and on RA, which is a typical and common IMID.6),7) coordinated processes, it has been demonstrated that cytokines are overexpressed and T- and B-cells are Pathogenesis of rheumatoid arthritis as accumulated in affected tissues in IMIDs.1),2) These a typical and common immune-mediated fl key players have been postulated as the potential in ammatory disease targets for intervention. Indeed, novel therapeutic The immune system is beneficial to humans by antibodies targeted against single molecules that are protecting them from infections caused by bacteria or intimately associated with disease pathogenesis, have viruses. There are two major pathways of immunity: led to significantly better outcomes of diseases in innate immunity as the first line of defense and clinical practice.3)–5) The therapeutic antibodies are acquired immunity that protects against specific classified into the category of drugs, designated as pathogens.8) There are unique diseases where inflam- mation is induced by the immune system, as seen in *1 Division of Rheumatology, Department of Internal autoimmunity, and not by infection or malignancy.9) Medicine, Keio University School of Medicine, Tokyo, Japan. fl † The immune-mediated in ammatory diseases include Correspondence should be addressed: T. Takeuchi, Divi- gout, where urate crystals formed in the body elicit sion of Rheumatology, Department of Internal Medicine, Keio fl University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo in ammation through the innate immune system, 160-8582, Japan (e-mail: [email protected]). and RA, where autoimmunity plays a central role in doi: 10.2183/pjab.93.038 ©2017 The Japan Academy No. 8] Table 1. Target molecules in immune-mediated inflammatory diseases CAPS RA JIA CD UC AS SpA PS PsA SLE pSS BD SSc GCA TA AAV AOSD FMF target biologics joint joint intestine intestine spine spine skin skin&joint fever systemic eye&mouth mucosa skin large vessel large vessel small vessel fever&joint adalimumab 䖂 ◎◎◎◎ ◎◎ ◎ certolizumab ◎ ◯ ◎ trial ◎◎◯ ◎ Ligand pegol TNFα golimumab ◎ ◯ ◎◎ ◎ infliximab ◎ × ◎◎◎ ◎◎ △ ◎ Receptor etanercept ◎◎ ◎ ◯ ◎◎ sirukumab ◯ clazakizumab ◯ × △ Ligand olokizumab ◯ × IL-6 vobarilizumab ◯ trial tocilizumab ◎◎ × × × △ ◎ ◎ trial Receptor Treatment of RA with biological agents sarilumab ◎ × Ligand namilumab trial △ GM-CSF Receptor mavrilimumab ◯ canakinumab × ◎ ◎ ◎ Ligand IL-1β rilonacept △△ ◎ Receptor anakinra ◎◎ trial ◎ IL-12/23 (p40) ustekinumab △ ◎ ◯ ◯ ◎◎ trial guselkumab △ ◯ △ risankizumab ◯ △ ◯◯ IL-23 (p19) tildrakizumab ◯ brazikumab △ ixekizumab △ ◯◯◎◎ Ligand IL-17 secukinumab △ × ◎ ◯ ◎◎ Receptor brodalumab × × ◯ ◎◎ belimumab △ ◎△ ◯ BAFF blisibimod × Ligand sifalimumab △ IFNα Receptor anifrolumab ◯ CD80/86 abatacept ◎◎△△ × trial ◎ × trial CD20 rituximab ◎△ △△◎ Integrin α4/β1 natalizumab × ◎△ vedolizumab ◎◎ Integrin α4/β7 etrolizumab ◯◯ approved, primarily in Japan, except for anakinra and rituximab for RA and abatacept for PsA (September 11, 2017). positive results in Phase 2 or 3 trial, proof of concept obtained, # no positive results in Phase 2 or 3, RA: rheumatoid arthritis, JIA: juvenile idiopathic arthritis, CD: crohn’s disease, UC: ulcerative colitis, AS: ankylosing spondylitis, SpA: spondyloathritis, PS: psoriasis, PsA: psoriatic arthritis, CAPS: cryopyrin associated periodic syndrome, FMF: familial medetrian fever, SLE: systemic lupus erythematosus, pSS: primary sjogren’s syndrome, SSc: 601 systemic sclerosis, GCA: giant cell arthritis, TA: Takayasu arteritis, AAV: ANCA associated vasculitis, AOSD: adult-onset Still’s disease 602 T. TAKEUCHI [Vol. 93, a) Joint appearance (hands) Early stage Established stage Late stage b) Pathological findings (synovial tissues) New vessel formation Lymphocyte infiltration Synovial hypertrophy Fig. 1. Clinical and pathological characteristics of rheumatoid arthritis. perpetuating joint inflammation by breaking toler- large number of inflammatory mediators, including ance, which surveys and prevents the immune pro-inflammatory cytokines (TNF, and IL-6), in- response against self (autoimmunity). RA affects duce matrix metallo-proteinases (MMP), promote 0.5% to 1.0% of the global population and is synovial proliferation, and induce osteoclast differ- recognized as one of the common diseases in humans. entiation (Figure 2). Three major cell types of RA is characterized by perpetual inflammation in the endothelial cells, T and B cells, and synovial cells joint synovium leading to joint destruction and are present in the synovial tissues in patients with disability (Figure 1).4),5) With respect to the patho- RA.4),5) Through interactions between these cells, genesis of RA, auto-reactive lymphocytes including pro-inflammatory cytokines such as TNF, and IL-6 CD4D T cells infiltrate into the joint through are released, thereby facilitating the lowering of the adhesion to the vessel wall by ,4O1 integrin– threshold for pain and activating T cells, B cells, VCAM-1 and ,LO2 integrin–ICAM-1 as an initial and macrophages (Figure 2). Activation of T cells is step of inflammation of the joint. After infiltration important in initiation and perpetuation of inflam- into the joints, lymphocytes
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