R HEUMATOID A RTHRITIS BMJ 2011;342: RA is a systemic inflammatory autoimmune disease with localised and general manifestations. It is characterised by polyarticular inflammation of synovial tissue, which causes pain, swelling and stiffness of the joints of the hands, wrists, and feet in particular. It results in functional limitations and may progress to joint destruction and extra-articular disease (e.g. Nodules, osteoporosis, vasculitis, lung fibrosis, peripheral neuropathy). SYNOVIAL TISSUE – the inside layer of the external fibrous joint capsule. It secretes a thick lubricating fluid

R HEUMATOID A RTHRITIS BMJ 2011;342: It is diagnosed through a combination of the amount of joint involvement, and serology (rheumatoid factor, anti- citrullinated protein antibodies, C reactive protein, ESR) More than a 12 week delay in referral to a rheumatologist is associated with a reduced chance of drug-free remission and increased risk for progressive joint damage The ultimate goal of therapy is a “cure” i.e. Clinical remission RA can have a gradual onset but damage still starts early

R HEUMATOID A RTHRITIS AMH 2011 Rationale for drug use – relieve symptoms and prevent damage to bones, joints and other organs Before starting treatment – baseline assessment, CVD risk, consequences of suppressing immune function, physical and occupational therapy requirements, education, referral to a rheumatologist Drug treatment * No evidence for clinical superiority of any individual or class of antirheumatic

R HEUMATOID ARTHRITIS T HERAPEUTIC G UIDELINES Between 15-70% of the risk of developing RA may be due to genetic factors RA is best characterised as a lymphocyte- mediated inflammatory disease The stimulating antigens are unknown Pro-inflammatory mediators

R HEUMATOID A RTHRITIS AMH 2011 Drug treatment Choice is based on disease severity and relative efficacy and toxicity of drugs Combinations of antirheumatics are used to improve efficacy but there is little evidence to inform appropriate choice Mild disease – sulfasalazine and hydroxychloroquine

RA – DRUG TREATMENT AMH 2011 Moderate – severe disease low dose methotrexate – appears less toxic than other immunosuppressants (azathioprine, cyclosporin, leflunomide), gold or penicillamine Methotrexate may need to be combined with cytokine modulators (also known as biological agents) or leflunomide to slow progression of joint damage Oral corticosteroids are well tolerated and work quickly but long-term use is undesirable. They reduce joint destruction and improve symptoms

RA – DRUG TREATMENT AMH 2011 The optimal dose of glucocorticoids in combination treatment is unknown ( BMJ 2011; 342) Withdrawal in remission often results in relapse – consider limiting the use of more toxic agents at this time Daily supplements of omega-3 fatty acids may reduce severity of symptoms (at the correct dose)

TNFα ANTAGONISTS NAMEACTS ONUSE AdalimumabTNFα RA, psoriasis, psoriatic arthritis, ankylosing spondylitis, IBD CertolizumabTNFα EtanerceptTNFα GolimumabTNFα InfliximabTNFα

CYTOKINE MODULATORS NAMEACTS ONUSE Abatacept Co-stimulation modulator. CD80, CD86 RA AnakinraIL-1RA Rituximab Reduces B lymphocyte induced T cell activation RA TocilizumabIL-6RA

RA – B IOLOGIC AGENTS TNF-alpha antagonists – they bind to TNF-alpha ADALIMUMAB ADA = chosen by manufacturer LIM = for immune and inflammatory diseases U = human MAB = monoclonal antibody INFLIXIMAB INF = chosen by manufacturer LI = for immune and inflammatory diseases XI = chimeric MAB = monoclonal antibody

RA - I MMUNOLOGY “mAbs to human targets are generated either in other species – for example, in mice – or through recombinant engineering. With chimeric mAbs, the variable region of a murine-derived mAb is fused to the Fc piece of a human IgG molecule. The resulting construct is approximately one quarter murine and three quarters human.” (Recombinant engineering – the use of viruses or yeast to create antibodies rather than mice) J Allergy Clin Immunol 2010; 125:

RA – I MMUNOLOGY Immune system cells originate from stem cells of the bone marrow They differentiate into lymphocyte stem cells or myeloid stem cells Lymphocyte stem cells produce T lymphocytes and B lymphocytes Myeloid cells produce granulocytes (neutrophils, eosinophils, basophils, mast cells, monocytes and macrophages – the last 2 cell types producing the cytokines TNF, IL-1 and IL-6) T lymphcytes bind to the antigen directly, through their surface receptors (i.e. CD (“cluster of differentiation”) receptors). Allergy. Arshad SH. Churchill Livingstone 2002

RA IMMUNOLOGY STEM CELL Lymphocyte stem cell Myeloid stem cell T lymphocyte B Lymphocyte Granulocytes (Neutrophil, basophils, eosinophils, mast cells, monocytes, macrophages) Bind directly cytokines Immunoglobulins autoantibodies Cytokines (TNFα, IL-1, IL-6)

RA - IMMUNOLOGY T lymphocytes, monocytes and macrophages contribute to immunological responses through release of cytokines B lymphocytes produce immunoglobulins or antibodies (i.e. IgG, IgA, IgM, IgD, IgE) An antibody molecule is Y-shaped. The stem of the Y = Fc fragment. It binds to the cell surface receptor The two forks = Fab ( ab = antigen binding) fragments Allergy. Arshad SH. Churchill Livingstone 2002.

A NTIBODIES Antigen binding Fab light chain heavy chain Fc Combines with complement Binds to macrophages Biologic activity

RA – IMMUNOLOGY B lymphocytes are thought to play a pathogenic role in RA by producing autoantibodies (i.e. rheumatoid factor, anticyclic citrullinated protein) IL-6 is a multifunctional cytokine that is involved in the acute inflammatory response. It induces the development of B cells, osteoclastogenesis, and acute phase proteins production in the liver. High levels of Il-6 have been found in the synovial fluids from inflamed joints of patients with RA J Allergy Clin Immunol 2010; 125:

RA – TNF J A LLERGY C LIN IMMUNOL 2010; 125: S TNF is a proinflammatory cytokine in RA, psoriatic arthritis, and ankylosing spondylitis TNF activates various cell types, promotes accumulation of immunocompetent cells at sites of inflammation by activation of the vascular endothelium, and stimulates synthesis of other pro-inflammatory cytokines (e.g. IL-1, IL-6) Both TNF and IL-1 mediate bone and cartilage destruction through activation of osteoclasts and macrophages to release destructive mediators (collagenase, prostaglandins)

C YTOKINE MODULATORS ANAKINRA is a recombinant Il-1ra (ra = receptor antagonist). TOCILIZUMAB is a humanised anti IL-6 receptor mAB that binds to both soluble and membrane-bound IL-6 receptor ABATACEPT is a soluble protein consisting of the extracellular domain of CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) linked to the Fc portion of IgG1 J Allergy Clin Immunol 2010; 125: S314-23