Irina Baltcheva February 11 th, 2013 Treating autoimmunity:

Irina Baltcheva February 11th, 2013 Treating autoimmunity: rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) Drug Literacy Program

M&S Drug Literacy Program Epidemiology and clinical manifestations

4 1 World Alzheimer Report 2010 SLE name  “lupus” (Latin for “wolf”) was first used during the Middle Ages to describe erosive skin lesions evocative of a “wolf’s bite”. SLE is the prototypic multisystem autoimmune disorder with a broad spectrum of clinical presentations encompassing almost all organs and tissues. The extreme heterogeneity of the disease has led some investigators to propose that SLE represents a syndrome rather than a single disease. | Drug Literacy Program | I. Baltcheva | 11.02.2013 | SLE & RA | Business Use Only A malar rash is present in approximately 46–65% of lupus sufferers and varies between different populations. Systemic Lupus Erythematosus (SLE): Background

Rheumatoid arthritis (RA): Background Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks flexible (synovial) joints. It can be a disabling and painful condition, which can lead to substantial loss of functioning and mobility if not adequately treated. 5 | Drug Literacy Program | I. Baltcheva | 11.02.2013 | SLE & RA | Business Use Only

RA is incurable, but treatable. Life expectancy: lifespan reduced by anywhere from three to 12 years Prevalence 1% in general 5-6% in some native American groups Less than 1% in people from Caribbean The incidence is about 3 cases per 10,000 population per annum. Are affected: Women 3-5 times as often as men. 3 times more common in smokers than non-smokers] A study in 2010 found that those who drank modest amounts of alcohol regularly were four times less likely to get rheumatoid arthritis than those who never drank. 6 | Drug Literacy Program | I. Baltcheva | 11.02.2013 | SLE & RA | Business Use Only SLE vs RA: Epidemiology SLE is incurable, but treatable. Life expectancy: In the 1950s, most people diagnosed with SLE lived fewer than five years. Today, over 90% survive for more than ten years, and many live relatively asymptomatically. 80-90% can expect to live a normal lifespan. Prevalence US: 51 per 100’000 (200 per 100’000 among african americans) Europe: 40 per 100’000 > 250’000 patients in the US Incidence has tripled in the last 40 years, due to improved diagnosis of mild disease. Are affected: Females in 90% of cases; African american and Latin american mestizos more than Caucasians

M&S Drug Literacy Program SLE – Pathology

13 | Drug Literacy Program | I. Baltcheva | 11.02.2013 | SLE & RA | Business Use Only Antigen presentation Antigen-presenting cells (APC) bind antigen on major histocompatibility complexes (MHC). This complex interacts with the T-cell receptor (TCR) and this might lead to inhibition or stimulation of T cells.

M&S Drug Literacy Program RA – Pathophysiology

Some definitions Cells of the cynovial membrane An osteoclast (from the Greek words for "bone" (Οστό) and "broken" (κλαστός)) is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone (organic dry weight is 90% collagen). This process is known as bone resorption. Osteoclasts and osteoblasts are instrumental in controlling the amount of bone tissue: osteoblasts form bone, osteoclasts resorb bone. Osteoclasts are formed by the fusion of cells of the monocyte-macrophage cell line.[2] Chondrocytes are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework (stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells of connective tissue in animals. Recent evidence indicates the involvement of Toll-like receptors (TLRs), which are key recognition structures of the innate immune system, at an initial stage of synovial activation. Hypothetically, microbial components or endogenous ligands, such as RNA from necrotic cells within the synovial fluid, activate RASFs through TLR signalling and lead to the up-regulated expression of pro-inflammatory cytokines and chemokines. These factors would then result in the attraction and accumulation of immune cells in the synovium and, through a stimulatory loop, to chronic inflammation. 20 | Drug Literacy Program | I. Baltcheva | 11.02.2013 | SLE & RA | Business Use Only

Innate immunity in RA Subtitle Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system as well as the digestive system. They are single, membrane-spanning, non-catalytic receptors usually expressed in sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have breached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. TLRs are a type of pattern recognition receptor (PRR) and recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). Activation of cells by microbial components and also by endogenous molecules via Toll-like receptor (TLR) results in the production of a variety of proinflammatory cytokines, chemokines, and destructive enzymes, some of which can characteristically be found in RA. 21 | Drug Literacy Program | I. Baltcheva | 11.02.2013 | SLE & RA | Business Use Only

M&S Drug Literacy Program SLE – Treatments

Treating SLE is challenging because disease is multisystemic, remitting and relapsing Current standard of care: Nonsteroidal anti-inflammatory drugs (aspirine, approved in 1948) (agents that treat the inflammation but not the underlying cause) Antimalarials (hydroxychloroquine, approved in 1955) Corticosteroids (approved in 1955) Immunosuppressive drugs Methotrexate Azathioprine Mycophenolate mfetil (MMF) Cyclosporine Belimumab (the only biologic approved in 2011) Above treatments are ineffective for some patients -> unmet medical need Many more biologics were tested, but failed: rituximab, abatacep, epratuzumab, abetimus, IDEC-131, etc. 24 | Drug Literacy Program | I. Baltcheva | 11.02.2013 | SLE & RA | Business Use Only

Hydroxychloroquine Overview Anti-malarial drug Mechanism of action: blocks the activation of toll-like receptors (TLR) on dendritic cells, thereby mitigating the inflammatory process. Remember: Toll-like receptors recognize DNA-containing immune complexes, which leads to the production of interferon and causes the dendritic cells to mature and present antigen to T cells. 25 | Drug Literacy Program | I. Baltcheva | 11.02.2013 | SLE & RA | Business Use Only

Corticosteroids Overview In technical terms, "corticosteroid" refers to both glucocorticoids and mineralocorticoids (as both are mimics of hormones produced by the adrenal cortex), but is often used as a synonym for "glucocorticoid". Glucocorticoids (GC) are a class of steroid hormones that bind to the glucocorticoid receptor (GR), which is present in almost every vertebrate animal cell. GCs suppress cell-mediated immunity by inhibiting genes that code for the cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and IFN-γ. This decreases the function and numbers of T lymphocytes. GCs suppress humoral immunity B cells produce less IL-2 B cells express less IL-2 receptors B cells proliferate less B cells produce fewer antibodies B cells can not present antigen to T cells. List of steroids: Hydrocortisone (cortisol), Cortisone, Prednisone, Prednisolone, Methylprednisolone, Dexamethasone, Betamethasone, Triamcinolone, Beclometasone, Fludrocortisone acetate, Deoxycorticosterone acetate (DOCA), Aldosterone. 26 | Drug Literacy Program | I. Baltcheva | 11.02.2013 | SLE & RA | Business Use Only

Methotrexate Overview Is an antimetabolite and antifolate drug. Interferes with the metabolism of folic acid. Mechanism of action in RA: Inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine, or the inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells. 27 | Drug Literacy Program | I. Baltcheva | 11.02.2013 | SLE & RA | Business Use Only Methotrexate (green) complexed into the active site of dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis (blue).

Cyclosporine Overview Is an immunosuppressant drug widely used in organ transplantation to prevent rejection. Reduces the activity of T cells. Mechanism of action: Binds to the cytosolic protein cyclophilin of lymphocytes. This complex of ciclosporin and cyclophilin inhibits calcineurin, which, under normal circumstances, is responsible for activating the transcription of interleukin 2. 28 | Drug Literacy Program | I. Baltcheva | 11.02.2013 | SLE & RA | Business Use Only IL-2 production & proliferation

M&S Drug Literacy Program RA – Treatments

Tumor necrosis factor-alpha (TNFα) Tumor necrosis factor-alpha (TNFα) is a cytokine produced by lymphocytes and macrophages Has various functions: It can cause cytolysis of certain tumor cell lines; it is a potent pyrogen, causing fever by direct action or by stimulation of interleukin-1 secretion; TNFα mediates the immune response by increasing the transport of white blood cells to sites of inflammation, and through additional molecular mechanisms which initiate and amplify inflammation. 39 | Drug Literacy Program | I. Baltcheva | 11.02.2013 | SLE & RA | Business Use Only

Rituximab (RTX): mechanism of action Rituximab is a monoclonal antibody (mAb) that binds to CD20, a surface receptor expressed on B cells. The resulting effect of RTX binding is death of B cells. The death can occur through 4 different mechanisms. Approved for the treatment of Non-Hodgkin’s lymphoma, rheumatoid arthritis (RA) and chronic lymphocytic leukemia (CLL) | IB | Estimating B-cell turnover parameters | Business Use Only 41

M&S Drug Literacy Program Auto-immune diseases: summary and conclusions

Common therapies (approved or tested) to both SLE and RA Corticosteroids – anti-inflammatory Hydroxychloroquine – blocks activation of TLR on dendritic cells Abatacept (approved for RA, not for SLE) – Costimulation blocker Rituximab (approved for RA, not for SLE) – B cell depletor Belimumab (approved for SLE, not for RA) – anti-BLyS (= anti-BAFF) 44 | Drug Literacy Program | I. Baltcheva | 11.02.2013 | SLE & RA | Business Use Only Abatacept Rituximab Belimumab IL-2 Cyclosporin Epratuzumab Hydroxychloroquine Corticosteroids

Treating auto-immune diseases Single-minded message 45 | Drug Literacy Program | I. Baltcheva | 11.02.2013 | SLE & RA | Business Use Only It’s complicated... Pathophysiology not fully understood. Several immune pathways, redundancy? Heterogeneous: patient sub-populations.

M&S Drug Literacy Program Appendix

References and sources Systemic lupus erythematosus: an update on current pharmacotherapy and future directions, Zahi Touma, Murray B Urowitz & Dafna D Gladma, 2013 Comparative Effectiveness of Current Treatments for Rheumatoid Arthritis, Allan Gibofsky, The American Journal of Managed Care, Vol.18, no.13, 2012. The Pathogenesis of Rheumatoid Arthritis, Iain B. McInnes, Georg Schett, N Engl J Med, December 8, 2011 Systemic Lupus Erythematosus, Anisur Rahman, and David A. Isenberg, N Engl J Med, February 28, 2008 Systemic Lupus Erythematosus: Pathogenesis and Clinical Features, George Bertsias, Ricard Cervera, Dimitrios T Boumpas, 2012 Biologics in the treatment of systemic lupus erythematosus, Aisha Lateefa,b and Michelle Petri, Current Opinion in Rheumatology, 2010, 22:504–509 Wikipedia 47 | Drug Literacy Program | I. Baltcheva | 11.02.2013 | SLE & RA | Business Use Only