rheumatoid arthritis

BIOTECHNOLOGICAL EVOLUTION OF ANTI-RHEUMATIC DRUGS

RHEUMATOID ARTHRITIS

Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology marked by a symmetric, peripheral polyarthritis. It is the most common form of chronic inflammatory arthritis and often results in joint damage and physical disability. Because it is a systemic disease, RA may result in a variety of extra-articular manifestations, including fatigue, subcutaneous nodules, lung involvement, pericarditis, peripheral neuropathy, vasculitis, and hematologic abnormalities.

The natural history of RA is complex and affected by a number of factors including age of onset, gender, genotype, phenotype and comorbid conditions, which make for a truly heterogeneous disease.

Frequently RA onset is insidious.

Common RA clinical manifestations are: pain, stiffness and swelling of the peripheral joints.

The classic clinical picture is characterized by symmetric polyarthritis interesting both hands with morning stiffness (lasting more than 1 hour).

Constitutional symptoms such as fatigue, malaise, morning stiffness are common

RHEUMATOID ARTHRITIS

AGE and SEX in AR

• Arthritis involving three or more joints.• Symmetrical arthritis involving hands, feet

or both• Morning stiffness (>1 h)• Fatigue• Dolor, tumor, calor, functio laesa.• Rheumatoid nodules (late manifestation)• ESR and CRP• RF and ACPA

CLINICAL MANIFESTATIONS

AR DIAGNOSIS (ACR/EULAR 2010)

Arthr Rheum 2010AR is diagnosed if score ≥6

Artrite con tumefazione fusiforme delle articolazioni interfalange prossimali (IFP) tipica nell’artrite

reumatoide

EARLY RA

Tumefazione e sublussazioni volari delle articolazioni metacarpofalangee

CHRONIC RA

CHRONIC RA

Deviazione ulnare e sublussazione delle articolazioni metacarpofalangee con tumefazione, noduli

reumatoidi. Spesso concomita atrofia muscolare della muscolatura

dorsale.

CHRONIC RA

NSAID

Systemic or local steroids (Prednisone)

Methotrexate

Sulfasalazine

Hydroxychloroquine

Leflunomide

Infliximab

Etanercept

Adalimumab

Rituximab / Abatacept

DMARDs

Anti TNFa

No longer used DMARDs• cyclophosphamide• penicillamin• tacrolimus• azathioprine• cyclosporine• gold salts

II line

BIOLOGIC DRUGS

DRUGS

DMARDs (conventional)

• Disease Modifying Anti-Rheumatic Drugs• They need months to achieve the full effect• Start treatment with NSAID or prednisone• DMARDs can be used in association (eg.,

MTX + HCLQ)• MTX is the first choice

Cartilage loss

IL-6

B cell

T cell

Macrophage

Dendritic cell

IL-10TNF-

TNF-IL-10

RF

Fix complement

Inflamed synovia

Inflammatory damage

TNF-

B cell

IL-6

B cell

Plasma cell

RFRF

RF

RF

IL-1

CYTOKINES IN RACytokines favours the interactions among macrophages, T cells, B cells, and nonhematopoietic cells (fibroblasts, connective tissue cells, and bone). Thus they are involved in the pathogenesis of RA and are potential therapeutic targets.

Brennan FM, McInnes IB. Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest. 2008 Nov;118(11):3537-45.

Biologic DMARDs

• Etanercept, Infliximab, Adalimumab (TNF)

• Anakinra (IL-1)

• Tocilizumab (IL-6)

• Abatacept (CTLA4)

• Rituximab (CD20)

Cytokines in RA

ANAKINRA

• IL-1 receptor antagonist• = Kineret 100 mg• 1 injection SC qd

ABATACEPT

• Fusion protein composed of the CTLA4 (Cytotoxic T-Lymphocyte Ag 4) extracellular domain fused to the Fc region of a human IgG1

• In order to be activated and produce an immune response, T cells need two different signals, both activated by antigen presenting cell s. One of those signals is the major histocompatibility complex (MHC), combined with the antigen, and the other signal is the CD80 or CD86 molecule.

• Abatacept binds to the CD80 and CD86 molecule, and prevents the second signal. Without the second signal, the T cell can't be activated.

• Abatacept was developed by Bristol-Myers Squibb and is licensed for the treatment of rheumatoid arthritis in the case of inadequate response to anti-TNFa therapy.

• Inhibits T-cells co-stimulation• = Orencia f 250 mg• 10 mg/kg• 2-4 vials (<60; 60-100; >100 kg) every 4 weeks

ABATACEPT

RITUXIMAB

• Chimeric monoclonal antibody (mouse/human) targeted against the pan-B-cell marker CD20,

• = Mabthera fl 500 mg IV• 1000 mg (2 vials) EV, followed by a second

infusion 2 weeks after• Causes a sustained depletion of B cells

Anti-TNFa DRUGS (1)

Elevated TNFα levels have been found in involved tissues/fluids of patients with RA, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn disease and ulcerative colitis. Elevated TNF levels in the synovial fluid are involved in the pathologic pain and joint destruction in immune-mediated arthritis. Biological activities of TNFα include the induction of proinflammatory cytokines (interleukins), enhancement of leukocyte migration, activation of neutrophils and eosinophils, and the induction of acute phase reactants and tissue degrading enzymes. Animal models have shown TNFα expression causes polyarthritis, and anti-TNFα drugs can prevent disease as well as allow diseased joints to heal.

Anti TNFa drugs are approved as second line agents for the treatment of AR refractory to Methotrexate and other conventional DMARDs.

Anti-TNF a DRUGS (2)

Infliximab (Remicade)Infliximab is a chimeric monoclonal antibody that binds to human tumor necrosis factor alpha (TNFα), thereby interfering with endogenous TNFα activity.

Adalimumab (Humira)Adalimumab is a recombinant monoclonal antibody that binds to human tumor necrosis factor alpha (TNFa), thereby interfering with binding to TNFα receptor sites and subsequent cytokine-driven inflammatory processes. Adalimumab decreases signs and symptoms of psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis. It inhibits progression of structural damage of rheumatoid and psoriatic arthritis. Reduces signs and symptoms and maintains clinical remission in Crohn disease and ulcerative colitis; reduces epidermal thickness and inflammatory cell infiltration in plaque psoriasis.

Etanercept is a recombinant DNA-derived protein composed of tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1Etanercept binds tumor necrosis factor (TNF) and blocks its interaction with cell surface receptors.

Etanercept (Enbrel)


Certolizumab pegol (Cimzia)

Certolizumab pegol is a pegylated humanized antibody Fab’ fragment of tumor necrosis factor alpha (TNFa) monoclonal antibody. Certolizumab pegol binds to and selectively neutralizes human TNFa activity. (Elevated levels of TNFa have a role in the inflammatory process associated with Crohn disease and in joint destruction associated with rheumatoid arthritis.) Since it is not a complete antibody (lacks Fc region), it does not induce complement activation, antibody-dependent cell-mediated cytotoxicity, or apoptosis. Pegylation of certolizumab allows for delayed elimination and therefore an extended half-life.

Adverse events and warnings• BK reactivation (pre-treatment screening required)• HBV reactivation (prophilaxis with lamivudine)• Increased risk of infection• Risk of anaphylaxis (Infliximab)• Exacerbation of demyelinating events (CNS)• Worsening of heart failure (NIHA III-IV)• Discontinuation of therapy during pregnancy or before surgery


Structural differences of TNFα inhibitors

IMMUNE COMPLEXES FORMATION

Bivalence of Adalimumab and Infliximab causes the formation of immune complexes of TNF with a molecular weight ranging between 600 and 5000 kD. This phenomenon is potentially responsible for the lysis of macrophages and T lymphocytes; it does not occur with Etanercept and Certolizumab. Both these drugs, infact, bind only one TNFa molecule, avoiding the formation of bridges.

INTERLEUKIN 6

• Interleukin 6 (IL-6) is a pleiotropic, pro-inflammatory cytokine • IL-6 is implicated in the pathogenesis of a variety of disease

states including inflammatory rheumatic diseases• Elevated serum IL-6 levels are seen in RA and correlate with

disease activity• Inhibition of IL-6 and/or its receptor represents a novel

approach for treatment of inflammatory diseases such as RA

Abbreviations used: α2M, α2-macroglobulin; CBM, cytokine-binding module; CIS, cytokine-inducible SH2 protein; CLC, cardiotrophin-like cytokine; CLF, cytokine-like factor; ERK, extracellular-regulated kinase; EZI, endothelial cell-derived zinc-finger protein; Fab, fragment antigen binding; FERM, four-point-one, ezrin, radixin, moesin; FKHR, forkheadrelated transcription factor; FN, fibronectin; Gab, Grb-associated binder; gp, glycoprotein; Grb, growth-factor-receptor-bound protein; Hck, haematopoietic cell kinase; IFN, interferon; IL, interleukin; IRS, insulin receptor substrate; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; KIR, kinase inhibitory region; KSHV, Kaposi’s sarcoma-associated herpes virus; MAPK, mitogen-activated protein kinase; MK2, MAPK-activated protein kinase 2; NES, nuclear export signal; NF-κB, nuclear factor κB; NLS, nuclear localization signal; Nmi, N-Myc-interactor; p, phospho-;; PH, pleckstrin homology; PKC, protein kinase C; PI3K, phosphoinositide 3-kinase; PIAS, protein inhibitor of activated STAT; PRMT, protein arginine methyltransferase; PTP, protein tyrosine phosphatase; R, receptor; s, soluble; SH2, Src homology 2; SHC, SH2 and collagen homology domain containing protein; SHP, SH2-domain-containing tyrosine phosphatase; SMRT, silencing mediator of retinoic and thyroid hormone receptors; SOCS, suppressor of cytokine signalling; SOS, Son of Sevenless; SSI, STAT-induced STAT inhibitor; STAT, signal transducer and activator of transcription; TNF, tumour necrosis factor.

Roche Medical Affairs. All rights reserved.

TOCILIZUMAB

Humanized monoclonal antibodyBinds to membrane-bound

and soluble forms of IL-6RBlocks IL-6 binding to

its receptorBlocks IL-6R signaling

Tocilizumab

CDR


Antagonist of the interleukin-6 (IL-6) receptorEndogenous IL-6 is induced by inflammatory stimuli and mediates a variety of immunological responsesInhibition of IL-6 receptors by tocilizumab leads to a reduction in cytokine and acute phase reactant productionTocilizumab is approved for the treatment of RA refractory to conventional DMARDs or anti TNF a drugsTocilizumab is generally used in association with MetothrexateDoses: 8 mg/kg of body weight, (not less than 480 mg) every 4 weeks

FEATURES AND INDICATIONS


gp130gp130

Tocilizumab binds mIL-6R and sIL-6R

IL-6 cannot bind

Membrane-bound signaling Trans-signaling

mIL-6R

sIL-6R

Tocilizumab Inhibits IL-6R Membrane-bound Signaling and Trans-signaling

Adapted from: Jones SA, et al. J Interferon Cytokine Res. 2005;25:241-253. Scheller J, Rose-John S. Med Microbiol Immunol. 2006;195(4):173-183. Mihara M. Int Immunopharmacol. 2005 Nov;5(12):1731-40.

P-MOA-ND-004


Tocilizumab: the largest clinical development programme in RA

1.Source: Data on file, F. Hoffmann-La Roche (Tocilizumab)2. www.emea.europa.eu/htms/human/epar/a.htm.

Prior to license:• > 4,400 RA patients treated

with Tocilizumab, with > 6,000 patient-years of exposure

• Consisted of two Phase II, five Phase III and two open-label extension studies, conducted in 39 countries, with a balanced geographical distribution

• Key biological and clinical aspects characterised in a broad range of RA patient populations

Patients enrolled in clinical studies for first biologic licence application

Tocilizumab1 Remicade2Humira2 Enbrel2 Orencia2

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CIA (collagen-induced arthritis)

1. Strain: DBA/1 male mice are the il gold standard for CIA model. Mice should be young (less than 4 months) to avoid the risk of spontaneous arthritis.

2. Materials: Type II collagen (2 mg/ml)Freund adjuvant containing M. tubercolosis (4 mg/ml)Normal saline solution (for controls)

CollagenFreund

adjuvant

Collagene e adiuvante vengono emulsionati in rapporto 1:1 a 4°CThe emulsion is loaded in 0.5 mL syringes and

it’s injected in the tail vein (50 l/mouse)

• Injection in the tail vein at 1.5 cm from the root of the tail

• Second injection (optional) 14-21 days after the first immunization to increase incidence

• Arthritis onset in 5-8 weeks after the first immunization

• Clinical evaluation 2-3 times a week starting from the third week after the first immunization

• Incidence of arthritis between 80-100%

METHODS

EVALUATION CRITERIA

Severity score

Degree of inflammation

0 No evidence of erythema and swelling

1 Erythema and mild swelling confined to the tarsals or ankle joint

2 Erythema and mild swelling extending from the ankle to the tarsals

3Erythema and moderate swelling extending from the ankle to metatarsal joints

4Erythema and severe swelling encompass the ankle, foot and digits or ankylosis of the limb

(a) A normal rear mouse paw and (b) an acute arthritic rear mouse paw

Lamoureux et al. Arthritis Research & Therapy 2006 8:R134

After the onset of the ARTHRITIS, the mice are sacrificed and paws are removed. The samples are then formalin-fixed and paraffin-embedded. Due to the presence of bone tissue, decalcification in hydrochloric acid is required before the inclusion.The preparation is subsequently cut with microtome and stained with hematoxylin-eosin.

HYSTOLOGICAL EVALUATION

(a) Normal proximal interphalangeal joint. (b) Inflammation and joint erosion in DBA/1 mouse 10 days after onset of arthritis. Haematoxylin and eosin.Autoimmune Disease: Animal Models. Richard Williams, Imperial College London, London, UK. Published online: October 2010

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