Immune modulation in rheumatology. Geoff McColl University of Melbourne/Australian Rheumatology Association

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1 Immune modulation in rheumatology Geoff McColl University of Melbourne/Australian Rheumatology Association

2 A traditional start to a presentation on biological agents in rheumatic disease is

3 Plasma cell RF IL-4 IL-6 IL-10 IL-4 IL-10 Th0 Th2 Macrophage IFN-γ IL-12 Interferon-γ B cell CD4 + T cell Synovium To OPGL hard CD11 TNF-α IL-1 IL-6 Osteoclast Fibroblast Chondrocyte Production of metalloproteinases and other effector molecules Migration of polymorphonuclear cells Erosion of bone and cartilage

4 OR

5 To hard

6 What do you need to know about biological agents in rheumatic disease? They are, in general, highly effective They are surprisingly well tolerated but are potentially highly toxic They are VERY expensive (>$20K/year)

7 To set the scene of RA management in 2007

8 RA Progression Severity (Arbitrary Units) Early RA Intermediate Late Inflammation Disability Radiographs Duration of Disease (years) Graph: Adapted from: Kirwan JR. J Rheumatol. 2001;28: Photo: Copyright American College of Rheumatology.

9 Early Aggressive Treatment of RA Successful treatment to limit joint damage and functional loss requires early diagnosis and timely initiation of disease modifying agent. The goal of treatment is to arrest the disease and achieve remission. 1 Disease onset American College of Rheumatology (ACR) Ad Hoc Committee on Clinical Guidelines Early Established End Stage Critical window of opportunity 70% of patients have radiographic damage within the 1 st 3 years of disease onset 2 1. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002;46: van der Heijde DM. Br J Rheumatol. 1995;10:

10 The Goals of RA Management The ultimate goals in managing RA in 2007 are to Prevent or control joint damage Prevent loss of function Eliminate pain/swelling Arrest disease progression with a goal of complete remission Maximize the quality of life for your patient American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002;46:

11 Single-drug therapy Evolution of Management Approaches in RA Treatment pyramid Biologic therapy Combination therapy Early intervention Aggressive therapy Pyramid inversion Courtesy Roy Fleischmann MD

12 R H E U M A T O L O G I S T P C P Establish diagnosis of RA early Arrange for DMARD therapy Periodically assess disease activity ACR Treatment Algorithm Adequate response Inadequate response MTX naïve MTX Other Combination monotherapy Change/add DMARDs Suboptimal MTX response Combination Other monotherapy Biologics Monotherapy Combination Multiple DMARD failure Adapted from: American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002;46: Symptomatic and/or structural joint damage

13 What are the current biological targets in rheumatic disease Tumour necrosis factor (TNF inhibitors) Interleukin 1 (IL-1RA) T-cell co-stimulation (CTLA4-Ig) B cells (anti-cd20, rituximab) Others

14 Disequilibrium of Cytokines in Joints of Patients with Rheumatoid Arthritis Pro-inflammatory Feldman M, et al. Rheum Arthritis. 1996;85:

15 TNF inhibitors Current agents Etanercept (Enbrel ) Adalimumab (Humira ) Infliximab (Remicade ) What we need to know about the TNF inhibitors Efficacy Toxicity Current place in RA therapy

16 Efficacy

17 TEMPO etanercept (S/C)

18 ARMADA adalimumab (S/C)

19 ATTRACT infliximab (IV)

20 Other rheumatic disease in which TNF inhibitors are effective Juvenile idiopathic arthritis Psoriatic arthritis Ankylosing spondylitis Behçet syndrome

21 Efficacy - conclusions All TNF inhibitors are effective All TNF inhibitors are more effective when combined with methotrexate Choice of TNF inhibitor is probably more informed by route of delivery than relative efficacy

22 Toxicity

23 Malignancies Bongartz et al JAMA, 2006

24 Specifically The risk of lymphoma is probably increased in RA patients treated with TNF inhibitors Whether the risk of solid malignancies is increased is unclear Current recommendations suggest that TNF inhibitors should not be used in patients with a current or recent history of malignancy

25 Infection Bongartz et al JAMA, 2006

26 Specifically The risk of reactivating latent TB is increased (often extra-pulmonary) when using TNF inhibitors and therefore (it is recommended that) all patients are screened using history, chest X-rays and Mantoux test Those patients with evidence of previous TB should be pre-treated with an anti-tb agent prior to commencing therapy

27 Other infectious issues The effect of TNF inhibitors on Hepatitis B and C is unknown and therefore their use in patients with these conditions is not recommended In the presence of any infection TNF inhibitors should be stopped and only recommenced when infection is controlled

28 Injection site/infusion reactions Adalimumab and etanercept injections may cause injection site reactions if severe these may respond to antihistamines or cessation of the drug Infliximab may cause infusion reactions and if severe these may require cessation or (acutely) antihistamines, cortisone or adrenalin

29 Cardiovascular disease Infliximab 10mg/kg has been associated with an increased risk of congestive heart failure Lower dose infliximab and standard dose etanercept and adalimumab have not been associated with worsening CHF The risk is unknown and therefore these agents need to be used with caution in patients with CHF

30 Pregnancy TNF inhibitor use is not recommended in pregnancy and if a patient falls pregnant whilst using them they should be stopped A study ascertained 185 RA patients who had fallen pregnancy while on TNF inhibitors and the pregnancy outcomes were (quite surprisingly) not different to normal

31 Other potential toxicity Neurological Demyelinating syndromes have been reported with TNF inhibitors (etanercept more than the others) Most resolve with discontinuation of the drug Auto-immune syndromes Infliximab increases the prevalence of raised titres of ANAs and dsdna antibodies Clinical correlates to these antibodies are rare

32 Other toxicity The TNF inhibitors are powerful new agents and therefore any unusual problem in a patient using them should be considered as a side effect and reported Ideally, all patients using TNF inhibitors should be enrolled in a registry (in Australia the Australian Rheumatoid Association Database ARAD)

33 Other biologic agents IL-1RA (anakinra) Modestly effective agent in RA Abatacept (CTLA4-Ig) Highly effective agent in RA and other indications Rituximab (anti-cd20 antibody) Effective therapy in RA, SLE and other indications

34 Regulatory environment in Australia Three TNF inhibitors are subsidised on the pharmaceutical benefits scheme (PBS) for the treatment of RA, PsA, JIA and AS Anakinra is subsidised for RA and JIA only Rituximab will be subsidised for RA shortly

35 PBS criteria These agents are expensive but their listing on the PBS recognises they are cost effective in the listed indications They must be prescribed by a rheumatologist or immunologist and there are strict criteria to be met for each indication in a written submission

36 Current place of TNF inhibitors for RA The TNF inhibitors (as per the ACR guidelines shown earlier) are used when appropriate mono- and combinationtherapy have failed to improve the patient using objective criteria (swollen joint count and raised ESR or CRP) To continue a TNF inhibitor patients must demonstrate response (using the same criteria) after 3 months and then 6 monthly thereafter

37 Horizon scanning New agents (many all expensive) Use of current biologic agents early Increased toxicity vigilance is required Better outcomes for patients with RA

38 Thank you Questions?