Biologic Therapy


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  • TNF Antagonists: Other Indications and Clinical Investigations There are a wide range of proven and potential clinical applications for TNF antagonists. Clinical trial results have confirmed the effectiveness of these preparations in Crohn's disease, psoriatic arthritis, psoriasis, ankylosing spondylitis, reactive arthritis, juvenile RA, and adult Still’s disease. TNF antagonists are currently being evaluated as treatment for vasculitis (eg, Wegener's disease, giant cell arteritis [GCA]), scleroderma, graft-versus-host disease, inflammatory myositis, interstitial lung disease, Sjogren’s syndrome, inflammatory eye and ear disease, asthma, hepatitis, sarcoidosis, Behcet's disease, and pyoderma gangrenosum.  
  • Cytokine Signaling Pathways Involved in RA CD4+ T cells might initiate the disease process in RA. Activated by antigens, these cells stimulate monocytes, synovial fibroblasts, and macrophages to produce the key proinflammatory cytokines TNF-  , IL-1, and IL-6 as well as to release matrix metalloproteinases (MMPs), enzymes that degrade connective tissue matrix. 1 TNF-  and IL-1 also inhibit synovial fibroblasts from producing tissue inhibitors of MMPs. 2 These two actions by TNF-  and IL-1, among others, are believed to result in the joint damage that occurs in RA. 1 Activated CD4+ T cells also contribute to joint damage by stimulating the development of osteoclasts by expressing osteoprotegerin ligands (OPGLs) and by stimulating B cells to produce immunoglobulins such as rheumatoid factor. 1 Activated macrophages, lymphocytes, and fibroblasts and their products can stimulate angiogenesis, a fact that may account for the increased vascularity of the synovium in rheumatoid joints. 1 Other cytokines involved in the complex cellular interactions that occur as part of the inflammatory process include IL-4, IL-10, IL-12, and IFN-  . In addition, CD11 and CD69 cells are involved in the cell-surface signaling that leads to the production of cytokines. 1 Choy EHS, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med . 2001;344:907-916. Shingu M, Nagai Y, Isayama T, Naono T, Nobunaga M, Nagai Y. The effects of cytokines on metalloproteinase inhibitors (TIMP) and collagenase production by human chondrocytes and TIMP production by synovial cells and endothelial cells. Clin Exp Immunol . 1993;94:145-149.
  • Biologic DMARDs There are substantial differences in pharmacokinetic properties among the biologic DMARDs being developed for the treatment of patients with RA. Etanercept is a soluble receptor formed from the fusion of two p75 TNF receptors to human immunoglobulin (IgG). Etanercept binds to TNF-  and lymphotoxin (LT)-  with an affinity of 10 10 M -1 . Because it has a half-life of 4.3 days, it is administered subcutaneously twice weekly (at a dose of 25 mg). 1 Infliximab is a chimeric TNF-  monoclonal antibody (mAb) comprising about 75% human and 25% mouse protein. Infliximab binds to TNF-  with an affinity of 1.8 x 10 9 M -1 . It has a half-life of 8 to 10 days and is administered intravenously in combination with MTX every 4 to 8 weeks (at a dose of 3 to 10 mg/kg). 2 Anakinra is a recombinant IL-1 receptor antagonist construct that binds to type I IL-1R with an affinity of 7.5 x 10 11 M -1 . Anakinra has a half-life of 4 to 6 hours and is administered subcutaneously once daily (at a dose of 100 mg). 3 Adalimumab is a fully human TNF-  mAb that binds to TNF-  with an affinity of 2.3 x 10 10 M -1 . Adalimumab has a half-life of approximately 2 weeks and is administered subcutaneously once every other week; the proposed dose is 40 mg eow. 4 Etanercept, infliximab, and adalimumab are produced in Chinese hamster ovary cells; anakinra is produced in an Escherichia coli expression system.   1. Enbrel ® (etanercept) [package insert]. Seattle, Wash: Immunex Corporation; 2002. 2. Remicade ® (infliximab) [package insert]. Malvern, Pa: Centocor, Inc; 2002. 3. Kineret ™ (anakinra) [package insert]. Thousand Oaks, Calif: Amgen Inc; 2002. 4. Salfeld J, Kaymakçalan Z, Tracey D. Generation of fully human anti-TNF antibody D2E7. Arthritis Rheum . 1998;41(suppl):S57. Abstract.
  • Inhibition of Cytokines Cytokines exert their damaging effects by binding to specific receptors, and there are several potential approaches that can be employed to block these effects. Cytokines can be neutralized through the use of antibodies or soluble receptors. With this approach, the cytokine never reaches the receptor on the cell of interest. This avenue for the treatment of RA has been taken with soluble TNF-  receptor fusion proteins, soluble IL receptors, monoclonal antibodies against TNF-  , and monoclonal antibodies against IL-6. Receptor antagonists or antibodies can bind to cytokine receptors on cells and prevent cytokines from binding. This blocks their actions on the cell in question. This approach to the treatment of RA has been taken with recombinant IL-1Ra and an antibody against the IL-6 receptor. Administration of anti-inflammatory cytokines can inhibit expression of inflammatory cytokines. This approach has been taken with IL-4 and IL-10.   Choy EHS, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med . 2001;344:907-916.
  • This slide demonstrates the effect of 3 infusions infliximab on the synovium evaluated between baseline on the left and at 12 weeks on the right Panels ab synovial lining hyperplasia cd vascularity ef neutrophil infiltration gh plasma cell infiltration
  • Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med. 2003;348:601-608. Abstract: BACKGROUND: Treatment with infliximab, a chimeric monoclonal IgG1 antibody against tumor necrosis factor, can result in the formation of antibodies against infliximab. We evaluated the clinical significance of these antibodies in patients with Crohn's disease. METHODS: In a cohort of 125 consecutive patients with Crohn's disease who were treated with infliximab infusions, we evaluated the concentrations of infliximab and of antibodies against infliximab, clinical data, side effects (including infusion reactions), and the use of concomitant medications before and 4, 8, and 12 weeks after each infusion. RESULTS: A mean of 3.9 infusions (range, 1 to 17) per patient were administered over a mean period of 10 months. Antibodies against infliximab were detected in 61 percent of patients. The presence of concentrations of 8.0 microg per milliliter or greater before an infusion predicted a shorter duration of response (35 days, as compared with 71 days among patients with concentrations of less than 8.0 microg per milliliter; P<0.001) and a higher risk of infusion reactions (relative risk, 2.40; 95 percent confidence interval, 1.65 to 3.66; P<0.001). Infliximab concentrations were significantly lower at four weeks among patients who had had an infusion reaction than among patients who had never had an infusion reaction (median, 1.2 vs. 14.1 microg per milliliter; P<0.001). Patients who had infusion reactions had a median duration of clinical response of 38.5 days, as compared with 65 days among patients who did not have an infusion reaction (P<0.001). Concomitant immunosuppressive therapy was predictive of low titers of antibodies against infliximab (P<0.001) and high concentrations of infliximab four weeks after an infusion (P<0.001). CONCLUSIONS: The development of antibodies against infliximab is associated with an increased risk of infusion reactions and a reduced duration of response to treatment. Concomitant immunosuppressive therapy reduces the magnitude of the immunogenic response
  • Biologic Therapy

    1. 1. The Biologic therapies Dr. R MUSA SPR rheumatology
    2. 2. TNF Antagonists : licensed indications and future use <ul><li>Confirmed in Trials </li></ul><ul><li>Crohn’s disease </li></ul><ul><li>Rheumatoid arthritis </li></ul><ul><li>Spondyloarthropathies </li></ul><ul><ul><li>Psoriatic arthritis </li></ul></ul><ul><ul><li>Psoriasis </li></ul></ul><ul><ul><li>Ankylosing spondylitis </li></ul></ul><ul><ul><li>Reactive arthritis </li></ul></ul><ul><li>Juvenile RA </li></ul><ul><li>Adult Still’s disease </li></ul><ul><li>Under Investigation </li></ul><ul><li>Vasculitis: Wegener’s disease, giant cell arteritis </li></ul><ul><li>Scleroderma </li></ul><ul><li>Graft-versus-host disease </li></ul><ul><li>Inflammatory myositis </li></ul><ul><li>Interstitial lung disease </li></ul><ul><li>Sjogren’s syndrome </li></ul><ul><li>Inflammatory eye and ear disease </li></ul><ul><li>Asthma </li></ul><ul><li>Hepatitis </li></ul><ul><li>Sarcoidosis </li></ul><ul><li>Behcet’s disease </li></ul><ul><li>Pyoderma gangrenosum </li></ul>Cush J. Rheumatology . 2003. In press.
    3. 3. Cytokine Signaling Pathways & TNF  Adapted from Choy EHS, Panayi GS. N Engl J Med . 2001;344:907-916. Copyright © 2001 Massachusetts Medical Society. All rights reserved. TNF secreted by macrophage TNF-  IL-1 IL-6 IFN-  IL-12 IL-4 IL-10 Macrophage RF IL-4 IL-6 IL-10 Plasma cell B cell Interferon-  Th0 Th2 Synovium OPGL CD4 + T cell CD69 CD11 CD11 CD69 Osteoclast Fibroblast Chondrocyte Production of metalloproteinases and other effector molecules Migration of polymorphonuclear cells Erosion of bone and cartilage
    4. 4. Biologic therapy Anakinra Infliximab Etanercept Adalimumab Human Chimeric Human Recombinant construct Type I IL-1R TNF-  TNF-  Primary binding target 4–6 hours 8–10 days 4.3 days Half-life Human TNF-  10–1 3.6 days IL-1Ra TNF-  mAb sTNFR construct Class TNF-  mAb 100 mg/d sc 3–10 mg/kg 4–8 wk iv + MTX 25 mg sc 2x/wk Administration 40 mg sc eow
    5. 5. Inhibition of Cytokines Adapted with permission from Choy EHS, Panayi GS. N Engl J Med . 2001;344:907-916. Copyright © 2001 Massachusetts Medical Society. All rights reserved. Inflammatory cytokine Normal interaction Neutralization of cytokines Receptor blockade Activation of anti-inflammatory pathways Cytokine receptor Soluble receptor Monoclonal antibody Monoclonal antibody Receptor antagonist Anti-inflammatory cytokine Suppression of inflammatory cytokines No signal No signal Inflammatory signals
    7. 7. Baseline 2 weeks One year SACROILIAC JOINT INFLAMMATION
    8. 8. Baeten et al Arthritis Rheum 2001 the effect of 3 infusions infliximab on the synovium evaluated between baseline on the left and at 12 weeks on the right
    10. 10. TB and Anti-TNF Recommendations <ul><li>Purified protein derivative (PPD) and chest x-ray (CXR) in all patients on biologics </li></ul><ul><li>PPD 0.1 mL is neither 100% sensitive or 100% specific, because there are as many as 25% false negatives </li></ul><ul><li>Sensitivity varies with cutoff 5 vs 10 vs 15 </li></ul><ul><li>Low cutoff for those at high risk </li></ul><ul><li>Treatment with isoniazid (INH) for 9 months for all PPD > 5 mm </li></ul><ul><li>Delay anti-TNF therapy if possible, avoid infliximab </li></ul>
    11. 11. Antibody Formation With TNF Inhibitors <ul><li>Monoclonal antibodies appear to form neutralizing antibodies in a portion of the population, regardless of whether they are human- or mouse-based </li></ul><ul><li>This may affect long-term efficacy </li></ul>5% neutralizing (Range 1% on MTX; 12% on monotherapy) 10% (HACA) < 5% (non-neutralizing) Adalimumab Infliximab Etanercept
    12. 12. Infliximab in Crohn’s Disease Influence of Immunogenicity on Duration of Clinical Response (N=125) Baert F, et al. N Engl J Med. 2003;348:601-608. 65 38.5 0 10 20 30 40 50 60 70 Days of Clinical Response Patients With Infusion Reactions* Patients Without Infusion Reactions *Infliximab antibodies detected (61%); cumulative incidence of infusion rxs (27%). P <0.001
    13. 13. The incidence of lymphomas is increased in RA, but. The apparent increase in lymphomas in patients treated with TNF inhibitors may be due to confounding by indication — that is, that patients with severe disease who are (historically) most likely to develop lymphomas are also the ones most likely to receive TNF inhibitors. TNF-alpha plays an important role in tumor surveillance, particularly lymphoma. Because of this, Using TNF-alpha blocking agents in the treatment of rheumatoid arthritis (RA) may increase the risk of developing malignancies. Clinical trials of TNF inhibitors have not identified an increase in tumor (including lymphoma) risk, but are limited by short observation intervals and small cohorts. Here, Geborek et al Bladstrom, Jacobsson 2003 Lymphoma With TNF Antagonists
    14. 14. Lymphoma With TNF Antagonists 5.4 (2.6 – 10.0) 6.4 (1.7 – 16.3) 2.31  3.47 (1.59 – 6.59) SIR Lymphoma (95% conf interval) 18 mo (2.0 – 42.0) 10-19 mo (6.4) 21 mo (0.1 – 4.6) Mean Time to Onset (range) 1/9 1/3 3/6 Hodgkin's/ Non-Hodgkin's † 10 4 6  9 Total No. 2468 (4870) 1298 (2458) 3389 (8336) Treated/Exposure Pt-No. Pt-Yr Adalimumab Infliximab Etanercept † Majority diffuse large B cell SIR=standardized incidence ratio
    15. 15. Spondyloarthropathy family of disorders Inflammatory condition primarily affecting the spine which have in common the presence of sacroilitis, the presence of the HLA B27 gene and characteristic extra-articular manifestation. example: Ankylosing spondylitis Psoriatic arthritis Reactive arthritis Reiter syndrome Enteropathic arthritis (IBD associated arthritis) Undifferentiated Spondyloarthropathy
    16. 16. Ankylosing Spondylitis <ul><li>Common inflammatory disease of the spine </li></ul><ul><li>Spinal deformity and disability </li></ul><ul><li>Progressive with symptoms beginning in the 2 nd or 3 rd and continuing into the 5 th and 6 th decade </li></ul><ul><li>Prior to the advent of biologics no effective treatments </li></ul>
    17. 17. Extra-axial features of AS <ul><ul><li>Peripheral joints (30% of patients) </li></ul></ul><ul><ul><li>Enthesopathy (up to 98%) </li></ul></ul><ul><ul><li>enthesitis inflammation at the site of insertion of ligaments and tendons on to bone this often progress to ossification periosteal new bone formation common site involved are Achilles tendon insertion can be quit painful. </li></ul></ul><ul><ul><li>Extra-articular manifestations </li></ul></ul><ul><ul><ul><li>Bowel (60% asymptomatic colitis), UC, Crohn disease </li></ul></ul></ul><ul><ul><ul><li>Cardiac (10%) Aortitis (ascending aorta),AVR, MVR, AV Block </li></ul></ul></ul><ul><ul><ul><li>Renal –Amylodosis, IgA nephropathy </li></ul></ul></ul><ul><ul><ul><li>Lung Apical lung fibrosis(colonize aspergi), limited chest expansion </li></ul></ul></ul><ul><ul><ul><li>Eye uveitis (20 – 30%) higher if HLA27+ 84% </li></ul></ul></ul><ul><ul><ul><li>Fever, weight loss, general fatigue, morning stiffness, improve symptoms with activities </li></ul></ul></ul>
    18. 18. Important diagnostic issues…. <ul><li>Which diagnostic criteria to use? </li></ul><ul><ul><li>modified New York criteria </li></ul></ul><ul><ul><li>vs </li></ul></ul><ul><ul><li>European Spondyloarthropathy Study Group criteria </li></ul></ul><ul><li>Delay in diagnosis AS does not occur after the age of 40’ </li></ul>
    19. 21. Sacroilitis by MRI Normal SI - SE T1 Fused SI - SE T1
    20. 22. Modified new York criteria 1984 (Van der Linden) Radiological criterion sacroilitis, Grade=/>2 bilat / Grade3/4 unilat Clinical criterion (2 out of the following 3) 1-Low back pain and stiffness for >3months improve with exercise but not rest 2-Limitation of motion of lumber spine in both the sagital and frontal planes 3-Limitation of chest expansion relative to normal value for age and sex
    21. 23. Instruments for assessment of AS 1-BASFI=Bath Ankylosing Spondylitis Functional Index <ul><li>Used to evaluate functional ability BASFI is scored as follows: </li></ul><ul><ul><li>8 VAS regarding function scored: </li></ul></ul><ul><ul><li>Easy 0 1 2 3 4 5 6 7 8 9 10 Impossible </li></ul></ul><ul><ul><li>2 questions regarding ability to cope with daily life scored: </li></ul></ul><ul><ul><li>Easy 0 1 2 3 4 5 6 7 8 9 10 Impossible </li></ul></ul>
    22. 24. 2- BASDAI= Bath Ankylosing Spondylitis Disease Activity Index
    23. 25. 3-Global Assessment: PtGA
    24. 26. 4-BASMI:SPINAL MOBILITY <ul><li>Lateral bending </li></ul><ul><li>Intermalleolar distance </li></ul><ul><li>Occiput to wall </li></ul><ul><li>Modified schober index </li></ul>
    25. 27. life impact of AS Suffer pain and disability Socio-economic impact because onset at early age Unemployment (>50%) and high insurance 50% develop hip arthritis at early age and require Hip replacement which more often require reoperation due to heterotopic ossification of the hip prosthesis Mortality higher 1.5 than general population due to Cardiac valvular disease Amyloidosis Osteoporosis occurs early in disease increase fracture Annual health cost of one patient=6720$
    26. 28. Conventional therapy for AS Aim: relieve pain and stiffness Regular physiotherapy Hydrotherapy NSAIDs (improvement within 24 hours if there is failure to response Probability of suffering from AS is as low as 3%) long term use do not alters structural progression of the disease (use mainly as symptomatic relieve of pain and stiffness) Risk of GI upset use Naprxone / Use COX2 inhibitor ?celebrex support in the NASS and OPD rheumatology clinic NOTES:Treatment of peripheral and axial disease are different May be spontaneous remission later in life
    27. 29. Rationale for TNF blockade <ul><li>TNF-  in AS </li></ul><ul><ul><li>Over-expression of TNF  in mouse model produces AS like disease </li></ul></ul><ul><ul><li>Abundant TNF-  mRna in Sacroiliac joint biopsy specimens from inflamed sacroiliac joints </li></ul></ul><ul><li>Good therapeutic effect in other autoimmune disease, IBD, RA </li></ul><ul><ul><li>60% AS patients have sub clinical colitis </li></ul></ul>
    28. 30. Sacroiliac Biopsy In Ankylosing Spondylitis Bollow M, Braun J. Ann Rheum Dis. 2000.
    29. 31. TNF  mRNA In Sacroiliac Biopsy In AS <ul><li>Inflamed sacroiliac joint of a young, female patient with AS </li></ul><ul><li>3 years disease duration </li></ul><ul><li>In situ hybridization </li></ul>Braun J et al. Arthritis Rheum. 1995.
    30. 32. BSR Guideline on Eligability for anti TNF therapy ( the same as ASAS Consensus) AS sessments in AS working group <ul><li>Initiation of therapy </li></ul><ul><ul><li>1-Ankylosing Spondylitis patient satisfies modified New York </li></ul></ul><ul><ul><li>criteria </li></ul></ul><ul><ul><li>2-Failed conventional therapy (2 or > NSAID each taken sequentially at maximum tolerated dose for 4 weeks </li></ul></ul><ul><ul><li>3-Active disease for at least 4 weeks </li></ul></ul><ul><ul><ul><li>BASDAI =/> 4 and </li></ul></ul></ul><ul><ul><ul><li>Physician global (specialist) yes/no </li></ul></ul></ul><ul><ul><li>Refractory disease </li></ul></ul><ul><ul><ul><li>Failed at least 2 NSAIDS at max tolerated doses during 3 month period and I/A steroids/SSZ if indicated </li></ul></ul></ul><ul><li>ASAS workshop, Berlin January 2003 </li></ul>
    31. 33. Contraindication <ul><li>Pregnancy or breast feeding </li></ul><ul><li>Active significant infection </li></ul><ul><li>Septic arthritis of prosthetic joint within last 12/12 or indefinitely if joint remain in site </li></ul><ul><li>Precautions TB and positive PPD test </li></ul><ul><li>Congestive heart failure (NYHA grade ¾) </li></ul><ul><li>Demyelination </li></ul><ul><li>adverse events </li></ul><ul><li>Major: Reactivation of TB, shingle, Sepsis, anaphylactic shock </li></ul><ul><li>Minor: Injection site reactions, infusion reactions, autoantibodies formation and lupus, Abnormal liver function tests </li></ul>
    32. 34. BSR definition of response to treatment (the same as ASAS consensus guidelines) <ul><li>Response </li></ul><ul><ul><ul><li>Time of evaluation at 6-12 weeks </li></ul></ul></ul><ul><ul><ul><li>BASDAI >50% improvement and absolute improvement >2 units and Physician global assessment of response to treatment </li></ul></ul></ul><ul><li>Infusions every 6-8 weeks </li></ul><ul><li>patient pain and patient global assessment, spinal mobility, CRP and BASDAI assessed in follow up on all patients </li></ul>
    33. 35. NASS <ul><li>Welcome to The Norwich Branch of The National Ankylosing Spondylitis Society (NASS). Run by Patients for Patients. We offer Support, Advice, and Exercise Sessions with Professional Supervision </li></ul>
    34. 36. Biologic Audit Rheumatology Department Watford G Hospital Dr R MUSA Dr A Hayee Margaret Brown
    35. 37. Total of 22 Patients currently on biologic therapy for Rheumatology indication at WGH <ul><li>23 rheumatoid arthritis patients ( 11 ) adalimumab (Humira) </li></ul><ul><li>( 3 ) infliximab (Remicade) </li></ul><ul><li>( 5 ) Etanercept (Enbrel) </li></ul><ul><li>Six RhA Patients their therapy suspended </li></ul><ul><li>(11) Patients waiting to start near further </li></ul><ul><li>2 RhA Patients have switch between more than one biologic therapy one still on therapy and one suspended </li></ul><ul><li>3 Ankylosing spondylitis Patients – 3 Etanercept (Enbrel) </li></ul><ul><li>Aims of the Audit to evaluate the current practice of Biologic therapy at Rheumatology Department for RhA & AS. </li></ul>
    36. 38. Age & sex distribution On therapy - 13 female all Rheumatoid arthritis patients 9 male six Rheumatoid arthritis and three AS All the six suspended patients are female Age range RhA(35 - 80) and AS(22 - 69)
    37. 39. Data available on 15 patients with Rh A
    38. 40. Data available on 15 patients with Rh A
    39. 41. Change in BASDI & BASFI score after 6 months Etanercept therapy in 3 patients with AS
    40. 43. Pre starting anti TNF visit <ul><li>1 st Anti TNF assessment by rheumatology specialist nurse </li></ul><ul><li>DAS28score,HAQ,SF36 </li></ul><ul><li>Blood: FBC,ESR,LFT,CRP,U&E </li></ul><ul><li>CXR, Heaf test </li></ul><ul><li>Anti TNF information given to the patient include discussion of side effect, consent taken from the patient </li></ul><ul><li>2 nd Anti TNF assessment by the RSN ( after one month ) </li></ul><ul><li>DAS28score ,HAQ,SF36 </li></ul><ul><li>Blood: FBC,ESR,LFT,CRP,U&E </li></ul>
    41. 44. 1 st visit post starting anti TNF <ul><li>Rheumatology specialist nurse review at 6/52 post antiTNF </li></ul><ul><li>DAS28score,HAQ,SF36 </li></ul><ul><li>Blood: FBC,ESR,LFT,CRP,U&E </li></ul><ul><li>Physician review (for infliximab infusion) </li></ul><ul><li>History focus on any sign of infection (sore throat, dysurea) </li></ul><ul><li>Examination also focus on sign of infection (temp, pulse..) </li></ul><ul><li>Review blood results </li></ul><ul><li>Patient will be reviewed by rheumatologist in OPD in 3/12 time </li></ul>
    42. 49. Thank you for attending