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1. 2 Advances in B-Cell Biology in the Treatment of Autoimmune and Inflammatory Diseases.

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Presentation on theme: "1. 2 Advances in B-Cell Biology in the Treatment of Autoimmune and Inflammatory Diseases."— Presentation transcript:

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2 2 Advances in B-Cell Biology in the Treatment of Autoimmune and Inflammatory Diseases

3 3 Learning Objectives Discuss recent advances in understanding how B-cell biology affects autoimmune rheumatic diseases (ARDs) Review new biologic agents that target B cells and their mechanisms of action Identify how studies of B-cell–targeted therapy are changing our understanding of integrated immune responses and the pathogenesis of ARDs

4 4 Outline B-cell biology in autoimmune disorders Overview of B-cell–targeting agents Recent developments in B-cell targeting in rheumatoid arthritis (RA) Recent development in B-cell targeting in other ARDs

5 B-Lineage Cells and Autoimmunity DC, dendritic cell; FDC, follicular dendritic cell; FO, follicular; GC, germinal center; IL, interleukin; LT, lymphotoxin; Mφ, macrophage; MZ, marginal zone; SLE, systemic lupus erythematosus; TNF, tumor necrosis factor. Adapted from Martin F, Chan AC. Annu Rev Immunol. 2006;24: Plasma cell Memory Bone Marrow Immature Pre BPro B Plasmablast Blast Spleen T2 MZ T1 Mature FO GC Auto- antibodies Graves’ disease Myasthenia gravis Pemphigus vulgaris SLE (RA) Immune complexes SLE RA B T DC Antigen presentation and costimulation Multiple sclerosis SLE RA T B FDC DC Lymphoid organogenesis Multiple sclerosis Sjögren’s syndrome RA Activation Inflammatory cytokines All autoimmune disorders T B TNF-  IL- 6 MMMM? LT 5

6 6 Why Are Some Plasma Cells Short-Lived and Others Long-Lived? Plasma cells, which arise after new immune exposures, are continuously generated in lymphoid tissues, and perhaps in pathologic ectopic lymphoid tissues (eg, rheumatoid synovium) There are different life expectancies of Ig-secreting plasmablasts (which can proliferate) and plasma cells (which cannot proliferate) Newly generated plasma cells are released into the bloodstream, then migrate to the bone marrow As long-term survival requires that they find a “niche,” they must displace “older” plasma cells from their survival niche for long-term survival Dörner T, Radbruch A. Immunity. 2007;27:

7 7 Bone marrow Plasmablasts Long-lived memory plasma cell B T Complex Interactions Determine Plasma Cell Survival Instruction of memory B cells by T cells -CD40/154 -ICOS/ICOS-L -SAP GC Adhesion -CD138 -CD44, 18, 11a -E-/P-selectin Chemokine systems -CXCR4/CXCL12 Soluble survival factors -IL-6 -IL-21 (?) -TNF, IL5 -BAFF/APRIL Chemokine systems -CXCR4/CXCL12 (?) Insoluble survival factors from -nurse cells -or stromal cells (within inflamed tissue) Intracellular survival regulators -↑ Bcl-2, Blimp1, XBP1, Aiolos -↓ BACH2 and Pax5 Competence Dörner T, Radbruch A. Immunity. 2007;27: Tarlinton D et al. Curr Opin Immunol. 2008;20:

8 8 Not All CD20+ B Cells Are Susceptible to Depletion Deletion is most efficient in blood CD20+ precursors and transitional and naïve B cells appear highly susceptible to deletion CD20+ B1 cells, MZ B cells, and GC B cells are resistant (GC in GALT Peyer’s patches) Most plasma cells are not directly affected by RTX (although in the tonsil a subset may express CD20) Effect of RTX on memory B cells and plasmablasts –Little is known about RTX effects on these cells in lymphoid organs IgG-producing plasma cells generally live longer than IgM producers GALT, gut-associated lymphoid tissue. Gong Q et al. J Immunol. 2005;174: Silverman GJ. Arthritis Rheum. 2006;54: Withers DR et al. Blood. 2007;109: Terstappen LW et al. Blood. 1990;76:

9 9 Does Extent of Reduction in Synovial B Cells Explain Clinical Response? B-cell depletion Nondepletion CD22 staining of synovial tissue Before Treatment4 Weeks After Treatment Vos K et al. Arthritis Rheum. 2007;56:

10 10 Changes in RA Synovial Patterns After RTX Baseline (pre-RTX) 4 Weeks8 Weeks16 Weeks24 Weeks B cells* (by histochemistry or CD20 transcripts) + ↓ predictive of clinical response at 24 weeks ↓↓ in clinical responders ↓↓ in clinical responders Plasma cells (by histochemistry) + ↓ (trends, NS) ND ↓↓ in clinical responders ND Immunoglobulins (by transcript analysis) + ND ↓↓ predictive of clinical response at 24 weeks † ND T cells and lymphocyte aggregates ‡ + No  ND ↓↓ in clinical responders ↓↓ in clinical responders CD68+ Mf + ↓ in lining M  No  ↓↓ in lining and sublining M  clinical responders ↓↓ in clinical responders At 12 weeks clinical nonresponders + IgM ACPA and high synovial CD79a+ CD20. *Level of immediate posttreatment synovial B-cell depletion is highly variable, even though high levels of blood-cell depletion are highly reproducible. † At 8 weeks, there was a significant decrease in Ig transcripts in patients with ACR50 or greater responses. ‡ Aggregates are only found in ~1/3 of RA biopsies. ACPA, anti-citrullinated protein/peptide antibodies; ACR, American College of Rheumatology. Kavanaugh A et al. Ann Rheum Dis. 2007;66(suppl 2):291 [abstract FRI0037]; Rosengren S et al. Ann Rheum Dis. 2007;66(suppl 2):298 [abstract FRI0059]; Thurlings RM et al. Ann Rheum Dis. 2007; 66(suppl 2):123 [abstract OP0229]; Dass S et al. Ann Rheum Dis. 2007;66(suppl 2):90 [abstract OP0123]; Teng Y et al. Ann Rheum Dis. 2007;66(suppl 2):299 [abstract FRI0063]; Teng Y et al. Ann Rheum Dis. 2007; 66(suppl 2):439 [abstract SAT0034]; Teng YK et al. Arthritis Rheum. 2007;56:

11 11 Responsible for marginal erosions and bone loss Osteoclast TNF- , IL-1, IL-6 IL-1, IL-6, TNF-  IFN-  T cell Plasma cell MM MM Immune complexes Complement fixation Induce M  secretion of proinflammatory cytokines B cell RF, anti-CCP antibodies TNF-  IL-1 IL-6 TNF-  IFN-  IL-17 RANKL FLS MMPs Cathepsins MMPs Cathepsins Model of RTX-Induced RA Synovial Changes in Clinical Responders BASELINE CCP, cyclic citrullinated peptide; FLS, fibroblast-like synoviocyte; IFN, interferon; MMP, matrix metalloproteinase; RANKL, receptor activator of NF-κB ligand; RF, rheumatoid factor. Silverman GJ, Boyle DL. Immunol Rev. 2008; 223:

12 12 Model of RTX-Induced RA Synovial Changes in Clinical Responders 4 WEEKS IL-1, IL-6, TNF-  IFN-  T cell MM MM Immune complexes Complement fixation Induce M  secretion of proinflammatory cytokines Responsible for marginal erosions and bone loss Osteoclast TNF-  IL-1 IL-6 TNF-  IFN-  IL-17 RANKL FLS MMPs Cathepsins Early synovial B-cell depletion is necessary but not sufficient! Trends toward ↓ in plasma cells in clinical responders (at 6 months) MMPs Cathepsins TNF- , IL-1, IL-6 RF, anti-CCP antibodies B cell X Plasma cell X Silverman GJ, Boyle DL. Immunol Rev. 2008; 223:

13 13 Model of RTX-Induced RA Synovial Changes in Clinical Responders 8 WEEKS IL-1, IL-6, TNF-  IFN-  T cell MM MM Immune complexes Complement fixation Induce M  secretion of proinflammatory cytokines Responsible for marginal erosions and bone loss Osteoclast TNF-  IL-1 IL-6 TNF-  IFN-  IL-17 RANKL FLS MMPs Cathepsins Early synovial B-cell depletion is necessary but not sufficient! Trends toward ↓ in plasma cells in clinical responders Significant ↓ in Ig transcripts in ACR50/70 clinical responders (at 6 months) Trends toward ↓ in lymphocytic aggregates and T cells MMPs Cathepsins TNF- , IL-1, IL-6 RF, anti-CCP antibodies B cell X Plasma cell X Silverman GJ, Boyle DL. Immunol Rev. 2008; 223:

14 14 Model of RTX-Induced RA Synovial Changes in Clinical Responders 16 WEEKS IL-1, IL-6, TNF-  IFN-  T cell MM MM Immune complexes Complement fixation Induce M  secretion of proinflammatory cytokines Responsible for marginal erosions and bone loss Osteoclast TNF-  IL-1 IL-6 TNF-  IFN-  IL-17 RANKL FLS MMPs Cathepsins Significant synovial B-cell depletion Significant ↓ in plasma cells Significant ↓ in T cells and lymphocytic aggregates Significant ↓ in CD68+ M  All in clinical responders at 6 months MMPs Cathepsins TNF- , IL-1, IL-6 RF, anti-CCP antibodies B cell X Plasma cell X X ? X Silverman GJ, Boyle DL. Immunol Rev. 2008; 223:

15 15 IL-1, IL-6, TNF-  IFN-  T cell MM MM Immune complexes Complement fixation Induce M  secretion of proinflammatory cytokines Responsible for marginal erosions and bone loss Osteoclast TNF-  IL-1 IL-6 TNF-  IFN-  IL-17 RANKL FLS MMPs Cathepsins Primary end point is clinical response at 24 weeks Effects on synovial cytokines/ chemokines have not been evaluated at later time points Direct studies on osteoclasts after RTX are not currently available MMPs Cathepsins TNF- , IL-1, IL-6 RF, anti-CCP antibodies B cell X Plasma cell X ? X X Model of RTX-Induced RA Synovial Changes in Clinical Responders 24 WEEKS Silverman GJ, Boyle DL. Immunol Rev. 2008; 223:

16 16 Insights From RA Synovial Biopsy Studies There are great variations in the histopathologic changes induced by RTX Based on small open synovial biopsy studies, there may be a sequence of changes in the synovia that leads to clinical response 1-6 B-cell depletion at 4 weeks may predict clinical response; subsequent↓ in plasma cells and Ig transcripts may predict clinical response 1,2,5 RTX-induced depletion of B-lineage cells, with loss of plasma cells and immune complex formation, may induce clinical responses by multiple pathways B-Cell Roadblock Hypothesis: As B cells are most susceptible to deletion in the blood, RTX benefits may derive from preventing reseeding of pathogenic B cells to the synovia 7 1. Kavanaugh A et al. Ann Rheum Dis. 2007;66(suppl 2):291 [abstract FRI0037]. 2. Rosengren S et al. Ann Rheum Dis. 2007;66(suppl 2):298 [abstract FRI0059]. 3. Thurlings RM et al. Ann Rheum Dis. 2008;67: Dass S et al. Ann Rheum Dis. 2007;66(suppl 2):90 [abstract OP0123]. 5. Teng YK et al. Arthritis Rheum. 2007;56: Teng Y et al. Ann Rheum Dis. 2007;66(suppl 2):439 [abstract SAT0034]. 7. Silverman GJ, Boyle DL. Immunol Rev :

17 17 Transcript Analysis of Synovial Biopsies May Explain How RTX Affects RA Pathogenesis Methods: Knee synovial biopsies at baseline (T0) and 12 weeks after RTX therapy (T12) from 8 patients with RA with incomplete response to anti-TNF therapy RNA expression analyzed with GeneChip ® slides Results: 206 genes ↓ and 330 genes ↑ between T0 and T12 Pathway analyses indicated down-regulated genes involved in cytokine activity and chemotaxis (eg, CCRL2, IL-2BR, CXCL1, CX3CR1) Up-regulated genes involved in bone mineralization, bone remodeling, and ossification (eg, BMP2, TWIST2, P2RX7, CD276) Conclusion: RTX induces specific changes in global gene expression in RA synovial tissue RTX may decrease overall inflammatory cytokine responses in the affected joint, but also induce increases in factors that protect and heal periosteal bone Gutierrez-Roelens I et al. Ann Rheum Dis. 2008;67(suppl 2):194 [abstract THU0182].

18 18 Conventional Immunosuppressive Therapy Can Deplete Peripheral Plasmablasts and Naϊve B Cells, but Not Memory B Cells Methylprednisolone Cyclophosphamide Odendahl M et al. J Immunol. 2000;165: Figure courtesy of T. Dörner (Berlin, Germany) 07/21/03 07/28/0309/09/03 CD19 CD27 1.2% 87.1% 11.7% 2.5% 72.1% 25.4% 6.7% 64.0% 29.2% Plasma cells/blasts CD27+ memory B cells

19 19 Are There Predictive Biomarkers of Response to RTX Treatment in RA? Open trial of 17 patients with refractory RA who received a first cycle of rituximab 12 patients responded with good EULAR responses a –6 patients with an early relapse (weeks 24–40) –6 patients with a late relapse (after week 40) 5 patients were classified as nonresponders 1 patient remained in remission after 1 cycle of treatment 11/17 patients received a second cycle of rituximab –2/11 were RF-negative, 3/11 were anti-CCP–negative a Response was defined as improvement in DAS28 ≥1.2. DAS28, Disease Activity Score including a 28-joint count; EULAR, European League Against Rheumatism. Roll P et al. Arthritis Rheum. 2008;58:

20 20 At Baseline, Higher CD27+ Memory B Cell Counts Correlated With Early Relapse in Clinical Responders After RTX Treatment CD27+ B cells/µL Before Therapy Early RelapseLate Relapse P =.045 (Week 24–40) (After Week 40) Roll P et al. Arthritis Rheum. 2008;58: Memory B cells are either IgD+ or IgD- At Time of B-cell Regeneration, Clinical Nonresponders Had Higher Levels of IgD+ CD27+ Memory B Cells – Lack of Persistent Memory B Cell Reductions ResponderNonresponder CD27+/IgD+ B cells a P =.019 a First time-point of regeneration (n = 12)(n = 5) CD19+/CD27+ B Cells/  l IgD CD27 naive memory

21 21 Summary In RA, levels of CD27+ memory B cells increase with disease duration 1 After RTX treatment, at time of B-cell regeneration, clinical nonresponders had higher levels of IgD+ CD27+ memory B cells –Lack of lasting memory B cell reductions Early relapse after the first RTX cycle was associated with higher CD27+ memory B cell counts prior to therapy and higher IgD+/CD27+ and IgD-/CD27+ B cell counts after first and second treatment cycle, compared with late-relapsing patients Yet even for nonresponders after the first cycle, RTX retreatment can still be effective Clinical response to anti-CD20 treatment may be primarily dependent on the reduction of blood memory B cells, and this may be linked to a reduction of plasmablasts 1. Fekete et al. J Autoimmun. 2007;29:

22 22 Epratuzumab: A Humanized Anti-CD22 Therapeutic Antibody CD22 first appears on B cells at the stage of antigen responsiveness CD22 acts as a coreceptor with the antigen receptor that can down- regulate antigen responses Interacts with inhibitory  2,6-linked sialic acid–associated glycoproteins Epratuzumab induces rapid CD22 internalization and phosphorylation In clinical trials for ARD and NHL Open phase I trial in 12 patients with SLE showed safety and some efficacy based on BILAG scores –All patients fulfilled ACR criteria –Majority of patients had low disease activity (median SLEDAI = 2) BILAG, British Isles Lupus Assessment Group; ACR, American College of Rheumatology; NHL, non-Hodgkin‘s lymphoma; SLEDAI, systemic lupus erythematosus disease activity index. Dörner T et al. Arthritis Res Ther. 2006;8:R74. doi: /ar1942. Jacobi AM et al. Ann Rheum Dis. 2008;67: How does epratuzumab work? What are the effects on the human immune system?

23 23 Epratuzumab Preferentially Reduced Peripheral Blood Naϊve B Cells; Plasmablasts and CD27+ Memory B Cells Are Less Affected Jacobi AM et al. Ann Rheum Dis. 2008;67: CD27- naive B cells/  l B cells absolute cell number CD27+ memory B cells/  lCD27++ plasmablasts/  l

24 24 Epratuzumab Modulates the Activation and Proliferation of B Cells in Patients With SLE Epratuzumab was shown to be safe in a phase I open trial Surface levels of CD22 were rapidly down-modulated Average reduction of 30% of total blood B-cell levels, that lasted for 12 weeks after last infusion Reductions primarily in naïve B cells, trend to increase in plasmablasts. No change in memory B cells Laboratory studies show epratuzumab causes impaired B-cell proliferative responses to in vitro experimental stimulation of T-cell–independent pathway CD22-targeted therapy may provide mechanistic advantages in patients with certain autoimmune diseases More studies are warranted Jacobi AM et al. Ann Rheum Dis. 2008;67:

25 25 Conclusions Studies with RTX have demonstrated an attractive safety/efficacy profile in RA and encouraged the development of newer agents A diversity of additional strategies for targeting B cells, as well as design of biologic agents, are currently under investigation Different B-cell subsets, including naïve B cells, plasma cells/blasts, and memory B cells, appear to make different contributions to pathogenesis The capacity to inhibit or delete each B-cell subset varies greatly based on the mechanism of action of the therapeutic agent Investigations into B-cell–targeted therapy are providing new therapeutic options as well as helping to elucidate previously unknown immunologic mechanisms of pathogenesis.

26 26 B-Cell–Directed Therapy for RA RA, rheumatoid arthritis.

27 27 Learning Objectives State the rationale of B-cell depletion for the management of RA and list at least 3 agents that are being studied in clinical trials Summarize the efficacy of B-cell–targeted therapy following DMARD and anti-TNF therapy failure Describe the safety of long-term and repeated courses of B-cell–targeted therapy and the nuances of fixed or on-demand retreatment Summarize the radiographic changes noted following B-cell–targeted therapy for RA DMARD, disease-modifying antirheumatic drug; TNF, tumor necrosis factor.

28 28 CD20: A Target on B cells 297-AA membrane-associated phosphoprotein (33–37 kDa) Not shed: No known membrane/secreted molecular analogues Selective expression: Not expressed on stem cells, pro-B cells, plasma cells, dendritic cells Anti-CD20 binding: –Does not rapidly modulate expression –Does not cause substantial internalization Differences in epitope binding are of unclear clinical significance with regard to safety or efficacy AA, amino acid. Kehrl JH et al. Immunol Today. 1994;15: ; Golay J et al. Blood. 2000;95: TRU-015 Ofatumumab CD20 Ocrelizumab

29 29 RTX in RA Timeline Data from studies featuring RTX in the treatment of RA are presented at the American College of Rheumatology (ACR) annual meeting The New England Journal of Medicine publishes the results of a phase IIa study of RTX in patients with moderate to severe RA DANCER, a phase IIb study of RTX in RA, meets its primary end point REFLEX, a phase III clinical study of RTX in RA, meets its primary end point DANCER, Dose-Ranging Assessment International Clinical Evaluation of Rituximab in RA; MTX, methotrexate; REFLEX, Randomized Evaluation of Long-Term Efficacy of Rituximab in RA; RTX, rituximab; TNF, tumor necrosis factor. RTX is approved in combination with MTX to reduce signs and symptoms in adult patients with moderately to severely active RA who have had an inadequate response to one or more TNF-antagonist therapies The REFLEX trial, a 2-year multicenter, randomized, double-blind, placebo-controlled phase III study of RTX therapy, is published, showing that a single course of RTX with concomitant MTX therapy provides significant and clinically meaningful improvements in disease activity in patients with active, long-standing RA who had an inadequate response to 1 or more anti-TNF therapies Results of an open-label extension analysis published: patients treated with repeated courses of RTX have sustained clinical responses with no new adverse events

30 30 RTX (REFLEX): EULAR Responses Based on RF/Anti-CCP While significantly more patients receiving RTX demonstrated ACR20 and EULAR responses compared with placebo recipients, seronegative patients (for RF and anti-CCP) did not respond as well Anti-CCP, anti–cyclic citrullinated peptide; EULAR, European League Against Rheumatism; RF, rheumatoid factor. Tak PP et al. Ann Rheum Dis. 2007;66(suppl 2):338 [abstract FRI0192]. a P >.0001 vs placebo, seropositive. b P =.05 vs placebo, seronegative. RF/Anti-CCP+ (Either or Both) a RF/Anti-CCP− b

31 31 Repeated Treatment With RTX Produces Sustained Efficacy in Patients With RA With an Inadequate Response to DMARDs DMARD, disease-modifying antirheumatic drug; DAS28, Disease Activity Score including a 28-joint count. Emery P et al. Arthritis Rheum. 2007;56(9 suppl):S151-S152 [abstract 266]. Patients (%) Week 24 (n = 57)

32 32 Patient-Reported Outcomes During RTX Treatment of Anti–TNF-  Refractory RA in Addition to ACR Responses a P <.0001 vs placebo + MTX. MCID, minimum clinically important difference; FACIT-F, Functional Assessment of Chronic Illness Therapy–Fatigue; HAQ-DI, Health Assessment Questionnaire Disability Index; PCS, physical component score; MCS, mental component score. Cohen SB, et al. Arthritis Rheum 2006;54: Keystone E et al. Arthritis Rheum. 2008;59: Patients (%) Achieving MCID a a a a a a Patients (%)

33 33 Repeated Treatment With RTX Produces Sustained Efficacy in Patients With an Inadequate Response or Intolerance to TNF Inhibitors Emery P et al. Arthritis Rheum. 2007;56(9 suppl):S151-S152 [abstract 266]. Week 24 (n = 96) Patients (%)

34 34 REFLEX: Change in Radiographic Outcomes at Week 56 JSN, joint space narrowing; TGS, total Genant-modified Sharp score. Keystone E et al. Ann Rheum Dis. 2007;66(suppl 2): [abstract SAT0011]. Mean Change P =.0046

35 35 REFLEX: Change in Radiographic End Points at Week 56 The effect of RTX in inhibiting joint damage was consistent for all subgroups examined (baseline: total Sharp score, DAS28, disease duration, CRP, HAQ, SJC, and TJC). The study was not powered to detect treatment differences within each subgroup; however, numerically similar and consistent results were observed for nearly all subgroups analyzed. CRP, C-reactive protein; SJC, swollen joint count; TJC, tender joint count. 1. Cohen S et al. Ann Rheum Dis. 2007;66(suppl 2):428 [abstract SAT0002]. 2. Keystone E et al. Ann Rheum Dis. 2007;66(suppl 2): [abstract SAT0012]. Mean Change in X-ray Score Change in Sharp–Genant Total Score at Week 56 by Anti-CCP Status at Baseline 1 (n = 11) (n = 78) Missing (n = 21) (n = 33) Negative (n = 85) (n = 129) Positive Mean Change ACR20 Nonresponders at Week 24 2

36 36 REFLEX: RTX Radiographic Findings in RA at 2 years X-rays at weeks 0, 24, 56, 104 Total Genant-modified Sharp score used –Linear extrapolation used for missing week 104 x-rays (30% of patients) Effects on JSN and erosions were similar 87% of RTX patients who did not progress in year 1, did not progress in year 2 The data are confounded by multiple therapeutic changes Cohen S et al. Ann Rheum Dis. 2008;67(suppl 2):189 [abstract THU0167]. No  TGS (%) TGS Year 1Year 2 RTX (n = 187) Placebo (n = 281) Baseline to 1 Year 1 Year to 2 Years RTXPlacebo

37 37 RTX Fixed Retreatment vs On-Demand Retreatment of RA Fixed and on-demand retreatment with RTX showed equal efficacy and safety Fixed retreatment was more effective in moderate responders and nonresponders to the first course Nonresponders improved significantly only after fixed retreatment Teng Y et al. Ann Rheum Dis. 2008;67(suppl 2):339 [abstract FRI0167]. Fixed Retreatment On-Demand Retreatment 0% 10% 20% 30% 40% 50% 60% 70% 64% 53% 28% 18% 4% 6% ACR 20ACR 50ACR 70 Patients (%)

38 38 N = 300. Finckh A et al. Ann Rheum Dis. 2008;67(suppl 2):127 [abstract OP-0249]. Switching Strategies When an Anti–TNF-α Fails: RTX or Alternate Anti–TNF-α Overall (%) Not effective ≥AE Switch to alternate anti-TNF-α (%) Adalimumab Etanercept Infliximab Significance Overall evolution of DAS 28 more favorable in RTX vs alternate anti–TNF-α Concomitant DMARD use Type of anti–TNF-α agent switch Type of prior anti–TNF-α failure –Efficacy –AEs P =.01 NS (Graph) Signif NS IMPROVEMENTIMPROVEMENT IMPROVEMENTIMPROVEMENT DAS 28 Δ From Baseline Not EffectiveAEs RTX (n = 101) Switch anti–TNF-α agent (n = 199) Type of Prior Anti–TNF-α Failure Significant Not significant

39 39 Subsequent RTX Treatment Courses: Incidence of Acute Infusion Reactions by Treatment Course All-exposure population by treatment course. SIE = serious infusion-associated event. van Vollenhoven RF et al. Arthritis Rheum. 2007;56(9 suppl):S147 [abstract 257]. SIEs occurred in <1% of patients during course 1 and 2 No SIEs were observed during course 3 or 4 Patients (%)

40 40 Design of B-Cell–Targeting Agents Human Mouse (red) Human IgG constant region Human variable regions Mouse (red) Rituximab (CD20) Ocrelizumab (CD20) Ofatumumab (CD20) Belimumab (BAFF) Epratuzumab (CD22) TRU-015 (CD20) Human Chimeric antibody SMIP Decoy receptors (Synthetic) fully human antibody Atacicept (BAFF and APRIL) (TACI-Ig) BR3-FC (BAFF) Human (green) AMG623 (BAFF) Baminercept-alpha (LT-  ) Synthetic peptide

41 41 Therapeutic Approaches to B-Cell Depletion Belimumab (antisoluble BAFF) Autoreactive B cells SLE RA Other diseases Atacicept (TACI-Ig) RTX (anti-CD20) Binds and eliminates CD20-positive cells Acts later in B-cell development Potently depletes Ig-secreting cells Neutralizes both BAFF and APRIL Acts broadly in B-cell development Potently depletes Ig-secreting cells Stem Cell Mature B cell Antibody-producing Plasma cells Transitional B cell Pro- B Cell Immature B cell Pre- B Cell Antigen stimulation Memory Cell CD19 Epratuzumab (Anti-CD22) Modulates B cell function With limited depletion SLE, systemic lupus erythematosus.

42 42 Therapeutic Approaches to B-Cell Depletion: Clinical Trial Status a Status as of July 17, Description Indications Approved RituximabChimeric anti-CD20RA Phase 3 a OcrelizumabHumanized anti-CD20 antibody based on RTX RA Belimumab Human antibody that binds/sequesters BAFF/BLyS, B-cell survival factor SLE Phase 2 a EpratuzumabHumanized anti-CD22 antibody SLE Baminercept AlfaSoluble LTß receptor IgG1 fusion protein RA TRU-015 Anti-CD20 SMIP (small modular immunopharmaceutical) RA OfatumumabHuman IgG antibody from humanized transgenic mice RA

43 43 Phase I/II dose-escalation RCT with OCR + MTX –175 patients in whom 1–6 DMARDs failed –≥8 TJC and SJC plus CRP ≥1 mg/dL or ESR ≥28 mm/h –Single infusion of OCR (400, 1000, 1500, or 2000 mg) or placebo –No peri-infusional corticosteroids 1° end point: ACR20 at week 24 Complete peripheral B-cell depletion Patients with incomplete response require 100 mg IV corticosteroids Ocrelizumab (OCR): Humanized Anti-CD20 mAb in RA ACR20ACR50ACR70 Patients (%) Placebo OCR 400 OCR 1000 OCR 1500 OCR 2000 ACR Results at Week 24 ESR, erythrocyte sedimentation rate; IV, intravenous; OCR, ocrelizumab; mAb, monoclonal antibody; RCT, randomized controlled trial. Tak PP et al. Ann Rheum Dis. 2008;67(suppl 2):127 [abstract OP-0250].

44 44 CD20 – Ofatumumab: Human Anti-CD20 IgG1 mAb Phase II trial in 225 DMARD/TNF incomplete responders –Ofatumumab IV day 1/15 or placebo; premedication: 100 mg corticosteroid; antihistamines; acetaminophen Primary end point: ACR20 week 24 No significant change in IgA, IgM, or IgG; all patients were human anti-human antibody–negative at 24 weeks 51% of all AEs occurred on infusion days –Majority were mild Common Terminology Criteria (CTC) grade 3 –None in placebo group –1 serious AE (SAE) in 700 group –3 SAEs in 1000 group No CTC grade 4 or 5 events Østergaard M et al. Arthritis Rheum. 2007;56(9 suppl):S793-S794 [abstract 2086].

45 45 CD20 – Ofatumumab: Human Anti-CD20 IgG1 mAb – Phase II Study Placebo AE (%) SAE (%)47911 SIE (%)4204 Conclusions –No apparent dose response –No limiting safety signals as yet a P <.05; b P < Placebo n = n = n = n = 54 ACR20ACR50ACR70 a b Patients (%) Østergaard M et al. Arthritis Rheum. 2007;56(9 suppl):S793-S794 [abstract 2086].

46 46 TRU-015 in Patients With RA: Phase II Dose-Ranging Study 24-week double-blind RCT in patients with incomplete response to MTX 227 patients in United States –≥6 tender joints and swollen joints; RF+ –Either increased ESR/CRP or morning stiffness >45 min 1 infusion, TRU-015 or placebo –200, 400, 800, or 1600 mg –Premedicated 1 grade 3 AE on infusion day (400-mg group) Conclusion: 800 and 1600 mg of TRU-015 IV once statistically superior to placebo at week 24 Burge D et al. Abstract presented at: ACR/ARHP Annual Scientific Meeting; November 6–8, 2007; Boston, Massachusetts; abstract L7. Pbo n = n = n = n = n = 57 SAE (%)22524 DAS28−1.2−1.6 −2.1 a −2 a ACR20% b 61 c ACR50% a 13 ACR70%26604 ∆ HAQ−0.37−0.5 −0.64−0.7 %↓ CRP a P <.05; b P =.003; c P =.008.

47 47 Repeated Administration of TRU-015 in Patients With RA SMIP protein against CD20 –Dose-dependent B-cell depletion Retreatment in 36/54 patients from phase I/IIa RCT –IV infusion: 5 or 15 mg/kg × 1 –INF every 6 months if B-cell recovery –Up to 6 courses given 4 AEs on day of infusion –3 mild (facial flushing, facial erythema, pruritus) –1 moderate (Baker’s cyst) Conclusions: Retreatment after B-cell recovery well tolerated R1, first retreatment; R2, second retreatment; URI, upper respiratory tract infection. Burge D et al. Ann Rheum Dis. 2008;67(suppl 2):128 [abstract OP-0252]. AEs (%) Initial (n = 54) R1 (n = 36) R2 (n = 29) Headache3187 URI2414 Fatigue2037 Edema19113 Bronchitis1767 Insomnia1563 Sinusitis13810 Rash1167 Pruritus1137 AEs >10%

48 48 LTβR-Ig (Baminercept) Human lymphotoxin-  receptor (LT  ) extracellular domain fused to human IgG1 Fc receptor acts as a decoy receptor for LT  Effective in murine models of arthritis: –Blocks induction of arthritis and decreases severity of arthritis in established disease Lymphotoxin  /  Pathway is implicated in: Liver, spleen, and lymph nodes Gut mucosa and Peyer’s patches LIGHT Pathway is implicated in: Mucosal and hepatic inflammation HVEM, herpes virus entry mediator. Baldassare A et al. Ann Rheum Dis. 2008;67(suppl 2):86 [abstract OP-0122]. Control of Lymphoid Microenvironments LIGHT HVEM T Cells B cells NK cells Activated T cells Dendritic cells LT  R Baminercept alfa Costimulation of T-cell activity Affects T-cell responsiveness (proposed) and enhanced survival LT  B cells, T cells, NK cells

49 49 LTβR-Ig (Baminercept) in RA Placebo dose-finding Phase IIa RCT: 47 pts – IR ≥1 DMARD; +MTX SC weekly injections x4 and observation to day 77: –6 dose cohorts: 0.01, 0.05, 0.1, 0.3, 1 and 3 mg/kg BAM versus PBO AEs >5%: PBO 55% and LTβR-Ig 67% –Headache: Placebo 9% and LTβR-Ig 19% –Flu-like symptoms in 25% within 24 h of first injection; ↓ with subsequent injections to 6–9% Continued clinical responses after week 4 despite discontinuation of treatment Phase IIb planned: 5, 50, 200 mg weekly Sample size: mg/kg PBOBAM 0.01BAM 0.05BAM 0.1BAM 0.3BAM 1.0BAM 3.0 Patients (%) ACR20ACR50ACR70 Baldassare A et al. Ann Rheum Dis. 2008;67(suppl 2):86 [abstract OP-0122].

50 50 Summary B-cell–directed therapy has demonstrated clinical and laboratory efficacy in RA Multiple other diseases potentially may be treated with B-cell–directed therapy Safety issues concerning long-term B-cell depletion are of concern, but data thus far are cautiously reassuring New strategies of B-cell targeting may provide more potent therapeutics in the future

51 51 Assessing Immunocompetence in Patients Treated With B-cell–Directed Therapies

52 52 Learning Objectives Define immunocompetence and review the impact of B-cell–directed therapies on humoral immunity Summarize the safety of B-cell–directed therapies with regard to the following clinical scenarios: repeated use, safety of switching to DMARD or TNF inhibitor after RTX failure, effects on serum immunoglobulins, and serious infection rates State clinical considerations for immunizing patients who are candidates for B-cell–directed therapy DMARD, disease-modifying antirheumatic drug; RTX, rituximab; TNF, tumor necrosis factor.

53 53 Outline Immunocompetence and the effects of B-cell– directed therapies Safety of B-cell–directed therapies –Long-term safety of repeated use –Effects on serum immunoglobulins –Serious infection rates –Safety of switching to DMARD or TNF inhibitor after RTX failure Immunization and B-cell–directed therapy Considerations for immunocompetence of newer B-cell– targeting agents BAFF, APRIL Progressive multifocal leukoencephalopathy (PML) in rheumatic diseases

54 54 Defining Immunocompetence: Promises and Problems With Biologic Therapies Immunocompetence is broadly defined as the capacity of the integrated immune response to defend against infections and malignancies An increased rate of infections is the gold standard for detecting compromised immune function, but: –Clinical trials are generally underpowered for rare events –Data collected across clinical trials and databases of such events are not uniform

55 55 Immunocompetence and B-Cell–Directed Therapy Humoral immunity is vital in protecting the host from bacterial infections Patients deficient in Ab are prone to polysaccharide encapsulated bacterial infections Experience in oncology fails to show that RTX adds risk of SIEs to traditional chemotherapy (except in HIV infections) RTX spares long-lived plasma cells, which are the primary source of antimicrobial Abs Ab, antibody; CCP, cyclic citrullinated peptide; dsDNA, double-stranded DNA; HIV, human immunodeficiency virus; RF, rheumatoid factor; SIE, severe infectious event. Looney RJ, et al. Arthritis Rheum. 2008;58:5-14. Antimicrobial Anti-dsDNA Anti-RBP antibodies (Ro, La, Sm/RNP) Survive weeks after RTX Survive months to years after RTX Protective vs pathogenic antibodies Antimicrobial Anti-dsDNA RF and anti-CCP antibodies Plasmablast (short-lived) Plasma Cell (long-lived) Pro-BPre-BImmatureTransitionalNaïveMemory CD20 RTX

56 56 Immunoglobulin Levels Following RTX Therapy Total immunoglobulin (Ig), IgM, IgG – Every 8–12 weeks after each course Always normal IgG & IgM: 761 (72%) –>1 Ig level 1 low IgM: 261 (25%) >1 low IgG: 67 (6%) Decreases are nonprogressive in most cases Patients undergoing repeated courses of RTX have been reported with severely depressed IgM levels, but background therapy has been nonstandardized and has included CTX CTX, cyclophosphamide; LLN, lower limit of normal. Genovese M et al. Arthritis Rheum. 2007;56(9 suppl):S149-S150 [abstract 261]. Popa C et al. Rheumatology (Oxford). 2007;46: C1C2C3C4 IgM IgG SIEs per 100 pt-yr Percent of Patients IgM/IgG

57 57 Long-Term Safety of RTX With Repeated Use 1053 patients (2438 patient-years) from 3 double-blind trials –1014 >6 months –957 >1 year –701 >2 years –120 >3 years Up to 7 treatments (1000 mg  2 IV, 2 weeks; ≥4 months from last infusion) –684 ≥2 courses; 400 ≥3 courses; 142 ≥4 courses Acute infusion reactions decreased with subsequent courses –1st infusion: C1, 23%; C4, 11% –2nd infusion: C1, 7%; C2, 2% 702 (67%) had ≥1 infection –URI: 32%; UTI: 11% No tuberculosis, opportunistic infections, or viral reactivation 36 malignancies in 32 patients (3%): 4 fatal; no lymphomas C, course; URI, upper respiratory tract infection; UTI, urinary tract infection. van Vollenhoven RH et al. Arthritis Rheum. 2007;56(9 suppl):S [abstract 257].

58 58 Long-Term Safety of RTX With Repeated Use C1C2C3C4 AEs SAEs Infections Infections per 100 pt-yr SIEs SIE per 100 pt-yr Safety of Additional Courses of RTX in Patients With Active RA: Open-Label Extension Analysis AE, adverse event; RA, rheumatoid arthritis; SAE, serious adverse event. Keystone E et al. Arthritis Rheum. 2007;56: A total of 1,039 patients received >1 course of rituximab. Of these, 570 received 2 courses, 191 received 3 courses, and 40 received 4 courses, for a total of 1,669 patient-years.

59 59 Serious Infection Rates by Immunoglobulin Levels With Repeated Use of RTX All-Exposure Population (n = 1053) Patients With Normal IgG and IgM (n = 761) Patients with Low IgM at Any Time (n = 261) Patients With Low IgG at Any Time (n = 67) Percentage of patients, % Serious infections per 100 pt-yr (95% CI) 5.4 (4.3–6.38) 4.9 (3.93–6.06) 6.4 (4.74–8.68) 6.8 (4.03–11.49) Genovese M et al. Arthritis Rheum. 2007;56(9 suppl):S149-S150 [abstract 261].

60 60 Long-Term Safety of RTX With Repeated Use Conclusion A progressive increase in the number of patients who have ≥1 Ig level below LLN is seen at some point with repeated infusions of RTX The rate of infections has been stable RTX should be used with caution in patients previously treated with biologics, and long-term studies are needed A more complete safety profile of RTX will emerge as more patients are treated, followed up for longer periods of time, and given more courses of RTX van Vollenhoven RH et al. Arthritis Rheum. 2007;56(9 suppl):S [abstract 257].

61 61 Rate of Serious Infections With Rituximab and Other RA Therapies Rituxan-exposed patients (n=1053) Biologic-treated patients (n=9868) (BSR Biologics Register) Biologic-treated patients (n=928) (German Biologics Register) DMARD-treated patients (n=1352) (BSR Biologics Register) DMARD-treated patients (n=601) (German Biologics Register) Incidence of Serious Infections per 100 Patient-Years BSR, British Society for Rheumatology. van Vollenhoven RH et al. Arthritis Rheum. 2007;56(9 suppl):S [abstract 257]. Listing J et al. Arthritis Rheum. 2005;52: Dixon WG et al. Arthritis Rheum. 2006;54:

62 62 Serious Infection Rates During Treatment With DMARDS or Anti- TNF Agents Following RTX Therapy All Patients Receiving Any DMARD or Biologic (n = 153) Patients Receiving DMARD/ Non–TNF Inhibitor or Biologic (n = 46) Patients Receiving a TNF Inhibitor (n = 46) BeforeAfterBeforeAfterBeforeAfter Total exposures, pt-yr SIEs, no Serious infections per 100 pt-yr (95% CI) 4.19 (1.88 – 9.33) 8.13 (4.82 – 14.3) 1.99 (0.28 – 14.1) 4.78 (1.19 – 19.0) 5.95 (2.67 – 13.3) 9.20 (4.79 – 17.7) All-exposure population. Genovese M et al. Arthritis Rheum. 2007;56(9 suppl):S150 [abstract 262].

63 63 Safety of Switching to DMARD or TNF Inhibitor After RTX Failure All PatientsDMARDs AddedTNF Inhibitor Added BeforeAfterBeforeAfterBeforeAfter Total exposures, pt-yr SAEs/100 pt-yr (n = 75)28 (40)24 (35)NR SIEs, no SIE/100 pt-yr % CI1.9–9.44.6– – –192.9– – patients (of 1053) withdrew from RTX extension studies Entered safety follow-up for up to 48 weeks for SAEs –Could be treated with DMARD(s) or TNF inhibitor –107 (70%) treated with TNF inhibitor and 46 (30%) DMARD(s) –Majority had CD19 counts

64 64 Can Patients Given Biologics, Including B-Cell–Depleting Therapy, Be Effectively Immunized?

65 65 Immunization and Immune Response Responses to immunization depend on intact immune response –T-cell–dependent antigens (peptide) –T-cell–independent (carbohydrate) –Response to neoantigens –Response to recall (booster) antigens How do newer targeted immunomodulatory therapies affect immunization responses?

66 66 Biologics and Immunization TNF antagonists may slightly decrease immune response to influenza immunization compared with MTX 1 B-cell depletion in RTX-treated patients with SLE significantly decreased response to pneumococcal vaccine and tetanus immunization in almost all patients, although partial responses were observed on return of peripheral B cells 2 Abatacept decreased response to neoantigens (  X174 and KLH) in patients with psoriasis 3 KLH, keyhole limpet hemocyanin; MTX, methotrexate; SLE, systemic lupus erythematosus. 1.Kapetanovic MC et al. Rheumatology (Oxford). 2007;46: Albert DA et al. Arthritis Rheum. 2006;54(9 suppl):S550 [abstract 1323]. 3.Abrams JR et al. J Clin Invest. 1999;103:

67 67 Response to Influenza Vaccine in RA Treated With Abatacept Previous data suggest that abatacept may blunt response to the T-cell–independent Ag pneumococcus in healthy controls and patients with RA Influenza is a T-cell–dependent Ag, with healthy individuals demonstrating seroconversion (4-fold) to 33%–44% of the time ARRIVE trial studied abatacept in patients in whom TNF inhibitors failed Substudy of 21 patients given influenza vaccine 7 days prior to abatacept in patients receiving long-term therapy Proportion of Patients Responding* to Different Numbers of Influenza Serotypes – 1 Month Post-immunization 75% of patients mounted an adequate response to at least 1 strain 1 month post-vaccination; 50% to 2 strains; 15% to all 3 MTX, consistent with previous studies, blunts response Abatacept does not appear to meaningfully impair response to influenza *Positive response defined as post-immunization antibody titer at least 4 times above baseline value. Ag, antigen; ARRIVE, Abatacept Researched in RA Patients With an Inadequate Anti-TNF Response to Validate Effectiveness. Schiff M et al. Arthritis Rheum. 2007;56(9 suppl):S392 [abstract 943].

68 68 RTX and Vaccination Following RTX administration, post-vaccination protection rates are decreased in response to –Pneumococcal vaccine 1 –Tetanus toxoid 1 –Trivalent influenza vaccine 2,3 1. Albert DA et al. Arthritis Rheum. 2006;54(9 suppl):S550 [abstract 1323]. 2. Gelinck L et al. Ann Rheum Dis. 2007;66(suppl 2):160 [abstract THU0116]. 3. Oren S et al. Ann Rheum Dis. 2007;66(suppl 2):363 [abstract FRI0275].

69 69 Immunization Responses With RTX in Patients With RA 4 patients treated with RTX (1000 mg  2) –Immunization with trivalent influenza A/B at 84 days during B-cell depletion 19 patients receiving TNF antagonists 20 healthy controls Evaluation of preimmunization and postimmunization titers to antigens Gelinck LB et al. Ann Rheum Dis. 2007;66:

70 70 RTX Impairs Ability to Respond to Influenza Vaccine in Patients With RA Response Defined as GMT > 40 units RA-RTX N = 4 RA-TNF N = 19 HC N = 20 A/H3N2 (%) A/H1N1 (%) Influenza B (%) GMT, geometric mean titers; HC, healthy controls. Gelinck LB et al. Ann Rheum Dis. 2007;66: A/H3N2A/H1N1Influenza B Pre-vaccination HC RA - TNF RA - RTX Vaccination PrePost Vaccination PrePost 4 2 Vaccination PrePost 4 2 Post-vaccination GMT

71 71 Immunization: Summary Consider immunization responses when treating patients with RA and when introducing new targeted therapies Live attenuated virus vaccines should be avoided in all patients receiving immunosuppressants (based on absence of data) Some immunomodulatory therapies may significantly attenuate the efficacy of other immunizations Timing of immunizations may be clinically important Evaluating larger numbers of patients treated with these agents alone and in combination with other DMARDS and concomitantly evaluating appropriate controls using standardized definitions of response are very important in guiding clinical care Appropriate immunization should be performed prior to initiation of RTX therapy Gelinck LB et al. Ann Rheum Dis. 2007;66:

72 72 Considerations for Immunocompetence of Newer B-Cell–Targeting Agents: BAFF, APRIL

73 73 Considerations for Immunocompetence of Newer B-Cell–Targeting Agents: Baminercept (LTßR-Ig) LTß-Ig is a fusion protein binding to LTα 1 ß 2 and LIGHT (members of the TNF family) on T, B, and NK cells –Blocks interaction with antigen-presenting and stromal cells The LT pathway regulates organization of the lymphoid microarchitecture and lymphoid trafficking LTß-deficient mice have absent secondary lymphoid tissue and profound immunodeficiency Partially deficient LTß mice are susceptible to a wide variety of pathogens: Listeria, Mycobacterium tuberculosis, viruses, and parasites 1,2 1. Xu G et al. J Immunol. 2007;179: Lin X et al. Int Immunol. 2003;15:

74 74 PML in Rheumatic Diseases PML is a neurologic disease caused by infection with the JC polyomavirus that occurs in susceptible patient populations Recently reported in 0.1% of patients receiving natalizumab, a promising drug for multiple sclerosis (also in clinical trials for RA and Crohn’s disease) Mechanism of action is unknown 70-year-old woman with SLE and HA previously treated with CTX, AZA, and long-term GC; developed vertigo and ataxia after 4 infusions of RTX –MRI had multiple brain lesions and biopsy showed PML –The patient died 1 year later 45-year-old woman with SLE since 1982, previously treated with CTX, IV methylprednisolone, and daily GC. CD4 count was low (<200). The patient received 3 courses of RTX with daily GC in 2003–2006 –In April 2006, she developed neurologic symptoms and signs and had multiple brain lesions by MRI, and was found to have JC virus in the CSF –The patient died in July 2006 AZA, azathioprine; CSF, cerebrospinal fluid; GC, glucocorticoids; HA, hemolytic anemia; MRI, magnetic resonance imaging. US Food and Drug Administration. FDA Alert: rituximab (marketed as Rituxan). December Available at: Accessed December 18, 2007.

75 75 PML and RTX PML has not been diagnosed in any patient to date in clinical trials Systematic reviews of PML and of rheumatic disease and PML have suggested that patients with SLE may have a unique susceptibility to PML 1 Rheumatologists should familiarize themselves with PML and consider it in the differential diagnosis of immunosuppressed patients with unexplained neurologic disease 1. Calabrese LH et al. Arthritis Rheum. 2007;56:

76 76 Immunocompetence and Biologic Therapies: Promises and Problems Efforts to improve our assessment of compromised immune responses in patients with rheumatic disease treated with biologics include: –Uniform assessment of infections (bacterial, opportunistic, and viral) across trials and databases –Uniform assessment of vaccine response from early clinical trials –Detailed assessment of in vitro immunity, including cellular humoral and innate responses

77 77 The Use of B-cell– Directed Therapies in SLE, Vasculitis, and Other Autoimmune Diseases SLE, systemic lupus erythematosus.

78 78 Learning Objectives Describe the rationale of B-cell depletion for the management of SLE, vasculitis, and other autoimmune diseases Summarize recent clinical trial data on the use of rituximab, belimumab, and epratuzumab in the treatment of SLE Summarize recent clinical trial data on the use of B-cell targeting in the treatment of Sjögren’s syndrome Summarize recent clinical trial data on the use of B-cell targeting in other vasculitides

79 79 B-Cell–Depletion Therapy in SLE B lymphocytes may play a central role in the pathogenesis of SLE –As precursors of antibody-secreting cells, B cells are the source of pathogenic autoantibodies –B cells are not merely the passive producers of immunoglobulins, but also play a central role in autoimmunity B-cell depletion has recently emerged as a promising therapeutic approach to the treatment of autoimmune diseases, including SLE

80 80 CTX, cyclophosphamide; dsDNA, double-stranded DNA; IV, intravenous; RTX, rituximab. 1. Edwards JC et al. N Engl J Med. 2004;350: Ng KP et al. Ann Rheum Dis. 2007;66(suppl 2):56-57 [abstract OP0020]. 3. Ng KP et al. Ann Rheum Dis. 2006;65: RTX B-Cell–Depletion Therapy in Patients With SLE: Long-Term Follow-Up and Predictors of Response Observations of nonrandomized clinical experience (since June 2000) in 41 patients with refractory SLE at University College, London 1-3 –Mean duration of follow-up 37 months (2 patients lost to follow-up) –Patients must have failed to respond to CTX or methotrexate –RTX 1 g IV  2 (14 days apart) + CTX RTX therapy showed efficacy –Mean duration of B-cell depletion was 4 months (range 2–15) –Serum immunoglobulins decreased but not below lower limit of normal –Anti-dsDNA antibody levels significantly reduced 6 months after B-cell– depletion therapy –Protein/creatinine ratio fell (but change did not reach statistical significance) 13 patients re-treated

81 81 11 (55%) of 20 patients who flared did so 6–12 months after treatment Predictors of lack of response –Patients with anti-ENA antibodies (anti-Sm or anti-La) were more likely to flare –Lower serum C3 at baseline was associated with shorter time to flare following B-cell–depletion therapy 2 (5%) of 39 patients in the cohort have died (varicella pneumonitis and SLE pancarditis) AEs: single cases of hematuria, self-limiting neutropenia, pneumococcal sepsis/pneumonia, serum sickness–like reaction, active pancreatitis, seizure RTX B-Cell–Depletion Therapy in Patients With SLE: Long-Term Follow-Up and Predictors of Response AE, adverse event; ENA, extractable nuclear antigen. 1. Ng KP et al. Ann Rheum Dis. 2007;66(suppl 2):56-57 [abstract OP0020]. 2. Ng KP et al. Ann Rheum Dis. 2006;65:

82 82 2-Year Extended Follow-Up of Open-Label Phase I/II Trial of RTX for Active, Refractory SLE RTX (500 mg IV weekly  4 in 5 patients and 1000 mg IV  2 on days 0 and 14 in 10) was administered to patients with active, refractory SLE (mean BILAG score 12.5, range 8–17) Peripheral B cells rapidly decreased by day 14 in all patients and remained low until 6 months post-treatment, except for 1 patient whose peripheral B cells remained low for 2 years –No significant change in Ig levels –  autoantibody levels and  complement levels in a majority of patients RTX resulted in sustained improvement of disease activity in 5 of 14 patients at 2 years –Mean BILAG scores improved from 12.5 to 4.6 –Mean background corticosteroid dose decreased from 25.2 to 7.7 mg –6 patients required repeated courses of RTX for persistent disease activity Severe AEs occurred in 7 patients, all with antiphospholipid antibodies (DVT [2], multiple infarctions [2], pulmonary infarction, MI, cerebral hemorrhage, transverse myelitis) 2 patients died (cerebral hemorrhage and catastrophic APS) APS, antiphospholipid syndrome; BILAG, British Isles Lupus Assessment Group; DVT, deep venous thrombosis; Ig, immunoglobulin; MI, myocardial infarction. Tanaka Y et al. Ann Rheum Dis. 2008;67(suppl 2):54 [abstract OP-0020].

83 83 SLE: Case Series of RTX (anti-CD20) Treatment of Patients With SLE Refractory to Conventional Therapy Among 22 patients, RTX treatment 1 : –Resolved anemia, thrombocytopenia, and/or cryoglobulinemia in all 18 patients with severe hematologic manifestations –Decreased daily proteinuria by ≥50% at 6 months in 4 (66%) of 6 patients with lupus nephritis Among 19 patients, RTX treatment 2 : –Improved thrombocytopenia in 7 (64%) of 11 patients within 3 months, resolved anemia in 3 (75%) of 4 patients, and improved cutaneous manifestations of lupus in 4 of 4 patients –Decreased levels of antiplatelet and anti-RBC antibodies, but not of anti-dsDNA antibodies Among 16 patients, RTX treatment 3 : –Improved disease activity (  BILAG score) in 9 (56%) of 16 patients –Did not prevent progression to stage 5 CKD in 5 patients with severe proliferative, crescentic lupus nephritis Although some manifestations of refractory SLE may improve, some forms of lupus nephritis may progress despite RTX therapy CKD, chronic kidney disease; RBC, red blood cell. 1. Amoura Z et al. Arthritis Rheum. 2007;56(9 suppl):S458 [abstract 1124]. 2. Lindholm C et al. Ann Rheum Dis. 2008;67(suppl 2):344 [abstract FRI0184]. 3. Sangle SR et al. Arthritis Rheum. 2007;56(9 suppl):S215 [abstract: 441].

84 84 RTX + IV CTX Induction for Patients With Lupus Nephritis RTX + IV CTX may serve as an alternative induction regimen for patients with severe lupus nephritis 1 –18 patients with biopsy-proven lupus nephritis (10 proliferative GN, 7 membranous GN, 1 unknown) –RTX 375 mg/m 2 IV weekly  4 + IV CTX (at weeks 1 and 4) –After 6 months, 17 (94%) of 18 patients had clinical improvement; 1 had early relapse Histologic examination showed significant improvement in most patients at 6 months –At 2 years (n = 17), 15 (88%) of 17 patients had persistent clinical improvement; 2 had relapsed MMF may serve as a maintenance regimen for patients with severe lupus nephritis, following RTX + IV CTX induction regimen 2 –35 patients with SLE and biopsy-confirmed active nephritis (ISN/RPS class IV [70%] or V [30%]), refractory to standard treatment Treated with RTX 750 mg IV + methylprednisolone 500 mg IV + CTX IV on days 1 and 15 Followed by maintenance MMF 1–2 g/d for 2 years –At end of 2 years, significant improvement in C3, C4, anti-dsDNA antibodies, and proteinuria in all patients; serum creatinine remained stable –No SAE; 6 patients had mild viral infections No comparison with induction regimens using methylprednisolone+ CTX alone or RTX alone ISN, International Society of Nephrology; MMF, mycophenolate mofetil; RPS, Renal Pathology Society; SAE, serious adverse event. 1. Jónsdóttir T et al. Ann Rheum Dis. 2008;67(suppl 2):54 [abstract OP-0021]. 2. Guzman RA et al. Ann Rheum Dis. 2008;67(suppl 2):219 [abstract THU0260].

85 85 EXPLORER: Efficacy and Safety of RTX in Patients With Moderate to Severe SLE Phase II/III randomized, double-blind, placebo-controlled study to evaluate efficacy and safety of RTX in patients (n = 257) with moderate to severe SLE receiving background prednisone therapy Primary end point: Proportion of patients who achieved either a major clinical response or partial clinical response measured by the BILAG index at 52 weeks Secondary end points: Time-adjusted AUC of BILAG disease activity, improvement in BILAG disease activity, time to flare, QOL, and proportion taking <10 mg prednisone daily Study did not meet its primary end point or any of its six secondary endpoints Reasons for failure unclear Clinical trial in lupus nephritis ongoing AUC, area under the curve; EXPLORER, A Study to Evaluate the Efficacy and Safety of Rituximab in Patients With Moderate to Severe Systemic Lupus Erythematosus; QOL, quality of life.

86 86 PML, progressive multifocal leukoencephalopathy. 1. Ng KP et al. Ann Rheum Dis. 2007;66(suppl 2):56-57 [abstract OP0020]; 2. Ng KP et al. Ann Rheum Dis. 2006;65: Tanaka Y et al. Ann Rheum Dis. 2008;67(suppl 2):54 [abstract OP-0020]; 4. Amoura Z et al. Arthritis Rheum. 2007;56(9 suppl):S458 [abstract 1124]; 5. Lindholm C, et al. Ann Rheum Dis 2008;67(suppl 2):344; 6. Sangle SR et al. Arthritis Rheum. 2007;56(9 suppl):S215 [abstract: 441]; 7. Jónsdóttir T et al. Ann Rheum Dis. 2008;67(suppl 2):54 [abstract OP-0021]; 8. Guzman RA, et al. Ann Rheum Dis. 2008;67(suppl 2):219 [abstract THU0260]; 9. releases/display.do?method=detail&id=11247; 10. Calabrese LH et al. Arthritis Rheum. 2007;56: RTX B-Cell–Depletion Therapy in Patients With SLE: Summary Observations of nonrandomized clinical experience in patients with refractory SLE at 7 institutions suggests therapeutic efficacy of RTX when used in addition to standard (anchor) therapy 1-8 –Serum immunoglobulin and anti-dsDNA antibody levels decreased for at least 6 months after treatment 1,2 –Presence of anti-Sm or anti-La antibodies or low C3 at baseline may identify patients who will flare after treatment 1,2 However, a prospective randomized, double-blind, placebo-controlled study of RTX in patients with moderate to severe SLE receiving background prednisone therapy failed to demonstrate efficacy 9 23 (64%) of 36 reported cases of PML in patients with rheumatic diseases have occurred in patients with SLE, most of whom had not received RTX 10

87 87 RCT, randomized controlled trial; SELENA, Safety of Estrogens in Lupus Erythematosus National Assessment; SLEDAI, SLE Disease Activity Index; SF-36 PCS, physical component score of theSF-36 health survey. 1. Ginzler E et al. Ann Rheum Dis. 2007;66(suppl 2):56 [abstract OP0018]. 2. Furie R et al. Ann Rheum Dis. 2008;67(suppl 2):53 [abstract OP-0017]. Phase II RCT of Belimumab in SLE: Combined Response Rate Is Significantly Higher for Belimumab-Treated Patients 1, 4, and 10 mg/kg belimumab dosed on days 0, 14, 28, and then every week through week 52 Changes in immunosuppressants, glucocorticoids permitted 46% combined response rate for patients with serologically active disease receiving belimumab versus 29% for placebo at week 52 1 No dose response observed 2 56% combined response rate for patients receiving belimumab at week 76 2 In subjects with serologically active disease, significant improvements in SLE disease activity shown by SELENA-SLEDAI, Physician’s Global Assessment and QOL (SF-36 PCS), and decreased BILAG 1A or 2B flares

88 88 1. Petri M et al. Arthritis Rheum. 2007;56(9 suppl):S527 [abstract 1316]. 2. Furie R et al. Ann Rheum Dis. 2008;67(suppl 2):53 [abstract OP-0017]. 3. Ginzler E et al. Ann Rheum Dis. 2008;67(suppl 2):217 [abstract THU0253]. 4. Merrill JT et al. Ann Rheum Dis 2008;67 (suppl 2):217 [abstract THU0254]. B-Cell Depletion With Belimumab in Patients With SLE Efficacy 1-3 –Although the primary study end point (a reduction in the SELENA-SLEDAI score) was not achieved, there were indications of efficacy over 3 years: Combined response rate of 46% at week 52 (n = 235); increased to 65% with belimumab treatment continued to week 160 (n = 170) Rate of SLE flares decreased progressively with belimumab treatment to 7% after 3 years Belimumab treatment allowed reduction of prednisone dose to  7.5 mg/d from >7.5 mg/d at baseline in up to 44% of patients after 1 year and in up to 62% of patients by 3 years Sustained response to belimumab is independent of type of autoantibody present at baseline Safety 4 –Belimumab is well tolerated in combination with antimalarials and immunosuppressive drugs –Similar incidence rates of AEs, SAEs, serious infections, and malignancies between belimumab- and placebo-treated patients during the first year of treatment –Incidence rate of AEs did not increase over time, during more than 3 years of belimumab exposure

89 89 Biomarkers –Changes correlated with clinical improvement observed over 2.5 years of belimumab treatment:  in C3 and C4 levels  in anti-dsDNA antibody levels  in IgG, IgM, and IgE levels (more in subjects with elevated levels at baseline) Reversion of anti-Sm and anti-RNP serologic findings from positive to negative in some belimumab-treated subjects Stohl W et al. Arthritis Rheum. 2007;56(9 suppl):S210 [abstract 426]. B-Cell Depletion With Belimumab in Patients With SLE

90 90 Petri M et al. Ann Rheum Dis. 2008;67(suppl 2):53 [abstract OP-0016]. B-Cell Depletion With Epratuzumab in SLE: RCTs 90 patients with SLE and moderate to severe flares randomized in 2 phase II RCTs, each of which was terminated prematurely because of interruptions in medication supply Up to 4 treatment cycles over a 48-week period –Placebo –Epratuzumab 360 mg/m 2 –Epratuzumab 720 mg/m 2 Primary end point: Reduction of all BILAG A to B, BILAG B to C, no worsening in other systems, no addition or increase in immunosuppressives/antimalarials or corticosteroids above tapering levels

91 91 HAHA, human antihuman antibody; ITT, intention to treat. 1. Petri M et al. Ann Rheum Dis. 2008;67(suppl 2):53 [abstract OP-0016]. 2. Wallace D et al. Ann Rheum Dis. 2008;67(suppl 2):212 [abstract THU0238]. B-Cell Depletion With Epratuzumab in Patients With SLE Patients in both epratuzumab groups had greater reductions in total BILAG scores from weeks 4 through 48, compared with placebo 1 Physician and patient global assessment scores were also significantly improved in the epratuzumab-treated groups 1 Overall efficacy was most consistent in the epratuzumab 360-mg/m 2 group 1 Epratuzumab-treated patients used less corticosteroid than placebo-treated patients over 24 weeks 2 AE incidence was similar among epratuzumab- and placebo-treated patients 2 Low incidence of immunogenicity (HAHA) 2 Placebo (n = 30) Epratuzumab 360 mg/m 2 (n = 34) Epratuzumab 720 mg/m 2 (n = 10)

92 92 B-Cell–Depletion Therapy in Patients With SLE: Summary To date, no B-cell–directed therapy is approved for the treatment of SLE Most clinical trials of both B-cell depletion and anti-BAFF therapy, thus far, have been of either inadequate design (open-label and uncontrolled) or flawed by interruptions in medication supply, making it difficult to determine the functionality of these therapies in this setting Safety signals in controlled clinical trials to date are modest, but caution clearly is indicated until better safety and efficacy data are available

93 93 B-Cell Targeting in Sjögren’s Syndrome (SS) Epithelial inflammatory disease driven by cellular and humoral factors No evidence of effective remittive therapy Strong evidence of –B-cell hyperactivity –Polyclonal B-cell activation –Hypergammaglobulinemia –Multiple autoantibodies: SSA/SSB, antifodrin, others –Elevated levels of BAFF Micrograph courtesy of Leonard Calabrese, DO Ramos-Casals M et al. Ann Rheum Dis. 2005;64:

94 94 GN, glomerulonephritis. Looney RJ. Arthritis Rheum. 2007;56: SS: Studies of B-Cell–Directed Therapy (anti-CD20 and anti-CD22) Uncontrolled studies have demonstrated symptomatic improvement (sicca) especially in early disease Extraglandular disease (vasculitis, GN, neuropathy) has been reasonably responsive QOL improved Non-Hodgkin’s lymphoma and SS often respond Serum sickness-like reactions have been reported

95 95 1. St. Clair EW et al. Arthritis Rheum. 2007;56: (suppl 9):S [abstract 1102]. 2. Levesque MC et al. Arthritis Rheum. 2007;56: (suppl 9):S445-S446 [abstract 1091]. RTX for Primary SS Open trial in 12 patients with SS and 1 or more severe disease manifestations (fatigue, parotid enlargement, neuropathy, interstitial pulmonary disease [IPD], purpura) treated with 1 g RTX, 100 mg methylprednisolone  2 10/10 fatigue; 3 parotid, 4 neuropathy, 1 IPD, 1 purpura Significant decrease in physician and patient global assessment, fatigue, and joint pain; no significant change for sicca assessments; no serum sickness or SAE related to drug All patients became B-lymphopenic; reconstitution was similar to that seen in studies of RTX in RA and SLE, with transitional and plasmablastic phenotype and a paucity of memory (CD27) B cells Larger placebo-controlled trials are needed

96 96 EU, European Union; USA, United States of America; VAS, visual analog scale. Dass S et al. Arthritis Rheum 2007;56:(suppl):S446-S447 [abstract 1094]. Safety and Efficacy of RTX in SS: First Randomized Placebo-Controlled Trial Primary SS causes significant symptoms but has no effective therapy Subjects: Primary SS by EU-USA criteria, antibodies to Ro and La, and fatigue >50% on VAS Treatment: RTX 1 g  2 with prednisone (tapering 60→30→0 over 14 days) or placebo Primary end point: ≥20% improvement in fatigue

97 97 Dass S et al. Arthritis Rheum. 2007;56:(9 suppl):S446 [abstract 1094]. Safety and Efficacy of RTX in SS: Results of the First Double-blind Randomized Placebo-Controlled Trial 18 available for analysis –Failure to reach primary end point for fatigue (VAS) –VAS fatigue improved 48% RTX vs 20% placebo (NS); 8/9 versus 5/9 achieved ≥20% improvement in fatigue VAS (NS); significant improvement in SF-36 –RTX patients had significant reductions in rheumatoid factor (RF) but not Ro, La, or IgG –3 SAEs with 1 serum sickness Marked variability of clinical responses

98 98 ANCA, antineutrophil cytoplasmic antibody. 1. Ruddy S et al, eds. Kelley’s Textbook of Rheumatology. 6th ed. Philadelphia, Pa: W.B. Saunders; Vassilopoulos D et al. AIDS. 2005;19(suppl 3):S123-S127. Vasculitis and B-Cell Targeting: Rationale Sansonno D et al. Blood. 2003;101: Zaja F et al. Blood. 2003;101: Multiple case reports and small series: Lamprecht P et al. Ann Rheum Dis. 2003;62: ; Cai FZ. J Rheumatol. 2006;33: ; Basse G et al. Transplantation. 2005;80: ; Quartuccio L et al. Rheumatology (Oxford). 2006;45: Kay J et al. N Engl J Med. 2005;353: Cryoglobulinemia-Mediated VasculitisANCA-Associated Vasculitis Keogh KA et al. Am J Respir Crit Care Med. 2006;173: Smith KG et al. Arthritis Rheum. 2006;54: Golbin JM et al. Arthritis Rheum. 2006;54(9 suppl):S527 [abstract 1265]. Aries PM et al. Ann Rheum Dis. 2006;65: ; Flossmann O et al. Ann Rheum Dis. 2006;65: Golbin JM et al. Clin Exp Rheumatol. 2007;25(1 suppl 44): S74-S76. Brihaye B et al. Clin Exp Rheumatol. 2007;25 (1 suppl 44):S23-S27.

99 99 WG, Wegener’s granulomatosis. 1. Golbin JM et al. Arthritis Rheum. 2006;54(suppl 9):S527 [abstract 1265]. 2. Molloy E et al. Arthritis Rheum. 2007;56(suppl 9):S769 [abstract 2020]. Repeated B-Cell Depletion in ANCA-Associated Vasculitis 2006: Golbin et al suggested repeated treatment with RTX and profound B-cell depletion are well tolerated in relapsing WG; B-cell depletion appears effective for maintaining remission and relapse was not seen in the absence of B cells or ANCA 2007: Molloy et al retrospectively reported 4 patients with refractory ANCA disease each responding initially to RTX therapy; all patients eventually relapsed despite ongoing B-cell depletion Until controlled studies are completed, the decision to use RTX therapy in ANCA-associated disease should be based on assessment of risk/benefit to the individual patient.

100 100 Rituximab: Updates in Vasculitis Wegener’s granulomatosis –Efficacy of RTX for refractory WG with ear, nose, and throat manifestations (N = 34) 30 (88%) of 34 patients with refractory WG responded well to RTX; therapeutic responses maintained during follow-up No long-term adverse effects documented; therapy failed in 3 patients –Patients with systemic WG refractory to, or intolerant of, other therapies randomly assigned to infliximab (3 mg/kg/mo for 1 month then 5 mg/kg/mo) or RTX (375 mg/m2/wk for 4 weeks, then once every 4 months) for 12 months (21 evaluable patients) Infliximab and RTX achieved comparable outcomes, and improved clinical disease course in 6/11 and 7/10, respectively Martinez Del Pero MA et al. Ann Rheum Dis. 2008;67(suppl 2):68 [abstract OP-0060]. Cohen P et al. Ann Rheum Dis. 2008;67(suppl 2):223 [abstract THU0273].

101 101 RTX in ANCA-Associated Vasculitis: Summary to Date In ANCA-associated vasculitis, most but not all preliminary (noncontrolled) studies of B-cell depletion suggest that this strategy is a safe and effective mechanism-based approach for remission induction and maintenance Repeated courses are equally effective and thus far associated with few infectious complications Limited trials in cryoglobulinemia with and without HCV infection have demonstrated efficacy and reasonable safety of anti-CD20 based therapy A large controlled trial of RTX for ANCA-associated vasculitis (RAVE) is fully recruited and analysis is pending (www.clinicaltrials.gov) HCV, hepatitis C virus.


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