Immunomodulators and immunosupressants October 22, 2013 Grant Hughes, MD C:\Users\Parul\Desktop\514px-Methotrexate_1u72_svg.png cyclophosphamide //upload.wikimedia.org/wikipedia/commons/7/7e/Mycophenolate_mofetil_skeletal.svg File:Mycophenolate mofetil skeletal.svg Objectives Understand beneficial immune actions of commonly prescribed rheumatology drugs Learn specific infection risks associated with each Appreciate secondary malignancy risk of certain drugs Appreciate how mechanisms of action guide off-label drug use for inflammatory and autoimmune diseases Immunomodulators and immunosupressants Key points Except for biologics, mechanisms of action are not well understood In general, glucocorticoids are used to limit immune-mediated injury Control of underlying autoimmunity relies on targeting proliferation, survival or activation of T cells, B cells and other antigen presenting cells Most important risk factors for infection are steroid use, active disease, and drug-induced leukopenia Excess risk of neoplasm is low for individual drugs Immunomodulators and immunosupressants General Mechanisms Anti-inflammatory Glucocorticoids Inhibitors of TNF-a, IL-6, IL-1b Colchicine NSAIDs Anti-proliferative Cyclophosphamide Methotrexate Azathioprine Leflunomide Modulation of T cells Abatacept MMF Cyclosporine Modulation of B cells Rituximab Belimumab Miscellaneous IVIg Tofacitinib Sulfasalazine Hydroxychloroquine Case 1 You have just prescribed high-dose steroids for a young woman with newly-diagnosed class IV lupus nephritis. Which of the following mechanisms is least important in preventing acute kidney injury in this setting? Decreased FcR expression on kidney-infiltrating monocytes and macrophages Decreased activation of glomerular vascular endothelium Decreased renal influx of neutrophils and monocytes Decreased levels of circulating anti-dsDNA antibodies Decreased inflammatory prostaglandin synthesis Glucocorticoids Mechanisms of action Binds glucorticoid receptor (GR) expressed in endothelial cells, leukocytes, synoviocytes Ligand-activated transcription factor (hours) Suppression via interactions with NF-kB Inflammatory genes (e.g., TNF-a, IL-8) Immune genes (e.g., IL-2) Activation: anti-inflammatory genes (e.g., DUSP1), genes of metabolism Rapid effects, “non-genomic” (minutes) High dose prednisone (>30 mg/d)  T cell receptor signaling  prostaglandin release  vascular endothelial activation nri2262-f3 Case 1 You have just prescribed high-dose steroids for a young woman with newly-diagnosed class IV lupus nephritis. Which of the following mechanisms is least important in preventing acute kidney injury in this setting? Decreased FcR expression on kidney-infiltrating monocytes and macrophages Decreased activation of glomerular vascular endothelium Decreased renal influx of neutrophils and monocytes Decreased levels of circulating anti-dsDNA antibodies Decreased inflammatory prostaglandin synthesis Glucocorticoids Mechanisms of action Binds glucorticoid receptor (GR) expressed in endothelial cells, leukocytes, synoviocytes Ligand-activated transcription factor (hours) Suppression via interactions with NF-kB Inflammatory genes (e.g., TNF-a, IL-8) Immune genes (e.g., IL-2) Activation: anti-inflammatory genes (e.g., DUSP1), genes of metabolism Rapid effects, “non-genomic” (minutes) High dose prednisone (>30 mg/d)  T cell receptor signaling  prostaglandin release  vascular endothelial activation nri2262-f3 Glucocorticoids - Mechanisms Glucocorticoids Anti-inflammatory actions  vascular permeability/dilation (NO)  neutrophil/monocyte migration (IL-8, ICAM1)  IL-1b, TNF-a, IL-6, GM-CSF, FcR (macrophages)  IL-10, TGF-b  PLA2, COX-2  collagenase Glucocorticoids Immunosuppressive actions Lymphopenia (T > B, CD4 > CD8) Redistribution to spleen/marrow/skin/sites of inflammation Apoptosis (high-dose)  T cell activation Tyrosine kinases IL-2 (calcineurin-dependent) LFA1, CD2 CD80/86 and MHC-II expression on APCs Immune deviation:  Th1 (IFN-g) Th2 (IL-10)  pDCs and IFN-a (SLE) B cell functions/Ig synthesis resistant to GC effects (and half-life of IgG is 14-21 days) Glucocorticoids Risk of Infection Dose-dependent Opportunistic infections: Mycobacterial disease (TB, non-TB) VZV reactivation (1.5 – 2x) Pneumocystis (> 20 mg/d) Daily dose of prednisone (mg) Increase risk of serious infection (AHR) Up to 5 1.3 5 – 10 1.8 10+ 3 20+ 5 JAMA 2011;306:2331. Rheum Dis Clin N Am 2012;38:727 JAMA 2011;306:2331. Rheum Dis Clin N Am 2012;38:727 Cyclophosphamide Mechanisms of Action Active metabolites: 4-OH-CYC, acrolein, phosphoramide mustard DNA crosslinker (inhibits synthesis) Chronic lymphopenia, CD4 > CD8, B cells (? Important) Specific suppression of autoAbs Prolonged reduction in CD4+ T cell functions http://www.medhelp.org/drug_images/ROX41290.JPG cyclophosphamide Glucocorticoids Risk of Infection Dose-dependent Opportunistic infections: Mycobacterial disease (TB, non-TB) VZV reactivation (1.5 – 2x) Pneumocystis (> 20 mg/d) Daily dose of prednisone (mg) Increase risk of serious infection (AHR) Up to 5 1.3 5 – 10 1.8 10+ 3 20+ 5 JAMA 2011;306:2331. Rheum Dis Clin N Am 2012;38:727 JAMA 2011;306:2331. Rheum Dis Clin N Am 2012;38:727 Cyclophosphamide Mechanisms of Action Active metabolites: 4-OH-CYC, acrolein, phosphoramide mustard DNA crosslinker (inhibits synthesis) Chronic lymphopenia, CD4 > CD8, B cells (? Important) Specific suppression of autoAbs Prolonged reduction in CD4+ T cell functions http://www.medhelp.org/drug_images/ROX41290.JPG cyclophosphamide Cyclophosphamide Risk of Infection Risk factors: Leukopenia Glucocorticoids Infections: Bacterial infection Opportunistic infections Pneumocystis jirovecii (CD4+ lymphopenia*) MTB Nocardia Aspergillus VZV, HPV *BMC Infect Dis. 2004;4:42 http://www.medhelp.org/drug_images/ROX41290.JPG cyclophosphamide Cyclophosphamide Risk of Malignancy Leukemia, skin CA, others Chromosomal damage, immune surveillance Synergizes with anti-TNF drugs (Arthritis Rheum. 2006;54(5):1608.) Bladder CA Risk increases with cumulative CYC, time Associated with cystitis, ? activation of BK virus http://www.medhelp.org/drug_images/ROX41290.JPG cyclophosphamide Cyclophosphamide Risk of Infection Risk factors: Leukopenia Glucocorticoids Infections: Bacterial infection Opportunistic infections Pneumocystis jirovecii (CD4+ lymphopenia*) MTB Nocardia Aspergillus VZV, HPV *BMC Infect Dis. 2004;4:42 http://www.medhelp.org/drug_images/ROX41290.JPG cyclophosphamide Cyclophosphamide Risk of Malignancy Leukemia, skin CA, others Chromosomal damage, immune surveillance Synergizes with anti-TNF drugs (Arthritis Rheum. 2006;54(5):1608.) Bladder CA Risk increases with cumulative CYC, time Associated with cystitis, ? activation of BK virus http://www.medhelp.org/drug_ima ges/ROX41290.JPG cyclophosphamide Azathioprine Mechanisms of Action TIMP and 6-TG suppress intracellular purine synthesis  B and T cell numbers  CD28 signaling  CD4+ T cell apoptosis  Ig synthesis  IL-2 secretion C:\Users\Parul\Desktop\AZA_metabolism.jpg Azathioprine Mechanisms of Action TIMP and 6-TG suppress intracellular purine synthesis  B and T cell numbers  CD28 signaling  CD4+ T cell apoptosis  Ig synthesis  IL-2 secretion C:\Users\Parul\Desktop\AZA_metabolism.jpg Azathioprine Risk of infection: RR 1.5 (Rheumatol 2007;46:1157-60) Viral infections VZV Reactivation of HBV Bacterial infections with neutropenia Predictable myelosupression Genetics Allopurinol UpToDate October 2013 C:\Users\Parul\Desktop\AZA_metabolism.jpg Eichelbaum M, Ingelman-Sundberg M, Evans WE. Annu Rev Med. 2006.57:119-137. Toxicity Allopurinol Febuxostat TPMT -/- 0.3% TPMT +/- 10% TPMT +/+ 90% Azathioprine Risk of Malignancy: SCC, NHL Renal transplant: 50 – 100 x risk RA patients: 1.5 – 10 x risk However, active disease and CYC use seem to be relatively stronger risk factors Azathioprine Risk of infection: RR 1.5 (Rheumatol 2007;46:1157-60) Viral infections VZV Reactivation of HBV Bacterial infections with neutropenia Predictable myelosupression Genetics Allopurinol UpToDate October 2013 C:\Users\Parul\Desktop\AZA_metabolism.jpg Eichelbaum M, Ingelman-Sundberg M, Evans WE. Annu Rev Med. 2006.57:119-137. Toxicity Allopurinol Febuxostat TPMT -/- 0.3% TPMT +/- 10% TPMT +/+ 90% Azathioprine Risk of Malignancy: SCC, NHL Renal transplant: 50 – 100 x risk RA patients: 1.5 – 10 x risk However, active disease and CYC use seem to be relatively stronger risk factors Azathioprine Risk of infection: RR 1.5 (Rheumatol 2007;46:1157-60) Viral infections VZV Reactivation of HBV Bacterial infections with neutropenia Predictable myelosupression Genetics Allopurinol UpToDate October 2013 C:\Users\Parul\Desktop\AZA_metabolism.jpg Eichelbaum M, Ingelman-Sundberg M, Evans WE. Annu Rev Med. 2006.57:119-137. Toxicity Allopurinol Febuxostat TPMT -/- 0.3% TPMT +/- 10% TPMT +/+ 90% Azathioprine Risk of Malignancy: SCC, NHL Renal transplant: 50 – 100 x risk RA patients: 1.5 – 10 x risk However, active disease and CYC use seem to be relatively stronger risk factors Azathioprine Risk of Malignancy: SCC, NHL Renal transplant: 50 – 100 x risk RA patients: 1.5 – 10 x risk However, active disease and CYC use seem to be relatively stronger risk factors Case 2 56 y.o. man taking MTX 15 mg weekly for erosive, seropositive RA. Ever since increasing dose from 10 to 15 mg/week, he has enjoyed excellent control of RA symptoms but has complained of persistent stomatitis. Addition of folic acid, 1 mg daily, to this patient’s regimen of MTX 15 mg/week is expected to Reduce MTX-associated stomatitis and MTX DMARD activity Reduce MTX-associated stomatitis but not MTX DMARD activity Have no effect on MTX-associated stomatitis Have no effect on either MTX-associated stomatitis or MTX DMARD activity C:\Users\Parul\Desktop\514px-Methotrexate_1u72_svg.png Methotrexate Mechanisms of action Anti-proliferative High doses (oncology): blocks folate-dependent pathways of purine and pyrimidine metabolism/protein synthesis At lower (rheumatology) doses: ? Anti-proliferative (T cells, synoviocytes) Mediated by MTXglu (4 months to reach steady state) Increased extracellular adenosine (anti-inflammatory) C:\Users\Parul\Desktop\514px-Methotrexate_1u72_svg.png Methotrexate Risk of Infection in RA (Rheumatology 2009;48:867) Minimal (except for neutropenia) Zoster: no compelling evidence Peri-operative: appears to be safe In RA, infection risk associated with active disease, GC use and biologics Risk of neoplasm (Seminars Diagnostic Pathol 2013;30:102) Likely small increased risk Diffuse large cell lymphoma, EBV+ Leflunomide Mechanisms of Action Anti-proliferative Inhibits pyrimidine synthesis Risk of Infection Low - modest Increased with simultaneous MTX or prednisone (Drug Saf 2009;32:1123) http://images.ddccdn.com/img/mol/DB01097.mol.t.jpg Case 3 With regard to protective antibody responses, treatment with rituximab is expected to Reduce levels of anti-VZV titers in someone with history of chicken pox Impair anti-pneumococcal polysaccharide responses after PPSV23 vaccination Have no effect on antibody titers after vaccination with live-attenuated virus, e.g. yellow fever virus Have no appreciable effect on anti-VZV titers in someone with a history of chicken pox Rituximab Mechanisms of Action Chimeric anti-CD20 Ab Rapid vs. delayed/prolonged effects B cell depletion (tissue/circulating) Apoptosis* Growth arrest FcgR-dependent Ab-mediated cytotoxicity** Complement-mediated lysis Targets naïve and memory B cells Decreases AutoAbs (RF, ANCA, anti-dsDNA) With single course, minimal reduction in serum Ig levels (why?) Pre-existing long-lived plasma cells unaffected by rituximab – why? CD20+ Rituximab Risk of Infection Serious infection rate of 4-6/100 patient-years (similar to anti-TNF, RR ~ 1.5 - 2) No apparent TB or OI signal in RA trials (unlike anti-TNF) HBV reactivation ? (in NHL) PML? (isolated cases) With repeated doses,  IgM, IgG and IgA (why?) Does this  infection rate? Rituximab Infusion reactions (30 – 45%, first infusion) Mild: Headache, F/C/S, back pain, mild tongue/throat tightness SIR: fever + muscular pain (lymphoma) Anaphylaxis: warning signs: urticaria, repetitive cough, wheeze, throat tightness, change in voice signs: urticaria, repetitive cough, wheeze, throat tightness, change in voice and restart at ½ rate (protocol) SIR: more APAP, steroids, demerol Anaphylaxis: airway protection, O2, volume, epinephrine + bronchodilators (protocol) Photo of medication Photo of medication Mycophenolate mofetil (MMF) Mechanisms of Action Targets for inhibition lymphocyte inosine monophosphage (IMP) dehydrogenase (IMPDH2) and de novo purine nucleotide synthesis  T and B cell proliferation  Ab responses (tetanus toxoid)*  lymphocyte adhesion molecules ? Anti-proliferative effects on vascular endothelium //upload.wikimedia.org/wikipedi a/commons/7/7e/Mycophenolate_mofetil_skeletal.svg File:Mycophenolate mofetil skeletal.svg Comparison of T cell drugs Abatacept Mycophenolate mofetil (MMF) Risk of Infection (transplant patients) VZV, CMV reactivation (renal transplant) Protective v. PJP? Rheum patients: SLE: unique risks (hypocomplementemia) Prior CYC Risk of neoplasm Theoretical //upload.wikimedia.org/wikipedia/commons/7/7e/Mycophenolate_mofetil_skeletal.svg File:Mycophenolate mofetil skeletal.svg Photo of medication Photo of medication Mycophenolate mofetil (MMF) Risk of Infection (transplant patients) VZV, CMV reactivation (renal transplant) Protective v. PJP? Rheum patients: SLE: unique risks (hypocomplementemia) Prior CYC Risk of neoplasm Theoretical //upload.wikimedia.org/wikipedia/commons/7/7e/Mycophenolate_mofetil_skeletal.svg File:Mycophenolate mofetil skeletal.svg Photo of medication Photo of medication Intravenous Ig (IVIg) Mechanisms of Action Inhibits activity of innate cells FcgRIIB (sialylated IgG) FcR blockade? E.g., splenic macrophages and ITP Anti-idiotype activity; increased catabolism of autoABs (FcRn) Inhibits antigen presentation T cell targeting:  Th1/Th17,  Tregs Decreased autoAb production (Fc, F(ab’)2) Intravenous Ig (IVIg) Risk of Infection Protective (in CVID) Risk of transmitted infection exceedingly low Risk of Neoplasm Unlikely Key points Except for biologics, mechanisms of action are not well understood Glucocorticoids are used to limit immune-mediated injury Control of underlying autoimmunity relies on targeting proliferation, survival or activation of T cells, B cells and other antigen presenting cells Most important risk factors for infection are steroid use, active disease, and drug-induced leukopenia Excess risk of neoplasm is low for individual drugs Immunomodulators and immunosupressants October 22, 2013 Grant Hughes, MD C:\Users\Parul\Desktop\514px-Me thotrexate_1u72_svg.png cyclophosphamide //upload.wikimedia.org/wikipedi a/commons/7/7e/Mycophenolate_mofetil_skeletal.svg File:Mycophenolate mofetil skeletal.svg Immunomodulators and immunosupressants