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Monitoring Biologic Therapy in Rheumatoid Arthritis and Psoriatic Arthritis

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Monitoring Biologic Therapy in Rheumatoid Arthritis and Psoriatic Arthritis Larry W. Moreland, MD Margaret J. Miller Endowed Professor for Arthritis Research Chief, Division of Rheumatology and Clinical Immunology October 25, 2018 Disclosures Research Funding • Bristol Myers Squibb • Genentech • Mallinckrodt • Pfizer • Roche Consulting • Boehringer Ingelheim - DSMB • Pfizer – DSMB • Xencor – DSMB Objectives • Names of biologics and targets in immune system • General adverse events with each biologic class • Guidelines for monitoring and prevention of side effects Rheumatoid Arthritis Pathogenesis Rheumatoid Arthritis Major Advances • Anti-citrullinated protein antibody (ACPA) • Etiologies are emerging (e.g. smoking, etc.) • Targeted immunotherapies Novel Therapeutic Targets in Rheumatology Disease Modifying Antirheumatic drugs (DMARDs) RA Treatment – 2018 Traditional Biological OTHER methotrexate - Anti-TNF - Jakinibs adalimumab tofacitinib sulfasalazine etanercept baricitinib hydroxychloroquine infliximab leflunomide golimumab certolizumab - Biosimilars azathioprine - Anti-IL-1 gold salts anakinra - Co-stimulatory abatacept - B-cell rituximab - Anti-IL-6 tocilizumab sarilumab Psoriatic Arthritis Therapies 2018 DMARDs Oral Biologics methotrexate Anti-TNF Anti-IL-17 leflunomide etanercept secukinumab sulfasalazine infliximab ixekizumab cyclosporine A adalimumab apremilast golimumab Co-stimulatory acitretin certolizumab blockers abatacept Anti-IL12/IL23 ustekinumab Jakinibs guselkumab tofacitinib Monitoring for toxicity of Biologics • Biologics often used in combination with other immunosuppressive agents • Monitor for methotrexate, leflunomide, hydroxychloroquine toxicity Rheumatoid Arthritis Traditional DMARDs: Key Points • Methotrexate is one of the most durable and frequently used disease-modifying antirheumatic drugs (DMARDs) in monotherapy as well as the cornerstone of combination therapy. • Leflunomide, sulfasalazine, and hydroxychloroquine are effective therapies in RA and are commonly employed in combination therapy. • Choice of DMARD therapy tailored to the individual patient, with attention given to age, fertility plans, concomitant medications, and comorbidities. Methotrexate • Baseline: • CBC, creatinine, AST, chest x-ray • Hepatitis serologies • Every 3 to 4 months: CBC, creatinine, liver enzymes • Avoid MTX in renal insufficiency • Contraindicated in pregnancy, use reliable form of contraception What next after Methotrexate (MTX inadequate or partial responders)? • “triple therapy” (MTX+HCQ+SSZ) • leflunomide • anti-TNF (5 approved by FDA) • abatacept (co-stimulatory blockade) • tocilizumab (anti-IL-6R) • sarilumab (anti-IL-6) • tofacitinib (janus kinase inhibitor) • rituximab (B-cell inhibition) Anti-TNF inhibitors Chimeric Monoclonal Ab Human recombinant Human recombinant Receptor/Fc fusion protein Antibody Human monoclonal Antibody Humanized Fab Fragment - Peg Benefits of TNF Blockade • Marked improvement in half to two-thirds of patients (most in combination with methotrexate) • Approved for treatment of RA, juvenile arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, inflammatory bowel disease • Significant disease modification • Dramatic normalization of acute phase reactant • Decreased frequency of cardiovascular events Contraindications/Caution to Use of Anti-TNF Agents • Moderate to Severe CHF • Active infection or TB • Active hepatitis B without treatment • MS or demyelinating disorder TNF Inhibitors: Safety • Infections - Bacterial - Tuberculosis - Other opportunistic infections • Demyelination • Injection/infusion-related events • Drug-induced SLE/vasculitis • Development of neutralizing anti-drug antibodies Screening for Latent TB • Tuberculin skin test • Interferon-� Release Assays (IGRAs) Tuberculin skin test • Detects cell-mediated immunity to M. Tb • Skin induration resulting from intradermal injection of purified protein derivative • Antigens shared by Mtb, M. bovis, Bacillus Calmette–Guérin (BCG) • Disadvantages • Limited sensitivity in immunocompromised • Limited specificity in patients with prior BCG • Boosting phenomenon • Requires 2 clinic visits Interferon-� Release Assays (IGRAs) • Measure of in vitro IFN-� production upon antigen stimulation • Stimulation with peptides that are restricted to the MTB genome (ESAT-6, CFP-10, TB 7.7) not present in BCG • Tests: - Quantiferon-TB Gold in-tube (ELISA, whole blood) - T-SPOT TB (ELISpot, PBMCS) • Advantages Single clinic visit Not affected by BCG history Rheumatoid Arthritis Risk of infections • Over 50 years ago first noted increased risk – Pathology of RA itself (break in self-tolerance) – “premature aging” of immune system in RA – Chronic comorbid conditions: Diabetes, COPD, functional decline – Lifestyle factors: smoking • Methotrexate • Glucocorticoids • TNF-α inhibitors and others Rheumatology 2013;52:53-61 Risk of Infection RA and PsA • SMALL absolute risk of bacterial, opportunistic, viral, and fungal infections with all biological therapies • ↑ risk due to disease itself • Anti-TNF: ↑ risk infection; respiratory, skin and soft-tissue • ↑ risk of Tb with anti-TNF NO ↑ risk with other classes of biologics • Probable (low) increased risk PML (progressive multifocal leukoencephalopathy) with RTX • ↑ risk shingles with all biologics, more risk with tofacitinib Best Practice and Research Clin Rheum 2015; 29:290-305 Arthritis Care & Research 2018; 70: 679-684 JAMA 2011; 306:2331-2339 Lancet 2015; 386: 258-265 TNF-α antagonists and the risk of hospitalization from serious infections • Large databases • Serious infections requiring hospitalization during first 12 months after initiation of TNF-α antagonist or nonbiologic regimens (Tb and opportunistic infections were not considered) • Initiation of TNFα antagonists compared with nonbiologic regimens, was not associated with an increased risk of hospitalizations for serious infections • Steroids: dose-dependent increase in infections Carlos G. Grijalva, et al; JAMA 2011; 306:2331-2339 Rheumatoid Arthritis Malignancy • Chronic inflammation and autoimmune diseases are associated with the development of malignancies • Regardless of treatment regimen, there is an increased frequency of malignancies: – Hodgkin’s lymphoma – Non-Hodgkin’s lymphoma – Leukemia – Myeloma – Lung cancer • Methotrexate is associated with risk of non-melanoma skin cancer • No data that biological therapies increase risk of malignancy • Melanoma risk with TNFi? Annals Rheum Disease 2017;76:386-391 Melanoma Research 2016;26:517-523 JAMA Dermatol 2016;52:164-172 Risk of invasive melanoma in patients with rheumatoid arthritis treated with biologics: results from a collaborative project of 11 European biologic registers • Large European collaborative study • No increase of melanoma with TNFi Ann Rheum Dis 2017;76:386-391 Immunogenicity of biologics • Exact incidence not known, most commonly seen with infliximab and adalimumab • May decrease efficacy • Co-administration of methotrexate will decrease anti-drug antibodies Percentage of patients developing antiadalimumab antibodies (AAA) per baseline methotrexate (MTX) dose group Ann Rheum Dis 2012;71:1914-1915 Paradoxical Reactions • Appearance of or exacerbation of pathological condition that usually responds to this class of drugs. • anti-TNF: new onset or worsening psoriasis, uveitis, sarcoidosis, pyoderma gangrenosum • anti-IL-6: new onset psoriasis • anti-IL-17: onset of IBD Anti-TNF agents Paradoxical Adverse events Cutaneous lesions • Types of rashes - psoriasiform lesions - plaque, palmopustular, guttate lesions - granulomatosus dermatitis - vasculitis - acute generalized exanthematosus pustulosis - neutrophilic eccrine hidradenitis - Sweet’s syndrome • seen with all 5 anti-TNF agents • onset variable: weeks to years Drug Safety Quarterly 2013;4:1-7 Interleukin-6 inhibition • Agents – tocilizumab (blocks IL-6R) – sarilumab (blocks IL-6R) – tofacitinib (Janus kinase inhibitor) – baricitinib (Janus kinase inhibitor) • Toxicities – Liver elevations (mild, reversible) – Neutropenia (mild, reversible) – Hypercholesterolemia – GI perforations, diverticulitis – Infections (skin) Janus kinase inhibitors Jakinibs block multiple aspects of cytokine signaling Current Opinion in Pharmacology 2012;12:464-470 Anti-IL-6 Monitoring − Baseline: CBC, liver enzymes, Hepatitis screen, Lipid profile, screen for latent TB − Follow up every 3 months – CBC, LFT, Creatinine − Lipid profile every 6 months Risk of Gastrointestinal Perforation Among Rheumatoid Arthritis Patients Receiving Tofacitinib, Tocilizumab, or Other Biologic Treatments • The risk of lower GI tract perforation associated with tocilizumab treatment, and possibly tofacitinib, is elevated compared to that associated with TNFi Arthritis Rheumatol. 2016; 68:2612-2617 Rituximab (anti-CD20) − Lymphoma − Rheumatoid arthritis − ANCA-associated vasculitis Granulomatosis with polyangitis (GPA) Microscopic polyangitis (MPA) Rituximab anti-CD20 • CD20 expressed on B-cells • Rapid depletion of B-cells • Primary adverse events – Infusion reactions, pre-treat with IV steroids – Hypogammaglobulinemia • can be severe, persistent • More common in lymphoma • 3.5% with RA – Infections • General infections • Hepatitis B virus reactivation • Progressive multifocal leukoencephalopathy (PML) International Reviews of Immunology 2017;0:1-8 J Autoimmunity 2015; 57:60-65 Hepatitis B Reactivation in Rheumatic Diseases Screening and Prevention • Risk for hepatitis B virus (HBV) reactivation is high for patients with chronic infection treated
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