Monitoring Biologic in and

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 (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 - Anti-TNF - Jakinibs certolizumab - Biosimilars - Anti-IL-1 salts - Co-stimulatory - B- - Anti-IL-6 Psoriatic Arthritis 2018 DMARDs

Oral Biologics methotrexate Anti-TNF Anti-IL-17 leflunomide etanercept sulfasalazine infliximab cyclosporine A adalimumab golimumab Co-stimulatory acitretin certolizumab blockers abatacept Anti-IL12/IL23 Jakinibs 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

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, , 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 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 • 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 stimulation • Stimulation with 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 • 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 • 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 with high-dose steroids, TNFi, and rituximab without antiviral prophylaxis, whereas it seems to be minimal for patients with past HBV infection. • HBV screening is required for all rheumatic patients before immunosuppressive therapies. • Prophylatic antiviral therapy is required for all patients starting long-term steroids and biologics. • Patients with past HBV infection receiving high-risk therapy , such as RTX, should be screened and monitored by HBV DNA measurements.

Rheum Dis Clin N Am 2017; 43: 133-149 J Infectious Dis 2017; 215: 566-573 Co-Stimulatory Blockers

Abatacept Multiple Costimulation Pathways Modulate Activity

APC T Cell Effect CD40 CD40-L + PD-1L PD-1 - ICOS-L ICOS + CD80/86 CTLA4 - MHC TCR + CD80/86 CD28 + PD-2L ? ?

B7-H3 ? ? Vaccines and Disease-Modifying Antirheumatic Drugs Practical Implications

• is reduced by rituximab and possibly abatacept, but is not reduced by methotrexate, anti- (TNF) therapy, tofacitinib, or tocilizumab. • Pneumococcal vaccine immunogenicity is reduced by rituximab, tofacitinib, and methotrexate, but it is not reduced by anti-TNF therapy or tocilizumab. • Live vaccines, such as shingles and yellow fever vaccines, are contraindicated in immunosuppressed patients, although observational data from patients inadvertently vaccinated while on biologic therapy suggest that this vaccine may be safer in the setting of some biologics than previously thought. • Important gaps in our understanding include the efficacy of the newer 13-valent pneumococcal conjugate vaccine in the setting of rheumatoid arthritis, safety of shingles vaccine in the setting of biologics, and the impact of newer biologic drugs on vaccine immunogenicity. • Rituximab profoundly reduces influenza and pneumococcal vaccine immunogenicity and vaccinations should be timed before rituximab or as long after rituximab dosing as compatible with vaccination schedules.

Rheum Dis Clin N Am 43 (2017) 1-13 Herpes zoster (shingles)

• Reactivation of varicella-zoster virus, predilection for elderly and immunocompromised • 1.5 to 2.0 fold higher risk • Morbidity, pain, long-term disability with post-herpetic neuralgia • Dissemination potential in immunocompromised • ? Individuals who are as young as age 40 could potentially benefit from vaccine • Vaccinate all patients age 50 to 80 before immunosuppression

JAMA 2013; 309: 887-895 Arthritis Rheum 2016; 68: 2328-2337 Zostavax®

• Live-attenuated vaccine • Prevention of HZ and its complications – ↓ HZ by 51% – ↓ PHN by 67% • FDA recommendations – Healthy adults ≥ 50 years recommendations • CDC recommendations – Healthy adults ≥ 60 years – OK in chronic medical conditions unless contraindicated • Contraindications – High dose steroids (≥ 20 mg/day prednisone), methotrexate, azathioprine, biologics, JAK inhibitors

MMWR 2018;67:103-108 Recombinant Zoster Vaccine - Shingrix • Non live recombinant, subunit combined with potent adjuvant • Administered in two IM doses • Adults ≥ 50 years • Phase 3 trial in > 38,000 participants – > 90% effective in preventing HZ – CDC: the preferred vaccine – No recommendations for use in pregnancy or adults immunocompromised Cardiovascular & Lipids

• Risk of cardiovascular disease in two-fold higher in RA patients • Risk factors: – Hypertension – Hyperlipidemia – Diabetes – Chronic systemic inflammation • Treatment with biologics (and MTX) results in elevations of total cholesterol and LDL cholesterol • Need for understanding mechanisms by which inflammation increases risk of CVD in RA

Arthritis Rheumatol 2015;67:327-329 Vascular Pharmacology 2016;81:22-30 Current Opin Rheum 2017; 29:277-284

Figure 1: Changes in mean LDL-C and HDL-C from baseline to 24 weeks among patients randomized to MTX + ETA, Triple Therapy or MTX monotherapy

HDL-C = high density lipoprotein cholesterol; LDL-C = low density lipoprotein cholesterol; TC = Total cholesterol All p values compared result at 24 weeks to baseline were p < 0.0001 There were no significant differences between the 3 treatment arms for any of the 3 different lipoproteins

Arthritis Rheum, 2013;65:1430-1438 What to do with biologics and other medications perioperatively? 2017 American College of Rheumatology/ American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients with Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty

Arthritis Rheumatol. 2017; 69:1538-1551 Management of Perioperative Medications for Rheumatoid Arthritis • Patients with rheumatic diseases undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA) are at increased risk for periprosthetic joint infection. • Appropriate management of antirheumatic medication in the perioperative period may provide an important opportunity to mitigate risk. • Nonbiologic disease-modifying antirheumatic drugs may be continued throughout the perioperative period in patients undergoing elective THA and TKA • Biologic medications should be withheld as close as 1 dosing cycle as scheduling permits prior to elective THA and TKA and restarted after evidence of wound healing, typically 14 days. Arthritis Rheum 2017;69:1538-1551 Anti-Rheumatic Drugs Also Confer Fetal Risks

FDA Pregnancy Risk Categories*: A/B: no evidence of risk in studies; C: risk cannot be ruled out; D: positive evidence of risk; X: contraindicated in pregnancy Therapy FDA risk category Hydroxychloroquine C Colchicine C (anti-BAFF) C Rituximab (anti-CD20) C Abatacept (T-Cell Costim C Blocker) Tocilizumab (anti-IL6R) C Tofacitinib (Jak inh) C Mycophenolate mofetil D Methotrexate X

Leflunomide X

• Up to 17% of pregnancies are inadvertently exposed to fetotoxic drugs

*Former classification system; Weber-Schoendorger et al., 2014; Prager et al., 2015 Treatment Options for RA during pregnancy

• RA can spontaneously remit during pregnancy • Hydroxychloroquine, sulfasalazine and non- fluorinated steroids – Yes • Methotrexate and leflunomide – No • TNFi: safe during pregnancy • Other biologics – scant data – Stop tocilizumab, rituximab, abatacept or tofacitinib

Expert Opinion on Pharmacotherapy 2016;17:1539-1547 Arthritis & Rheumatology 2018;70:1359-1363 Expert Review of Clinical Immunology 2016;12:937-944 Arthritis & Rheumatology 2018;70:1399-1407 Recently available biologics for Psoriatic Arthritis IL-17 emerging as new drug target for autoimmunity

Langley NEJM 2014 IL-17 and IL-12/IL-23 Psoriatic Arthritis – new biologics

• Agents – ustekinumab (Stelara) – IL12/IL23 – guselkumab (Tremfya) – IL-23 – secukinumab (Cosentyx) – IL-17A – ixekizumab (Taltz) – IL-17A

• Monitoring – Screen for latent Tb – No increased risk for serious infection or malignancies – No routine labs needed Role of Primary Care Physicians in Rheumatoid Arthritis

• RA patients co-managed with Rheumatologist • Recognize toxicities of medications and initiate appropriate and timely workup • Recognize the risks for infections and ensure immunization status is current • Monitor and aggressively treat cardiovascular risk factors • Mental health management • Monitor and treat/prevent osteoporosis