From Bloodwork to Biologics: Things We Should Know About Rheumatology

From Bloodwork to Biologics: Things We Should Know About Rheumatology Dr. Philip Baer Mississauga Halton LHIN Primary Care Clinic Day November 19, 2016

Faculty/Presenter Disclosure i Faculty/Presenter: Dr. Philip Baer Relationships with commercial interests: Grants/research support: Speaker s bureau/honoraria: Consulting fees: Eli Lilly, Pfizer, Abbvie, Amgen, Janssen Eli Lilly, AstraZeneca, Pfizer, Abbvie, Amgen, Sobi, Merck, Roche, Janssen, BMS, Takeda, Johnson & Johnson, Novartis, Sanofi-Genzyme Other:

ii Disclosure of Commercial Support This program has received financial support in the form of an educational grant: N/A This program has received in-kind support in the form of logistical support: N/A Potential for conflict(s) of interest: N/A

Mitigating Potential Bias iii Potential sources of bias identified in the preceding 2 slides have been mitigated as follows: Information presented is evidence-based Recommendations made are evidence- or guidelinesbased rather than personal recommendations of the presenter The Speaker completed the CPFC Mainpro Declaration of Conflict of Interest form evidencing compliance with Mainpro requirements, a requisite for this program to be given accredited status

Learning Objectives Understand the correct pre-biologic therapy workup for rheumatic disease patients, using RA as a prototype Monitor rheumatic disease patients regarding comorbidities and issues with biologic therapies Correctly order laboratory tests in rheumatology

Clinical Spectrum of RA: From Bad to Worse In the absence of optimal treatment

Evolution of RA Treatment MTX, Oral gold Anakinra Adalimumab Tocilizumab Gold HCQ, Steroids SSZ D-Pen, AZA Leflunomide Infliximab Etanercept Rituximab Abatacept Golimumab Certolizumab Tofacitinib ASA 1900 1930s 1950s 1960s 1970s 1980s 1998/9 2002 2008 2010 2012 2014 Gold (monotherapy) Era MTX Era Biologic Era Treat Signs and Symptoms in Established Disease Combination and Biologic Rx Disease Modification

Rheumatic Diseases Treated with Biologics Rheumatoid Arthritis Juvenile Idiopathic Arthritis Psoriatic Arthritis (and Psoriasis) Ankylosing Spondylitis (and Axial SpA and IBD) Vasculitis (GPA/MPA) SLE (rarely)? Giant Cell Arteritis/PMR

Biologic Therapies

Newest: IV golimumab; SC tocilizumab and abatacept; biosimilar infliximab

JAK-STAT Inhibitors RA: Newest Agents Oral tofacitinib (Xeljanz) approved in 2014 Oral baracitinib (in Phase 3 trials) and many others IL-6 inhibitors Sarilumab; Sirukumab Biosimilars (Subsequent Entry Biologics) Inflectra (infliximab) approved in Canada 2014 Biosimilar etanercept (Brenzys) approved 2016 Many more to come

RA: Side Effects of TNF Antagonists Infection - common/opportunistic (TB) Bone marrow suppression (rare) Psoriasis-like rashes Malignancy (non-melanoma skin cancers) Exacerbation of CHF Exacerbation of MS

www.rheuminfo.com

66 year old woman RA for 12 years RA Case Swollen joints 2, tender joints 4 ESR 30 Happy with RA control Husband calls to cancel her follow-up appointment: She died of a heart attack last week.

RA Case Revisited 66 year old woman Smoker Total cholesterol 6.6 mmol/l BMI 29 BP 140/90 Sedentary

RA and Cardiovascular Disease Inflammation Inflammation

CV Risk: Think of RA Like Diabetes Variable Goal LDL-C < 2.6 mmol/l BP <130 SBP & <80 DBP Smoking Stop Blood glucose A1C < 7.0 Obesity Weight loss Consider low dose ASA

RA: Practical Management Tips RA patients on biologic and non-biologic DMARDs Monitoring lab tests Surgery Infections Immunizations Pregnancy Malignancy

NEW 2011/2012 CRA Recommendations for the Pharmacological Management of RA with Traditional and Biologic DMARDs http://rheum.ca/en/publications/cra_ra_guidelines

RA: Monitoring Lab Tests Bhupinder, who is on Methotrexate for RA, asks what labwork is required as part of routine monitoring of her condition What if she were on other traditional DMARD therapy? What if she were on biologic DMARD therapy?

RA: Drug Initiation Monitoring

RA: Monitoring Lab Tests

Real Life Vignette 1 I get back a low hemoglobin of 72 on routine monitoring of a 43 y.o. female RA patient on MTX who was stable 6 weeks ago at the last visit, when her Hgb was 116 WBC and platelets are wnl ESR and CRP are wnl I quickly contact patient and FP No one told me patient had new heavy menstrual bleeding and was already seeing a gynecologist

Real Life Vignette 2 I give a patient a form for q6week monitoring of her MTX therapy (CBC, liver enzymes, renal function, ESR, CRP) At 2AM one night, I am awoken by the lab telling me that the patient has a critical lab value Random glucose of 32 Moral: Please don t take a rheumatologist s lab requisition and add your own unrelated tests to it

RA: Surgery Ashley, who has been on Methotrexate and an anti- TNFα agent for 12 months, calls because she is booked for an elective hysterectomy in 3 months She wants to know if she should stop any of her drugs

Perioperative Care Recommendation 1. Methotrexate can be safely continued in the perioperative period for RA patients undergoing elective orthopedic surgery. 2. Biologics should be held prior to surgical procedures. The timing for withholding therapy should be based on the individual patient, the nature of the surgery, and the pharmacokinetic properties of the agent. Biologic DMARDs may be restarted postoperatively if there is no evidence of infection and wound healing is satisfactory. Level of Evidence I II, IV Strength Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165 A C 27

RA: Active Infection Mark, who has been on an anti-tnfα agent for just over 2 months, calls because he has a sore throat He wants to know if he should stop therapy

Intercurrent Infections & anti-tnfα Agents Mild infection (e.g., common cold) Continue treatment with increased vigilance Moderate or severe infection Stop treatment Treat promptly with antibiotics Discuss immediately with rheumatologist Tuberculosis suspected Stop treatment Discuss immediately with rheumatologist Product monographs for Enbrel, Humira, Remicade and Simponi

Latent Tuberculosis Infection (LTBI) Recommendation 3. Screening for latent tuberculosis infection (LTBI) is recommended prior to starting Anti-TNF therapy (II), abatacept (ABAT) and tocilizumab (TCZ) (IV). Screening should consist of a history including an assessment of LTBI epidemiologic risk factors, physical exam, tuberculin skin test (TBST) and a chest x-ray in high-risk groups (II). Physicians should exercise clinical judgment as to the need to repeat screening in patients who tested negative in prior screening and have new epidemiologic risk factors (IV). Level of Evidence II, IV Strength B Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165 30

Latent Tuberculosis Infection (LTBI) Recommendation 6. Biologic agents may be started 1-2 months after the initiation of latent tuberculosis infection (LTBI) prophylaxis. Level of Evidence II, IV Strength B Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165 31

RA: Immunizations Jean, 54, was prescribed an anti-tnfα agent by her rheumatologist in July It is now October, and she wants to know if she should get her annual flu shot

RA: Immunizations

Vaccination Live attenuated vaccines Bacillus Calmette Guérin (BCG) Influenza - nasal Measles/mumps/rubella (MMR) Polio - oral Smallpox Typhoid (oral) Varicella/ Herpes Zoster Yellow fever Classification of Common Vaccines Inactivated/killed vaccines Diphtheria Hemophilus influenza type B (protein conjugate) Hepatitis A Hepatitis B Human Papilloma Virus (HPV) Inactivated poliomyelitis (IPV) Influenza - intramuscular Meningococcal Pertussis Pneumococcal (23-valent polysaccharide) Pneumococcal (seven-valent protein conjugate) Rabies Tetanus* Typhoid - intramuscular * Tetanus + diphtheria toxoids adsorbed + component pertussis (Tdap); tetanus + diphtheria (Td); component pertussis + diphtheria + tetanus toxoids adsorbed (DTaP) Public Health Agency of Canada (PHAC) Canadian Immunization Guide: http://www.phac-aspc.gc.ca/publicat/cig-gci/ p01-eng.php Rahier et al. Rheumatology 2010. Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165 34

RA: Pregnancy Sandra is on combination DMARD therapy She is 28, has one infant son and would like to have more children

Pregnancy and RA RA improves in pregnancy, although not in those with highly active disease. Ensure good disease control before conception 75-85% of RA patients improve significantly during pregnancy Post-partum flare is avoidable with medications 90% of RA patients will flare post-partum within first 6 months Providing tighter RA control during pregnancy improves maternal and baby health outcomes Treating pregnant RA patients is not necessary Rheumatoid arthritis does not affect pregnancy outcome

Pregnancy: FDA drug categories Biologics Certolizumab Etanercept Adalimumab Abatacept Infliximab Rituximab Golimumab Tocilizumab Non-biologics Hydroxychloroquine Leflunomide Methotrexate Sulfasalazine B B B C B C B C C X X B A controlled studies in humans show no risk B no evidence of risk in animals, no controlled studies in humans OR evidence of risk in animals, not confirmed in humans C evidence of risk in animals, no controlled studies in humans OR no studies available in animals or humans; potential benefits may justify the potential risk D positive evidence of human fetal risk, but potential benefits may outweigh the risks X - contraindicated in pregnancy Temprano K et al. Rheumatoid Arthritis and Pregnancy: Treatment and Medication. Available at http://emedicine.medscape.com/article/335186- treatment. Accessed Sep 10, 2009; U.S. Prescribing Information for Cimzia, Enbrel, Humira, Orencia, Remicade, Rituxan, Simponi.

Class Agent FDA Comments NSAIDs Celecoxib C Diclofenac C Ketorolac C Piroxicam C All Others B 3 rd Trimester D Minimal first and second trimester risk Significant maternal and fetal effects in third trimester Corticosteroids Prednisone C Cortisone All others D C Minimal risk

www.rheumatology.org

RA: Malignancy Sandra has had RA for 3 years and is not controlled with triple DMARD therapy. A biologic therapy is indicated but she had breast cancer 6 years ago. She is now in remission after surgery, chemotherapy and radiation. Which treatments would be reasonable?

Malignancy Summary of CRA Recommendations for Malignancy in RA (Recommendations 10-13) An option Use with caution (Risk unknown/ no evidence) Use with caution; (Some evidence of increased risk) Active Malignancy (Receiving Chemotherapy/Radiation) * * * History of Malignancy Lymphoma Non-melanoma skin cancer Solid tumor Sulfasalazine Hydroxychloroquine Rituximab Methotrexate Leflunomide Sulfasalazine Hydroxychloroquine Methotrexate Leflunomide Sulfasalazine Hydroxychloroquine Abatacept Tocilizumab Abatacept Rituximab Tocilizumab Abatacept Rituximab Tocilizumab * Treatment decisions should be made on a case-by-case basis in conjunction with a cancer specialist & the patient. Methotrexate Anti-TNF Anti- TNF Anti- TNF (melanoma) Bombardier et al. The Journal of Rheumatology 2012; 39:8; doi:10.3899/jrheum.120165 41

RESOURCES

www.rheuminfo.com

www.choosingwiselycanada.org/materials

45 CASE STUDY 60 year old woman Reasons for referral Left knee OA Chronic low back pain with DDD Enclosures with referral Cumulative patient profile ECG X-rays left hip and knee Labs

46 CASE STUDY Labs CBC Chemistry panel TSH, B12, ferritin Urinalysis RF ANA Anti-dsDNA All negative

ARE CERTAIN TESTS REQUIRED WHEN REFERRING TO A RHEUMATOLOGIST? NO! Depends on the clinical scenario Knee problems do not require an MRI, and may not even require an X-ray Low back problems do not require an MRI RF, ANA, Complement studies, ENA antibodies, and HLA B27 are poor screening tests

M-H LHIN RHEUMATOLOGY REFERRAL WEBSITE http://mississaugahaltonhealthline.ca/specialistsearch/esisp ecialistdirectorysearch.aspx

M-H LHIN RHEUMATOLOGY REFERRAL WEBSITE Details to accompany referral: Lab work Imaging All relevant reports

RHEUMATOID FACTOR (RF)

RHEUMATOID FACTOR: POSITIVE TESTS RA 50-90% SLE 15-35% Sjogren s syndrome 75-95% Systemic sclerosis 20-30% Polymyositis/dermatomyositis 5-10% Cryoglobulinemia 40-100% MCTD 50-60% Age >70 10-25% Bacterial endocarditis 25-50% Hepatitis 15-40% Sarcoidosis 3-33% Pulmonary silicosis 30-50% Primary biliary cirrhosis 45-70% Malignancy 5-25%

RF TESTS ARE + IN 5% OF PEOPLE OVER 40

INFLAMMATORY ARTHRITIS IN PATIENTS SENT FOR RF TESTING Final diagnosis in 235 patients sent for RF testing NID RA Other IA Crystal ReA PMR NID=Non-inflammatory disease IA=Inflammatory arthritis ReA=Reactive arthritis, PMR=Polymyalgia rheumatica

REPEAT RF TESTING ONCE RF HAS BEEN + No value BCMA RA Guideline

ANTI-CYCLIC CITRULLINATED PEPTIDE ANTIBODY (ANTI-CCP)

BACKGROUND: CYCLIC-CITRULLINATED PEPTIDE ANTIBODY TEST Test detects the presence of autoantibodies to citrullinated peptides in serum Formation of antibodies to cyclic-citrullinated peptide (CCP) is very specific for adult patients with RA False positives are seen in active TB, Sjogren s, SLE, scleroderma, and inflammatory myositis

DIAGNOSTIC ACCURACY OF ANTI-CCP ANTIBODY AND RF FOR RA Anti-CCP RF Sensitivity 67% 69% Specificity 95% 85% + Likelihood Ratio 12.46 4.86 - Likelihood Ratio 0.36 0.38 Anti-CCP antibodies are more specific than RF for diagnosing RA and may better predict erosive disease Nishimura et al. Ann Int Medicine 2007; 146: 797-808

HLA-B27 ANTIGEN (HLA-B27)

RECOMMENDATION 2 2. Don t order an HLA-B27 unless spondyloarthritis is suspected based on specific signs or symptoms. Guidelines: Assessment of SpondyloArthritis International Society (ASAS) Guidelines 3e Initiative in Rheumatology

HLA-B27 TESTING HLA-B27 is positive in 5-14% of Caucasians HLA-B27 is positive in 7% of Canadians 90% of AS patients are B27 positive But, of 100 B27 + people, only 2 have AS and only 5 have a B27 related disease Low back pain is a ubiquitous condition

HLA-B27 TESTING HLA-B27 is not useful as a single diagnostic test in a patient with low back pain in the absence of other spondyloarthropathy (SpA) signs or symptoms The post-test probability of a + HLA-B27 in a patient with chronic low-back pain alone would not exceed 30% If HLA-B27 is used, at least 2 SpA signs or symptoms, or the presence of positive imaging findings, need to be present to classify a patient as having axial SpA

ANTI-NUCLEAR ANTIBODIES (ANA)

ANA TESTING Should not be used to screen subjects without specific symptoms ANA are present in many nonrheumatic conditions such as infections, medications, other medical conditions, and even in healthy people (up to 20%) In patients with low-test probability, positive ANA results can be misleading and may precipitate further unnecessary testing, erroneous diagnosis or even inappropriate therapy Mahler, Journal of Immunology Research 2014

ANA-IFA TITRES The higher the titre, the more likely the + ANA test is clinically significant 1:40 1:80 1:160 1:320 In patients with disease, higher titres suggest more active disease 1:640 control

ANA + 1/80: GENDER AND AGE 0verall 13.8%

CONDITIONS ASSOCIATED WITH POSITIVE ANA

The American Journal of Medicine Volume 126, Issue 4, Pages 342-348, April 2013

LIMITED VALUE OF + ANA 232 Patients with +ANA AARD 9% No AARD 91% AARD = ANA-associated rheumatic disease

PPV OF HIGHER ANA TITRES REMAINS LOW 30.00% 25.00% 20.00% 15.00% 10.00% AARD SLE 5.00% 0.00% 1:40 1:160 1:640

ANA TESTING: BOTTOM LINE

RECOMMENDATION 1 1. Don t order ANA as a screening test in patients without specific signs or symptoms of systemic lupus erythematosus (SLE) or another connective tissue disease (CTD) Guidelines: American College of Pathologists British Columbia Ministry of Health American College of Rheumatology Italian Society of Laboratory Medicine Guidelines

RHEUMATOLOGY TESTS AND COSTS IN ALBERTA 2012-2014 Test ANA RF Anti-CCP HLA-B27 Total costs Number 63,000 83,000 18,000 350 ordered Cost ($) 3,780,000 1,660,000 900,000 1200 6,340,000 1/50 Albertans had an ANA test in this period

TESTING: RF, CCP, ANA, ESR, CRP Status Number + tests Diagnoses at 1 year Serology done 68 28 1 SLE, 4 RA, 3 PMR Serology not done 798 n/a No rheumatic diseases Patients in Edmonton 2013-14 referred to a single rheumatologist from primary care with 6-24 weeks of joint pain/stiffness/swelling and no prior diagnosis of a rheumatic disease and no prior serology

ANA-IFA PATTERNS Homogeneous Speckled ANA patterns loosely correlate with specific Centromereantibodies and diagnoses Nucleolar

EXTRACTABLE NUCLEAR ANTIBODIES (ENA) ENA Sm RNP Ro, La Topoisomerase Jo1 SLE MCTD/Overlaps SLE Sjogrens SLE Scleroderma Polymyositis Neonatal lupus Subacute cutaneous LE

Don t test ANA sub-serologies without a positive ANA and clinical suspicion of immune-mediated disease Tests for anti-nuclear antibody (ANA) sub-serologies (including antibodies to double-stranded DNA, Smith, RNP, SSA, SSB, Scl-70, centromere) are usually negative if the ANA is negative Exceptions include: anti-jo1, which can be positive in some forms of myositis occasionally, anti-ssa, in the setting of lupus or Sjögren s syndrome Broad testing of autoantibodies should be avoided; instead the choice of autoantibodies should be guided by the specific disease under consideration

ANA: CLINICAL SUSPICION OF SLE ANA + AntidsDNA Anti-ENA C3 C4 CH50 Disease activity Diagnosis Diagnosis Disease Activity

TAKE HOME POINT Serologic tests for rheumatologic diseases are SUPPORTIVE rather than DIAGNOSTIC

RESOURCES

WWW.CHOOSINGWISELYCANADA.ORG

WWW.RHEUMTALKS.COM

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