Learning Objectives

• Review the laboratory testing in the work up of systemic Cases in erythematosus and Rheumatology • Discuss the recent evidence for the management of autoimmune diseases such as systemic lupus Sandeep K. Agarwal, MD, PhD erythematosus and rheumatoid arthritis Chief Section of Immunology Allergy and Rheumatology Director of Biology of Inflammation Center

Case 1: 36-year-old woman with chief Case 1 (slide 2) complaint of knee pain

• Pain in front of both knees when she runs • Would you order blood tests? and squats, feels swollen • If so, what tests? • No other joint pain, no stiffness in the morning. Acetaminophen helps • More specifically, would you order the “rubber stamp • ROS negative for fevers & chills, rash, oral rheumatology workup” sores, nasal congestion, chest pain, • ESR, CRP, RF, CCP, ANA, anti-dsDNA, anti-Smith, anti-RNP, anti- shortness of breath, abd pain, n/v/d, muscle weakness, paresthesias Ro, anti-La, anti-histone, anti-scleroderma 70, anti-centromere, anti-Jo1, anti-cardiolipin, lupus , anti-beta2 • MSK exam small joints of hands, wrists glycoprotein, anti-smooth muscle , anti-mitochondrial Ab, elbows nl, shoulders good ROM, hips full Lisa, 36, ROM, knees with patellar clicking, no anti-proteinase-3, anti-myeloperoxidase, and for good measure an effusions, vastus medialis atrophy, ankles Knee pain ACE level! and MTPs nl Case 1 (slide 3) Case 2: 36-year-old woman with joint pain

• Dx: patellofemoral pain • Started a few months ago, with pain in fingers (PIPs), wrists and knees. • No evidence by history or examination of an inflammatory • Subjective swelling. Pain worse in the arthritis morning, feels stiff for about an hour but will loosen up with moving around • No autoimmune serologies or inflammatory markers are • Ibuprofen helps indicated. • ROS negatives: fevers, chills, weight change, oral sores, nasal sores, shortness • Can consider CBC and CMP if you are going to prescribe of breath, abdominal pain/n/v/d, muscle Flor, 36, NSAIDs weakness, skin rash • ROS positives: hair has been thinning the Joint pain past few weeks, fatigue. Last summer had chest pain that was worse with breathing that resolved with NSAIDs

Case 2 (slide 2) Case 2 (slide 3)

• MSK Examination: • Would you order blood tests? • DIP nontender, no synovitis • PIP tender and + soft tissue fullness bilaterally • If so, what tests? • MCP nontender, no synovitis • More specifically, would you order – ESR, CRP, RF, CCP, ANA, anti-dsDNA, anti-Smith, anti-RNP, anti-Ro, anti-La, • Wrists trace effusion, no warmth or redness, decreased dorsiflexion with slight tenderness anti-histone, anti-scleroderma 70, anti-centromere, anti-Jo1, anti-cardiolipin, lupus anticoagulant, anti-beta2 glycoprotein, • Elbows, shoulders, hips with good ROM, nontender anti-proteinase-3, anti-myeloperoxidase • Knees with small warm effusions bilaterally no crepitus • Ankles and MTPs negative Case 2 (slide 4) ABIM Choosing Wisely – • Dx: Inflammatory polyarthritis Rheumatology • Differential diagnosis: rheumatoid arthritis, psoriatic arthritis, systemic , hypothyroidism, …… Don’t test ANA sub-serologies • Yes, you should order lab work without a positive ANA and clinical • Start with CBC, CMP, urinalysis, TSH, ANA, RF, CCP suspicion of immune-medicated • Defer additional testing for preliminary tests results diseases • Consider x-rays of affected joints • Refer rheumatology

Arch Pathol Lab Med. 2000: 124(1): 71-81; Arthritis and Rheum 2002: 47(4): 434-44. Am J Clin Path 2002: 117(2): 316-24

Antinuclear (ANA) Antinuclear Antibodies • “False positives” : • directed against a variety of • 1:40 : 32% of healthy controls nuclear antigens • 1:80 : 13% of healthy controls • Procainamide, • SLE : >95% ( some studies say 99.9%) • >1:320 : 3% of healthy controls hydralazine, minocycline, • ANAs also seen : diltiazem, penicillamine, • Scleroderma ~90% • Hyper/Hypothyroid, autoimmune hepatitis, primary INH, quinidine, • MCTD >95% biliary cirrhosis, idiopathic pulmonary arterial methyldopa, hypertension, hepatitis C, endocarditis, HIV, TB, chlorpromazine • Polymyositis/dermatomyositis ~60-75% mononucleosis • Anti-TNF agents • Medications (see list on the right) • Possible – phenytoin, • Rheumatoid arthritis ~40% rifampin, lithium, IFN, • False negatives: less common others…….. • Sjögren's syndrome ~50% • Anti-Ro antibodies can still be present with a negative ANA test (SLE, Sjogrens) • Discoid lupus ~15% UpToDate.com • Anti-Jo-1 (myositis) Antinuclear Antibodies: Assays Case 2 (slide 5) • Gold standard method for detection is immunofluorescence using • WBC 4.5, Hct 31, Plt 95 HEp2 cells as the substrate • CMP nl • Cons: Visual test, inter-observer variability • Urinalysis: no WBC, no RBC, no , no • HEp2000 cells can improve sensitivity with transfection of Ro60 antigen glucose • Solid phase assays replacing IFA (Less specific and less • ANA 1:640 sensitive) • RF, CCP neg Pros: Can handle high demand, less expensive, less technical • Additional antibodies are ordered given expertise, more automated positive ANA: Cons: • Anti Smith positive Flor, 36, • No standardization of antigen selection • Negative: anti dsDNA, RNP, Ro, La, • Limited number of antigens Joint pain cardiolipin • Biochemical nature of the antigen (native antigen, linear antigen) • Fixation & coating, calibrators, etc. • C3 85, C4 12 UpToDate.com

ANA: Sub-Serologies Case 2 (slide 6) Antigen Clinical Associations in SLE Prevalence (%)

Double stranded DNA Renal disease, marker for disease activity 40-60% • A diagnosis of systemic Smith Antigen (Sm) 20% lupus erythematosus is Subacute cutaneous lupus, photosenitivity, Ro/SSA 40% neonatal lupus, Sjogrens made. Low prevalence of renal disease, Sjogrens La/SSB 10-15% Hydroxychloroquine syndrome Ribonuclear protein (U1- 200 mg twice a day Mixed connective tissue disease 30-40% • Flor is told to get annual RNP) eye exams to screen for Hypercoagulable states, thrombocytopenia, Phospholipids 30% , verrucous endocarditis macular toxicity Histones Drug related SLE (not specific)

Ribosomal P Psychosis and depression 10-40% Systemic Lupus Erythematosus (SLE) SLE: Clinical manifestations • Constitutional Symptoms • RENAL • Chronic, multisystem autoimmune disease • Fatigue, myalgia, weight loss, fever • GLOMERULONEPHRITIS • Can affect almost every system • Mucocutaneous • Pulmonary • Oral or nasal ulcers (usually painless), • Serositis, pleurisy, pleural effusions, acute • Most common is skin, MSK, mild hematologic, serologic rashes, alopecia (scarring or pneumonitis nonscarring) • Prevalence 20-240 per 100,000 persons • Interstitial lung disease, diffuse alveolar • Musculoskeletal hemorrhage • Incidence 1-10 per 100,000 per-years • Arthralgias, inflammatory arthritis, • Cardiovascular myositis, avascular necrosis • Typically presents ages 15-64 • Pericarditis, myocarditis, verrucous endocarditis, • Raynaud’s phenomenon (15-30%) coronary artery disease!!!!! • Females>males • Hematologic • Neurologic • African American, Hispanic and Asian populations at risk of • Leukopenia, thrombocytopenia, • Neuropsychiatric lupus, cognitive impairment anemia (AOCD, AIH) more severe disease • Ophthalmologic, Gastrointestinal, etc

Case 2 (slide 7) SLE: lab monitoring

• Blood pressure monitoring • 6 months later, she returns to clinic • CBC screening for cytopenias with 50% improvement in joint pain, • CMP screening for renal impairment and low albumin stiffness and swelling, mild pleurisy, • Urinalysis screening for microscopic hematuria and proteinuria no rash. • Urine protein:creatinine ratio • Complement C3 and C4 • Methotrexate is started but she • A decrease can indicate lupus activity does not tolerate it. She returns • Anti-dsDNA antibodies with the same symptoms two weeks Flor, 36, • An increase titer can indicate lupus activity later. Joint pain • No indication to repeat ANA, anti RNP, anti Ro, anti La – do not change with lupus activity • What labs are needed?

Hahn et al. ACR 2012 Lupus Nephritis Guidelines. Arth Care Res. 2012, Vol 64(6): 797-808 SLE: Indications for Renal Biopsy Case 2 (slide 8)

• All patients with clinical Increasing serum Confirmed Combinations of the evidence of previously creatinine without proteinuria of ≥1.0 following, assuming Labs untreated active Lupus compelling gm per 24 hours the findings are glomerulonephritis alternative (either 24-h urine confirmed in ≥2 • WBC 4.5, Hct 32, Plt 110 causes specimens or spot tests done within a should get a biopsy (e.g., sepsis, protein/creatinine short period of time • Cr 1.0 (unless STRONGLY hypovolemia, or ratios acceptable) in the absence of contraindicated) medication) LOE: C alternative causes. • Urine : no RBC, no protein LOE: C (A)Proteinuria ≥0.5 • Activity vs. chronicity gm per 24h + • C3 80, C4 12 Flor, 36, hematuria, • Rule out other causes defined as • dsDNA titer negative Joint pain (ATN, hypocalcemia, ≥5RBCs per hpf. hypotension, (B)Proteinuria ≥0.5 thrombotic) gm per 24h + cellular cases • What are the treatment options in a patient with active SLE (arthritis, LOE: C pleurisy, hypocomplementemia) despite hydroxychloroquine?

Hahn et al. ACR 2012 Lupus Nephritis Guidelines. Arth Care Res. 2012, Vol 64(6): 797-808

Belimumab (Benlysta) Belimumab in SLE (BLISS-52 trial)

• Fully human immunoglobulin (IgG1), monoclonal antibody • Phase 3, RCT, 48 week trial • Primary endpoint- SLE Responder against soluble human B-lymphocyte stimulator (BLyS) • Patients with active SLE, no Index (SRI) • B-lymphocyte stimulator (BLyS) renal or CNS disease • Reduction in at least 4 points in • Also known as B-cell activating factor (BAFF) or TNF ligand superfamily • No prior rituximab, no cytoxan SELENA-SLEDAI, no new BILAG member 13b in past 6 months, no IVIG or A organ domain score, no more than 1 new BILAG B organ • Binds to mature Bcells and induces proliferation and inhibits apoptosis prednisone > 100 mg/day in past 3 m domain score, no worsening in • Belimumab has been FDA approved for treatment active SLE Physician Global not responsive to antimalarials • 3 arms • Currently not indicated in SLE patients with active renal or CNS disease • Belimumab 1 mg/kg (288 patients) • Belimumab 10 mg/kg (290 patients) • Adverse effects: Infusion reactions, immune suppression, increased risk • Placebo (287 patients) of infections • 1 year Lancet. 2011 Feb 26;377(9767):721-31. Belimumab in SLE (BLISS-52 trial) Belimumab in SLE (BLISS-52 trial)

Belimumab Placebo 1 mg/kg v. P 10 mg/k v. P 1 mg/kg 10 mg/kg Belimumab Placebo placebo value placebo value Adverse event 92% 92% 92% 1 mg/kg 10 mg/kg (n>1) SRI Response 1.55 1.83 51% 58% 44% 0.0129 0.0006 Serious adverse Rate (1.1-2.19) (1.3-2.6) 16% 14% 13% event Reduction > 4 1.51 1.71 points in SELENA 78% 81% 73% 0.0189 0.024 Discontinued (1.07-2.14) (1.21-2.41) SLEDAI due to adverse 6% 5% 7% >25% Reduction 1.89 1.75 event 21% 19% 12% 0.0252 0.05 in prednisone (1.08-3.31) (0.99-3.08) Infections 68% 67% 64% Serious 8% 4% 6% infection

Lancet. 2011 Feb 26;377(9767):721-31. Lancet. 2011 Feb 26;377(9767):721-31.

SLE: Clinical Pearls Case 3: 58-year-old woman with joint pain in hands Only order ANA if you strongly suspect an autoimmune • Presents with joint pain in her hands localized to base of disease thumb, PIP and DIP. She has also noted pain in her knees. • No swelling, 5-10 minutes of morning stiffness. Pain worse in First order the ANA by immunofluorescence and if positive the evenings. Better with acetaminophen and ibuprofen then order subserologies and complement levels • ROS negative except 10 lbs of weight gain Lupus patients should be screened routinely for development of glomerulonephritis • MSK exam : • DIP and PIP enlarged, bony, no synovitis. The ANA does not need to be repeated in a patient with known SLE • MCP no synovitis • Wrists and elbows no effusion FROM Treatment options depend on the extent of involvement Hiral, 58, • Shoulders FROM nontender Hydroxychloroquine • Hips nontender with decrease ROM Joint pain in Methotrexate, azathioprine • Knees with crepitus no effusion hands Belimumab • Ankles and MTPs negative Mycophenolate, cyclophosphamide • What labs would you order? RF? CCP? ANA? ESR? CRP? Case 3 (slide 2) Case 4: 58-year-old woman with joint pain in hands • Presents with joint pain in her hands localized to MCP & PIP. She has also noted pain in her wrists, ankles and MTPs. • Dx: osteoarthritis • +Subjective swelling, 90 minutes of AM stiffness. Slight improvement w ibuprofen • No evidence by history or examination of an • ROS positive for fatigue but negative for rashes, pleurisy, CP, SOB, abd inflammatory arthritis pain/n/v/d/blood in stools, muscle weakness, paresthesias, back or neck pain/stiffness • No autoimmune serologies or inflammatory markers MSK DIP nontender exam: PIP and MCP with soft tissue swelling c/w synovitis, tender are indicated. Wrists with effusions, decrease dorsiflexion Elbows no effusion FROM nontender • Can consider CBC and CMP if you are going to Shoulders and shoulders FROM nontender Knees with crepitus no effusion Maria, 58, prescribe NSAIDs Ankles with subtalar effusion and tenderness to inversion eversion MTPs + squeeze tenderness Joint pain in • What labs would you order? RF? CCP? ANA? ESR? CRP? hands

Case 4 (slide 2) Approach to the patient with articular pain

• Dx: Inflammatory polyarthritis • Differential diagnosis : rheumatoid arthritis, psoriatic arthritis, • Arthralgia: pain in or around joint systemic lupus erythematosus, hypothyroidism, …… • Inflammatory vs structural • Articular vs periarticular • Yes, you should order lab work • Start with CBC, CMP, urinalysis, TSH, ANA, RF, CCP • Arthritis: inflammation of a joint, usually accompanied by • Defer additional testing for preliminary tests results pain, swelling, and stiffness • Consider X-rays of affected joints Structural joint abnormality vs. Synovitis Classic Hand Joint Distribution

STRUCTURAL SYNOVITIS SUBJECTIVE Symptoms with use Symptoms with use and rest • Osteoarthritis – DIP (Heberden’s nodes) and PIP Minimal AM stiffness Prominent AM stiffness (Bouchard’s Nodes), 1st MC-C joint Gradual worsening course Course may fluctuate No acute exacerbation Flares common No systemic symptoms Systemic symptoms common • Psoriatic Arthritis – DIP and PIP OBJECTIVE Primarily weight bearing joints and Weight bearing joints, fingers and affect fingers wrists, elbows, shoulders Crepitance and bony hypertrophy Soft tissue swelling • Rheumatoid Arthritis – PIP and MCPs X-rays usually positive X-rays negative early (MRI better at early) Cartilage loss localized, new bone Cartilage loss diffuse, erosions growth

Rheumatoid Arthritis Rheumatoid Arthritis: Epidemiology

• Systemic progressive inflammatory disorder • Affects 1% of population • Predominantly manifests in the synovial membrane of • Female: Male ratio 2.5:1 diarthroidal joints • Peak incidence is 4th to 6th decades of life • Untreated, most patients have a chronic fluctuating course • Worldwide distribution, affects all ethnic groups leading to joint destruction, deformity, and disability • Genetic predisposition • Causes significant short-term and long-term functional • Monozygotic concordance rate 15-30%, dizygotic concordance disability rate 5% • Associated with shorter-life expectancy due to • Shared epitope : QKRAA or QRRAA on DRb chain cardiovascular, infectious and malignant causes • HLA DRB*0401,*0404, *0101 alleles • PTPN22, STAT4, TRAF-C1 locus, CTLA4, PADI4 Rheumatoid Arthritis: Clinical Features RA : Extra-articular Manifestations

Symptoms • Rheumatoid Nodules • Atherosclerotic Disease •Pain • Stiffness • Distribution • Osteoporosis • Sjogrens Syndrome • Swelling • Symmetric • Weakness • Muscle Weakness and • Anemia • Deformity • Distal joints more than Myositis • Fatigue proximal • Felty Syndrome • Malaise • Rheumatoid Vasculitis Physical Examination • PIP, M CP, M T P, wr ist, • Lymphoma ankle > elbow, knee, • Tenderness to palpation • Scleritis and episcleritis • Synovial thickening shoulder, hip • Joint effusions • Lung Disease • Erythema • Decreased Range of Motion • Pericarditis/Myocarditis • Subluxation

RA: Natural History • Clinical Course • 10% may remit within 3-6 months • 60-70% variable sine wave course with overall progressive worsening • 10-20% relentless progression • 70% have erosive changes detectable by x-rays by 2 years (MRI earlier) • After 20 years, 60% of patients will have significant functional disability Early RA • Increased incidence of • Infections • Cardiovascular disease • Lymphoma • Decreased Life Expectancy • Standardized mortality rate of 1.70 • Men live 7 years less • Women live 3 years less RA: RA: Progressive Progressive X-ray Damage X-ray Damage

2009 2014 2009 2014

Rheumatoid Factor • Antibodies against the Fc portion of IgG • Sensitivity for RA : 60-70% • Specificity for RA : 70-80% Advanced • Also found in RA • Other autoimmune disease • Healthy people (5%) • 3-25% of elderly • Bacterial endocarditis • Hepatitis B or C • Tuberculosis • Syphilis • Malignancies Anti-Cyclic Citrullinated Peptide Antibodies Rheumatoid Arthritis: Treatment (aCCP) GOALS OF THERAPY APPROACH TO THERAPY • Citrulline is a non-standard amino acid • Elimination of joint pain and • Rapid referral and diagnosis stiffness • Created by de-imination of arginine residues by Peptidylarginine • Early intervention with DMARD deiminase (PADI) • Prevention of flares therapy • Prevention of joint destruction • Single or multidrug approach • Sensitivity for RA : 50-75% • Return to full function and prevent • Use of NSAIDs and corticosteroids • Specificity for RA : 90-95% loss of function as adjunctive agents • Can be detected 1.5-9 years prior to the dx of RA • Establishment and maintenance of • Careful monitoring for side effects remission • Prevention of glucocorticoid- • Titers of RF and CCP do not correlate with RA disease induced osteoporosis activity

Rheumatoid Arthritis: Available Therapeutics DMARDs ABIM Choosing Wisely – • Antimalarials (hydroxycholorquine) • Sulfasalazine • Methotrexate Rheumatology • Leflunomide (Arava) Biologics • TNFα inhibitors • Etanercept (Enbrel) - TNFa receptor Fusion Protein Don’t prescribe biologics for • Infliximab (Remicaide) – chimeric anti-TNFa antibody • Adalimumab (Humira) – fully humanized anti-TNFa antibody rheumatoid arthritis without a trial of • Golimumab (Simponi) - fully humanized anti-TNFa antibody • Certolizumab pegol (Cimzia) – pegylated Fab fragment methotrexate or other conventional • Anakinra (IL1 receptor antagonist, Kineret) • Abatacept (CTLA-4 Ig, Abatacept) • Rituximab (antiCD20 ab, Rituxan) non-biologic DMARDs. • Tociluzumab (Anti-IL6Receptor, Actemra) JAK Inhibitors: Tofacitinib (Xeljanz), Baricitinib (Olumiant)

NSAIDs & Corticosteroids Arthritis Care and Research 2012: 64(5):625-39 Ann Rheum Disease 2010: 69(6): 964-75 Traditional DMARDs for RA Rheumatoid Arthritis: Combination Therapy? PREMIER Trial: MTX vs Adalimumab vs Both TEMPO Trial MTX vs etanercept vs both Agent Usual Dosage Adverse Effects Monitoring ACR50: Year 1 Methotrexate 10–25 mg weekly Hepatotoxicity, CBC and CMP every 8 (oral or myelotoxicity, weeks 62% Low disease Remission subcutaneous) pneumonitis 46% 41% activity (DAS<1.6) Sulfasalazine 1,000–1,500 mg Hepatotoxicity, CBC and CMP every 3-4 (DAS<2.4) twice daily (oral) myelotoxicity months Week Week Week Week Leflunomide 10–20 mg daily Hepatotoxicity, CBC and CMP every 8 ADA+MTX ADA MTX 24 52 24 52 (oral) myelotoxicity weeks Methotrexate 32% 35% 14% 14% Hydroxychloroquine 200–400 mg daily Macular, Annual ophthalmology ACR20: Year 1 alone (n=228) dermatologic, and GI exam Etanercept 32% 39% 13% 18% upset 73% 63% alone (n=223) 54% Glucocorticoids 5-15 mg QAM Osteoporosis, Bone density if prolonged Methotrexate + 51% 61% 30% 27% (prednisone) elevation of blood steroids Etanercept (n=231) sugar, infection, weight gain, etc etc ADA+MTX ADA MTX

Sweiss N, Hushaw LL. J Infus Nurs. 2008;32(15):S4-S17; van Vollenhoven RF. Nat Rev Rheumatol. 2009;5:531–541. FC Breedveld et al. Arth Rheum 2006. D ven der Heijde et al. Arth Rheum. 2006

Rheumatoid Arthritis: Combination Therapy? Key Safety Risks of Biologic Agents PREMIER Trial: MTX vs Adalimumab vs Both TEMPO Trial MTX vs etanercept vs both ACR50: Year 1 TNF inhibitors Abatacept Rituximab Tocilizumab

62% • Infections • Infections • Infections • Infections Low disease Remission 46% 41% activity (DAS<1.6) • CHF • COPD • Administration • Elevated liver In year 2, responses were (DAS<2.4) ADA+MTXsustained in ADA the combination MTX Week Week Week Week • Rare: drug- exacerbation reactions enzymes treatment group, and continued to 24 52 24 52 Methotrexate 32% 35% 14% 14% induced lupus, • PML • Elevated lipids be superior to responses in the alone (n=228) ADA andACR20: MTX monotherapy Year 1 MS • Neutropenia Etanercept 32% 39% 13% 18% 73% groups 63% alone (n=223) • GI perforations 54% Methotrexate + 51% 61% 30% 27% Etanercept Abatacept. Prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/125118s0016lbl.pdf. (n=231) Anakinra. Prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/103950s5039lbl.pdf. Rituximab. Prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/103705s5256lbl.pdf. ADA+MTX ADA MTX Tocilizumab. Prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/125276lbl.pdf. Furst DE, et al. Ann Rheum Dis. 2007;66:iii2-iii22. Pucino F, et al. Am J Health-Syst Pharm. 2006;63:S19-S41. FC Breedveld et al. Arth Rheum 2006. D ven der Heijde et al. Arth Rheum. 2006 Krueger GG, et al. N Engl J Med. 2007;356:580-592. JAK-STAT Signaling Janus kinase 3 (JAK3)

Cytokine • Expressed in T-cells, B-cells, and NK cells • Involved in signal transduction by receptors that Extracellular Region employ the common gamma chain (gc) of type I cytokine receptors JAK JAK Intracellular P P P • IL-2R, IL-4R, IL-7R, IL-9R, IL-15R, IL-21R Region P Nucleus

STAT STAT • Mutations in JAK3 lead to severe combined P P STAT Regulate Gene immunodeficiency (SCID)

STAT expression P STAT P

STAT dimer Adapted from Yamaoka K et al. Genome Biol. 2004;5:253. forms

Tofacitinib JAK Inhibitor: Tofacitinib ORAL Standard Trial • Trade name: Xeljanz • Phase 3, 52-week RCT (N=717) 28.3% (30/106) patients had an ACR20 Response for placebo • Small molecule inhibitor of JAK1 and 3 (less JAK2) • Inadequate response to MTX, • November 2012 approved by FDA for treatment of biologic naïve 51.5% (101/196) patients had an AR20 Response to Tofacitinib 5 mg moderately to severely active RA that has an • Tofacitinb vs adalimumab (anti-TNF) vs placebo for 6 52.6% (103/196) had an ACR20 inadequate response to methotrexate months followed by tofacitinb response to Tofacitinib 10 mg for 6 months (99/199) had an ACR20 • Primary outcomes: ACR20, 47.2% DAS28, HAQ-DI at 6 months response to Adalimumab 40 mg

• Similar number of patients with ACR50 and ACR70

Van Vollenhoven et al. NEJM. 2012; 367:508-19 JAK Inhibitor: Tofacitinib Tofacitinib vs Methotrexate ACR20 Response • Increase risk of infections • 6 month RCT of 958 • Tofacitinib (n=397): 76.1% methotrexate naïve RA • Methotrexate (n=186): 50.5% • Elevations in LDL patients • Reductions in neutrophil counts • Methotrexate 20 mg vs ACR70 Response tofacitinib (5mg or 10mg) • Tofacitinib (n=397): 37.7% • Primary endpoint ACR70 • Methotrexate (n=186): 12.0% and Sharp Scores Adverse effects: Neutropenia, increased LDL, LFT abnl and elevated Cr noted Cancer risk ? Infection risk? Fleischmann et al. NEJM. 2012; 367:495-507 Lee et al NEJM 2014

Screening Prior to Biologics and RA: Clinical Pearls JAK inhibitors Only order ANA, RF, CCP if you strongly • Assess infection risk suspect an autoimmune disease • PPD or quantiferon gold for TB exposure RA should be suspected in patients with prolonged morning stiffness, swelling and • Hepatitis B and C serologies polyarthritis • CBC for cytopenias, lipid panel and CMP for baseline Early diagnosis and treatment is effective in • Screen for comorbities treating symptoms & preventing joint damage • Class III or IV CHF – avoid TNFi and disability • COPD - avoid abatacept Monotherapy and combination therapy with synthetic DMARDs and biologics require close • Diverticular disease – avoid tocilizumab ? monitoring for side effects and infections