504 EXAM IV Lecture Review - Rx Study Guides · rxns, Antibody formation (low dose MTX helps prevent Ab formation and prolongs drug’s utility) - Anti-TNF a Agents: First-line biologics

Glucocorticoids (GC): GC are among the most effective anti-inflammatory and immunosuppressive therapeutic options, and have thus become a cornerstone of therapy for many rheumatic disorders – but check place-in-therapy.

- Place in Therapy: Used as adjunctive therapy in combination with other DMARDs. RA is the only disease in which GC therapy is often started and maintained at a low dose as additional therapy. Highly effective,<10mg/day

- Joint-Sparing Effect: Theorized to be based on the inhibition of pro-inflammatory cytokines IL-1 and TNF TNFa: Major player in pro-inflammatory response, induces more cytokine production, expression of adhesion molecules

- Forms: The two forms of TNFa are related by TACE, the TNFa Converting Enzyme o Membrane-Bound: TNFa (26kDa) o Soluble TNFa (17kDa)

- Receptors: Though similar, the two TNFa receptors differ in their intracellular domain and signaling pathway o TNFR-1: Constitutively expressed in all tissues, capable of inducing apoptosis via Death Domain.

§ Internalized TNF recruits TRADD, leading to DNA degradation and cell death. o TNFR-2: Only expressed on Immune cells, capable of inducing NFkB signaling pathways

§ Activation recruits TRAF2, activating NFkBà Production of cytokines, inhibition of apoptosis § Produces: pro-inflammatory TNFa and IL-1b, Upregulation of Adhesion molecules (ICAMs)

- Targets for Inhibition of TNFa: TNFa molecule, TNFR, TACE, Signaling pathway, NFkB Infliximab (Remicade): Biological DMARD - Chimeric (25% murine, 75% human) mAb

- MoA: “Neutralize Cytokines”. Bind and neutralize both Soluble and Membrane-bound TNFa - AE: Infusion Rxn (itch, flush, N), HA, Abdominal pain.

o Increased risk of infection due to immunosuppression. (URTI – Tuberculosis) o Increased risk of non-Hodgkins lymphoma o Immunogenicity: Patient develops HAMA (human anti-nouse Ab) towards Infliximab. Thus, we efficacy

has a limited timeline, which can be extended by concurrent immunosuppressive therapy. Tocilizumab (Actemra): Biological DMARD – Humanized mAb

- First anti-IL6R mAb approved for arthritis, used for moderate to severe RA for those who have failed an anti-TNF. IL-6 is a chemical messenger involved in destructive immune responses, found overproduced in the joints

- MoA: “Receptor Blockade”, targets the IL-6 receptor Abatacept (Orencia): Biological DMARD – Fusion Protein Checkpoint Inhibitor

- MoA: Modified IgG domain recognizes CD80/86, binds and prevents CD28 interaction, producing negative feedback to inhibit T cell activation and inhibiting inflammatory cytokine production

Janus Kinase Inhibitors: The first oral DMARD (2012) – newest drugs to combat RA - Drug: Tofacitinib (Xeljanz) - MoA: Jakinhibs interrupt signaling downstream of a multiplicity of cytokines by inhibiting cytokine receptors,

rather than blocking one cytokine at a time. AE: Increased serious infections (Infection-risk) (12/1) Chevalier Lecture: Rheumatoid Arthritis Epidemiology: Affecting 1-2% of people world-wide, this disease affects 3x as many women as men and is one of the most common causes of disability. It has been associated with decreased life expectancy

- Risk Factors: Smoking (x3, and worse prognosis!), Genetic Susceptibility (mom/dad? +6%), Gender specific factors (hormones?), Occupational exposure, infectious triggers, presence of autoantibodies (RF, anti-CCP)

Pathophysiology: Autoimmune disease characterized by an imbalance of pro-/anti-inflammatory cytokines. Patients present with chronic inflammation and proliferation of synovial tissue (Synovitis), which can invade the cartilage and bone producing erosions ~ breakdown of bone in the joint space. Once damaged, it is irreversible Clinical Presentation: RA is usually a disease of the small joints

- Symmetrical Joint Swelling (Synovitis) - Morning Stiffness lasting ³ 1 hour - Low-grade fever, weight loss, fatigue, weakness, loss of

appetite - Joint pain, tenderness, and muscle aches - In the hands, the Proximal interphalangeal and

Metacarpophalangeal joints are most commonly affected - Late Complications: Ulnar Deviation, Boutonniere

deformities, and Muscular atrophy. Bony erosions. Significant difficulty performing Activities of Daily Living (ADLs)

RA Disease Course: Most commonly, RA has a gradual rather than abrupt onset. Patients will experience a waxing and waning of inflammation, that progressively worsens correlating with structural changes. Eventually, joint destruction and deformity ensues.

- Extra-Articular Manifestations: Occurring in 40% of patients, it is critical to assume and monitor for complications such as: Vasculitis, Interstitial Lung Disease, Myositis, CAD, CHF, PVD, Anemia, Neutropenia

Diagnostic Criteria for Rheumatoid Arthritis - American College of Rheumatology (ACR): RA Diagnostic Criteria: Put out in 1987, but still used

o At least 4 of 7: Morning Stiffness, Arthritis in ³ 3 joint areas, Arthritis of hand joints, Symmetric Arthritis, Rheumatoid Nodules, Serum Rheumatoid Factor (RF, also anti-CCP), Radiographic changes

- ACR/EULAR Modified Criteria: Released in 2010, aimed to diagnose disease earlier for studies and trials o ³ 6 Points = Definite RA. Points distributed to 4 categories: o Joint Involvement o Serology: RF and anti-CCP(occurs in 70% of cases, but predicts with 97-99% of confidence RA dx) o Acute Phase Reactants: Monitor CRP and ESR (Sed. Rate), Used to monitor medication efficacy o Duration of Symptoms: Viral infection may present similar to RA, \ ³ 6weeks à rule out viral

- Evaluating Disease Activity – During Treatment, utilize the DAS28 Score to monitor treatment progress o DAS28: Disease Activity Score. Scored 0-9.4, this is the most commonly used tool by physicians treating

RA. Major Components: Inflammatory Markers (CRP, ESR) and ADL interview. (Remission < 2.6) Treatment Goals

Control Disease: Prevent Joint Destruction Alleviate Pain Maintain ADLs

Maximize QoL Ultimate Goal: No swelling, pain, stiffness, fatigue, à Induce complete remission

Non-Pharmacologic Therapy - Rest the joint, rest your body. Get 8 hours of sleep nightly - Physical Therapy (PT): Maintaining passive range of motion and engaging in exercise will help maintain joint

function and muscular integrity. Achievement of Ideal Body Weight (IBW) is ideal ;) - Stop Smoking Now.

Non-DMARDs - Corticosteroids

o Drugs: PO (Prednisone, Methylprednisolone) and IV (Triamcinolone, Methylprednisolone) o Function: Control symptoms quickly (days), Offer some anti-erosive effects. o Indication: First-line therapy for the treatment of Acute Flares (higher doses). May be used at low doses

(<7.5mg/day) chronically for maintenance. May be used Systemically or Intra-articularly o Limitations: Highly preferred to avoid corticosteroid long-term use due to adverse effects. Try to add a

disease-modifying (steroid-sparing) agent, like [Osteoporosis = Bisphosphonates], [HyperTG = Statin] o Monitoring: BP, CMP, Glucose (hyperglycemia), WeightÝ, HT, Weight and fluid retention, Cataracts

- NSAIDs o Function: Used for anti-inflammatory effects, analgesic effect is merely an additional benefit o Dosing: Must be taken regularly, continuously, to be effective. Effect may take 2-3 weeks. o Monitoring: BP, CBC, SCr, LFT

Prior to DMARD Therapy - Understand the Risk: Many DMARDs are hepatotoxic, some are CV damaging, and all are Myelosuppressive - Labs: Serology, Titers, Organ Function - Vaccinations: Avoid live attenuated vaccines while on biologic DMARDs! Killed vaccines only. - Tests/Exams: Consider ECHO, Infection history - Therapy Initiation: START ASAP! DMARDs can help reduce the progression of the disease, and take a while (1-

3mo) to work. Begin as soon as possible, providing Coverage with an NSAID or ‘Roid until it kicks in. DMARDs- Non-Biological - MTX, SSZ, HCQ, LFN –

- Methotrexate (MTX) Cornerstone of therapy o Place in Therapy: Initial DMARD in most cases, prevalent in later stages. o MoA: Dihydrofolate reductase inhibitor, inhibiting purine synthesis leading to reduced cell turnover of

dividing cells. Additionally, it inhibits production of IL-1 (pro-inflammatory) o Dosing: Initial Dose 10mg PO/qWeekly, max 25mg weekly. 2.5mg tabs. Onset 1-2mo

§ Supplement with 1-3mg/qday Folic Acid to decrease stomatitis, N/D, Alopecia o ContraX: Boozers, Pregnancy (Teratogenic, X), Renal/Liver Impairment, Lung disease

DMARD? = Disease-Modifying Anti-Rheumatic Drugs

- Leflunomide (LFN) Alt to MTX o Place in Therapy: Used as an alternative to MTX, ~equal efficacy and toxicity. o MoA: Dihydroorotate dehydrogenase inhibitor, inhibiting pyrimidine synthesis leading to reduced

lymphocyte production. o Tox: Enterohepatic Recirculationà Long half-life, up to 2 years to eliminate, (Teratogenic, X)

- Sulfasalazine (SSZ) To be used in combo with HCQ ± MTX o Place in Therapy: Used in combination with HCQ or MTX. Onset in 1-3mo o AE: Major GI (N/V/D) which wane over time (take with food), Rash. Sulfa allergy

§ Skin and urine may turn orange, educate them that its ok to be a carrot o Warfarin DDI: Protein-binding issue, SSZ knocks off Warfarin, INRÝ

- Hydroxychloroquine (HCQ) Slow and nice comforting med to be used in combo with SSZ±MTX o Place in Therapy: Used in combination with SSZ and/or MTX. Slow onset, 2-6mo o MoA: Downregulates the immune response by reducing antigen processing by pH adjustment, thus

lowering APC activities. o AE: Well-tolerated, watch for GI or rash. o Ocular Toxicity: Potential for corneal crystal deposits. Get yearly eye exams! Sx? à D/c!

§ Sx: blurry vision/decreased vision. Will resolve upon d/c. § Retinopathy: Irreversible damage that is asymptomatic, a bull’s eye maculopathy. Loss of

peripheral vision, slowly progressing to loss of central vision § Risk factors: High dose, high cumulative dose, Renal/hepatic impairment, old, eye issues

- Pregnancy/Fertility Concerns in Non-biologic DMARDs o HCQ and SSZ = Ok! Ok for breast feeding and pregnancy o MTX: Category X. Avoid in Pregnancy and Breastfeeding. D/C 3mo before tryna conceive o LFN: Category X. Avoid in Pregnancy and Breastfeeding. Requires Washout if tryna conceive

§ Wash-Out: Without wash out, may take up to 2 years to reach low Teriflunomide levels • Cholestyramine 8g TID x11d -OR- Act. Charcoal Suspension 50g BID x11d

Advancement of DMARD Therapy – Therapy should be modified if: - (1) Repetitive Flares, (2) Unacceptable Disease Activity, (3) Progressive Joint Damage - Add a bDMARD or Jak Inhibitor if continued activity on non-bioDMARDs

o Options: Monotherapy of bDMARD or increased combination therapy o Anti-TNFa therapies are generally first-line in this case, due to efficacy and clinical experience

DMARDs- Biologic - - Administered parenterally (SubQ, IV), bDMARDs begin to show efficacy rather quickly (days-weeks) compared

to non-bioDMARDs, with their maximal improvement in 12-16 weeks. They’ve been used in other immune-related disorders, such as ankylosing spondylitis, CD, and UC. Unfortunately, they are expensive with serious side effects and often require prior authorizations from their insurance.

- Place in Therapy: Used in Moderate-Severe RA as mono- or combination with non-bioDMARDs. It can be used as a steroid sparing agent, and patients generally continue their current non-bioDMARDs.

- Serious Overlapping AE: Do NOT combine ³ 1 bDMARD. Infection, Malignancy, Neutropenia, Injection site rxns, Antibody formation (low dose MTX helps prevent Ab formation and prolongs drug’s utility)

- Anti-TNFa Agents: First-line biologics due to (1) Efficacy, (2) Fast onset, (3) SubQ dosing o Choosing: There is no evidence that any one Anti-TNF is better than another, may switch within class o Understanding the Risks: Infection, Malignancy, Skin Cancer, Hepatosplenic T-Cell Lymphoma

§ Infection Risk: Patients are susceptible to opportunistic invaders, TB/latentTB, HepB reactivation • TB Test performed before initiating therapy

o (+) à Get X-Ray à (+) à Check Sputum for AFB à (+) à Specialist! o LTB identified? Start Isoniazid therapy (x9mo), after 1 month may start anti-TNF o (-) à Start Anti-TNF

• HepB check for Surface Ag and Core Ag before starting § Malignancy Risk: Lymphomas and Leukemia are most common § Skin Cancer: Especially non-melanoma skin cancer

o AE: Psoriasis, Lupus-like syndrome, Injection site rxns, worsening of HF (ContraX Stage 3/4), CNS Demyelinating disorders (Optic neuritis, MS, Seizures), Neutropenia, Hepatotoxicity)

o Pregnancy: Certolizumab is the safest due to minimal placental transfer, though contraindicated in the last trimester of pregnancy. Tofacitinib is the only bDMARD that gets into breast milk

§ Fetus exposed to biologics? Avoid live vaccinations for 6 months (ContraX Rotavirus Vacc)

- Abatacept (Orencia): Soluble fusion protein mimicking CTLA-4 – Inhibiting T cell activation o Efficacy: Onset in 4 weeks, as a result this is often not a chosen therapy. Though SubQ dosing! o AE: HA, URI, Infection, Nausea, Malignancy, Infusion Rxns o ContraX: COPD and Smokers

- Rituximab (Rituxan): Anti-CD20 mAb – Depletes B cells o Dosing: To be used in combination with MTX. Infusion on Day 0, Day 15, then once every 6 months o Advantages: No increased incidence of TB or malignancy. Recommended biologic for patients with

Cancer hx o Disadvantages: Infusion reactions are very intense and common (38-45%)

§ ContraX In CVD patients due to risk of Cardiac Arrhythmias § REMS ‘Touch’: PML risk due to previous JC virus infection - Fatal 30-50% § Cancer Hx + HepB Hx = Reactivation of Hep B [Prescreen for HepB+C]

- IL-6 Inhibitors: Tocilizumab (Actemra), Sarilumab (Kevzara) SubQ formulations o MoA: Decreases IL-6 mediated signaling to slow inflammatory processes o ContraX: ANC<2000 PLT<100,000 (Toc) PLT<150,000 (Sar) ALT/AST > 1.5x ULN o AE: GI perforation and Dyslipidemia (monitor lipids)

- Janus Kinase Inhibitor (JAK)- New class to be used as monotherapy or in combo with MTX o Tofacitinib (Xeljanz): Blocks Jak Stat pathway, thus influencing cellular process of hematopoiesis and

immune cell function § This is an oral medication with excellent bioavailability, requiring 70% liver metabolism and

30% renal excretion. It is ineffective if used with 3A4 inducers, toxic if used with 3A4 inhibitors § AE: Lipid changes, GI perforation, TB infections, malignancy. Avoid using with other

immunosuppressant medications such as AZA, TAC, CSA § ContraX: Using with another bDMARD, ANC<1000, CBC<500, Hb<9

Monitoring: It is critical to understand that monitoring does not always mean we are checking for toxicity or general negative effects. The most important component of therapy to monitor is Efficacy

- Efficacy Monitoring: Presence of inflammation, xray progression, degree of pain, duration of morning stiffness, duration of fatigue, reduction in ESR or CRP (our inflammatory markers), DAS28 scores

- Toxicity Monitoring: Depends on the therapy – Excellent chart, check it