More Than Growing Pains: Therapeutic Review of Juvenile Idiopathic Arthritis (JIA)

Transcription

1 More Than Growing Pains: Therapeutic Review of Juvenile Idiopathic Arthritis (JIA) Brittany A. Bruch, PharmD PGY2 Ambulatory Care Pharmacy Resident University of Iowa Hospitals and Clinics November 10, 2015 Disclosure Brittany A. Bruch has no actual or potential conflicts of interest to report Off-label use of medication will be discussed in this presentation Goal To gather a broad understanding of juvenile idiopathic arthritis (JIA) and the treatment options available for these patients. 1

2 Objectives pharmacists At the completion of this activity, the participant will be able to: Understand the pathophysiology of JIA Recognize ACR (American College of Rheumatology) criteria for JIA Develop evidence-based recommendations for pediatric patients with JIA Discuss adverse effects of treatment regimens Know laboratory and clinical monitoring parameters associated with prescribed regimens Objectives technicians At the completion of this activity, the participant will be able to: Understand the pathophysiology of JIA Recognize ACR criteria for JIA Recognize adverse effects of treatment regimens History of JIA First cases reported in the mid-to-late 1800s Published in 1891 but took several years to become known throughout medical literature Famous faces Kaiser H. The first person to describe juvenile chronic arthritis. Zeitschrift fur Rheumatologie 2009;68.3: Images: 2

3 Prevalence About 1 in every 1,000 children develops some type of juvenile arthritis Estimates of 1.7 to 8.4 million patients worldwide Image: Etiology Primarily unknown Genetics Triggering factor Environment Illness (perinatal and childhood) Trauma Hormones Clinical manifestations Swelling, pain, heat, and stiffness Any joint, but commonly knees, ankles, wrists, elbows, and hips Active disease can also include fatigue, anorexia, weight loss, and growth suppression Systemic disease may also present with high fever and a skin rash Image: 3

4 Patient case History of present illness PK is a 20 month old male Left knee swelling for the past 2 months Loss of range of motion and warm to the touch Morning stiffness for approximately 20 minutes Partial response to ibuprofen Which of PK s clinical manifestations are consistent with JIA? a. Joint swelling b. Joint warmth c. Morning stiffness d. All of the above Pathophysiology Image: TNF: tumor necrosis factor; IL: interleukin Image: McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nature Reviews 2007;7:

5 TNF: tumor necrosis factor; IL: interleukin Image: McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nature Reviews 2007;7: Diagnosis Age at onset <16 years old Arthritis (swelling, effusion, limited range of motion, tenderness, or pain) in 1 joint Duration of 6 weeks Lab tests are not specific Synovial fluid analysis Differential diagnosis for joint pain Ringold S, et al Update of the 2011 American College of Rheumatology Recommendations for the Treatment of Juvenile Idiopathic Arthritis. Arthritis and Rheumatism 2013; 65(10): Patient case Physical exam Swelling of both elbows without pain or redness X-rays ruled out fracture(s) Labs Lab test Reference range Value Anti-nuclear antibody presence of 1:160 (positive titer) (ANA) Erythrocyte sedimentation 0-15 mm/hr 34 mm/hr rate (ESR) C-reactive protein (CRP) <0.5 mg/dl 1.4 mg/dl Rheumatoid factor (RF) presence of negative 5

6 Classification Polyarthritis: 5 joints Oligoarthritis: <5 joints Systemic: arthritis with systemic fever Images: Assessment and prognosis Core measures 1. Physician global assessment of disease activity 2. Patient/parent global assessment of overall well-being 3. Functional ability 4. Number of joints with active inflammation 5. Number of joints with limited range of motion 6. ESR Assessment by ACR scales ACR 30: improvement in any 3 out of 6 core measures with no more than 1 of the remaining measures worsening by >30% Also ACR 50, ACR 70, ACR 90 Giannini E. Preliminary definition of improvement in juvenile arthritis. Arthritis and Rheumatism 1997;40(7): Disease complications Uveitis Osteopenia Muscle disease Generalized growth abnormalities Skin and subcutaneous tissue changes 6

7 Uveitis Severe complication of JIA Highest risk in patients with oligoarticular disease, early age of onset, and positive ANA Symptoms include pain, redness, headache, photophobia, and changes in vision Complications can include adhesion of the iris and lens, cataracts, glaucoma, or blindness Images: Petty R, Laxer R, Wedderburn L. Juvenile Idiopathic Arthritis. Textbook of Pediatric Rheumatology (7th ed.). Elsevier Goals of therapy Relieve acute pain Prevent permanent damage to joints Induce remission of disease Improve quality of life Decrease negative effects on school, work, or social relationships AJC: active joint count Ringold S, et al Update of the 2011 American College of Rheumatology Recommendations for the Treatment of Juvenile Idiopathic Arthritis. Arthritis and Rheumatism 2013;65(10):

8 AJC: active joint count Ringold S, et al Update of the 2011 American College of Rheumatology Recommendations for the Treatment of Juvenile Idiopathic Arthritis. Arthritis and Rheumatism 2013;65(10): First line therapy Medication Mechanism Dosing Onset of action Adverse effects Monitoring Intra-articular glucocorticoids declined production of T lymphocytes triamcinolone hexacetonide: 10 to 40 mg dependent on weight and joint size within a day skin changes at injection site minimal systemic absorption expected Leflunomide* modifies cytokine production 10 to 20 mg daily dependent on weight (oral) within 4 weeks abdominal discomfort, dyspepsia, diarrhea, rash, alopecia complete blood count (CBC), liver function tests (LFTs) Methotrexate folate antagonist 0.3 to 0.6 mg/kg/wk (oral or subcutaneous) **plus folic acid 1 mg daily within 3 to 6 weeks; continued improvement for up to 12 weeks abdominal discomfort, nausea, oral ulcers, increased risk of infection, bone marrow suppression, hepatotoxicity CBC, serum creatinine, LFTs Non-steroidal antiinflammatory drugs (NSAIDs) inhibition of cyclooxygenase enzymes to decrease prostaglandin production ibuprofen: 30 to 40 mg/kg/day in 3 to 4 divided doses (oral) naproxen: 10 to 15 mg/kg/day in 2 divided doses (oral) within few days to a week abdominal discomfort, acute kidney injury, antiplatelet effects serum creatinine, electrolytes, blood pressure Black box warnings are noted in bold *off-label usage Methotrexate [package insert]. Sellersville, PA: Teva Pharmaceuticals USA; Leflunomide [package insert]. Sellersville, PA: Teva Pharmaceuticals USA; Patient case Plan Methotrexate 5 mg weekly (12.1 kg 0.4 mg/kg/dose) Naproxen 125 mg twice daily (12.1 kg 10 mg/kg/dose) Folic acid 1 mg daily Physical therapy of affected joints Ophthalmology every 3 months Return to clinic in 4-6 weeks Lab value Reference range Pre-therapy On therapy WBC k/mm k/mm k/mm 3 RBC m/mm m/mm m/mm 3 Hemoglobin g/dl 12.1 g/dl 11.4 g/dl Serum creatinine mg/dl 0.3 mg/dl 0.4 mg/dl AST u/l 41 u/l 48 u/l ALT 5-30 u/l 20 u/l 23 u/l 8

9 Methotrexate Disease modifying anti-rheumatic drug (DMARD) First published study in children was in 1986 Typically well-tolerated Can be administered orally or subcutaneously Beneficial in combination therapy regimens Giannini, Edward H., et al. "Methotrexate in resistant juvenile rheumatoid arthritis: results of the USA USSR doubleblind, placebo-controlled trial." New England Journal of Medicine 1992;326(16): Methotrexate Population: n = 127 patients Study design: prospective randomization for 6 months Methotrexate 10 mg/m 2 /week Methotrexate 5 mg/m 2 /week Placebo Results: Improvement in symptoms (p = 0.013) Methotrexate 10 mg/m 2 : 63% Methotrexate 5 mg/m 2 : 32% Placebo: 36% Also evaluated pain on motion, pain severity, effects on range of motion, and ESR Only 3 patients discontinued due to mild-to-moderate adverse effects Giannini, Edward H., et al. "Methotrexate in resistant juvenile rheumatoid arthritis: results of the USA USSR doubleblind, placebo-controlled trial." New England Journal of Medicine 1992;326(16): Patient case Returns to clinic More joint pain while playing Increased clumsiness Won t fully extend knees Eye inflammation diagnosed as uveitis Prescribed prednisolone eye drops Consider whether systemic therapy should be modified 9

10 Patient case Returns to clinic Several additional episodes of uveitis which require topical steroid therapy Another episode of active uveitis resulted in an increase in methotrexate dose to 25 mg weekly (32.1 kg 0.8 mg/kg/dose) Compared to a normal methotrexate dosing range of 0.3 to 0.6 mg/kg/week, what toxicity would you expect PK to develop with this dose? a. Worsened joint pain b. Nausea c. Itching d. Drowsiness AJC: active joint count Ringold S, et al Update of the 2011 American College of Rheumatology Recommendations for the Treatment of Juvenile Idiopathic Arthritis. Arthritis and Rheumatism 2013;65(10): AJC: active joint count Ringold S, et al Update of the 2011 American College of Rheumatology Recommendations for the Treatment of Juvenile Idiopathic Arthritis. Arthritis and Rheumatism 2013;65(10):

11 Anti-TNF agents Mechanism: bind endogenous TNF to inhibit inflammatory reactions Adverse effects: infections, injection site reactions, malignancies, tuberculosis Monitoring: tuberculosis, hepatitis, CBC, serum creatinine, LFTs Medication Dosing Onset of action Effective for uveitis? Adalimumab (Humira ) 10 to 40 mg every other week (subcutaneous) within 4 weeks with continued improvement for up to 12 weeks yes Etanercept (Enbrel ) 0.8 mg/kg weekly (subcutaneous) within 4 weeks with continued improvement for up to 12 weeks no Infliximab* (Remicade ) 3 mg/kg at 0, 2, and 6 weeks; then 3 to 6 mg/kg/dose every 8 weeks (intravenous) in combination with methotrexate within 1 week with continued improvement up to 6-12 weeks yes Black box warnings are noted in bold *off-label usage Adalimumab[package insert]. North Chicago, IL: AbbVie, Inc; Etanercept [package insert]. Thousand Oaks, CA: Immunex Corporation; Infliximab [package insert]. Horsham, PA: Janssen Biotech, Inc; Patient case Returns to clinic Another episode of uveitis Substantial joint pain during school athletics Following several more episodes of uveitis, a decision is made to escalate PK s systemic therapy. Is there a specific biologic agent that would be favored based on his disease presentation? a. Adalimumab b. Etanercept c. Golimumab d. Infliximab monotherapy Adalimumab (Humira ) Disease modifying anti-rheumatic drug (DMARD) Approved for use in pediatric patients in 2008 Effective for uveitis Lovell, Daniel J., et al. "Adalimumab with or without methotrexate in juvenile rheumatoid arthritis." New England Journal of Medicine (2008):

12 Adalimumab (Humira ) Population: n = 171 patients Study design: prospective for weeks 16 week run-in with adalimumab 32 week double-blind phase with randomization to adalimumab or placebo Results: ACR 30 at week 16 No methotrexate: 64/86 (74%) Methotrexate: 80/85 (94%) Disease flare (p = 0.03) Adalimumab: 43% Placebo: 71% Disease flare (p = 0.02) Adalimumab with methotrexate: 37% Adalimumab with placebo: 65% 14 patients experienced adverse effects within study Lovell, Daniel J., et al. "Adalimumab with or without methotrexate in juvenile rheumatoid arthritis." New England Journal of Medicine (2008): Other biologics Medication Mechanism Dosing Onset of action Adverse effects Abatacept (Orencia ) binds CD80 and CD86 to inhibit T cell activation via CD28 mediated activation <75 kg: 10 mg/kg; >75 kg: refer to adult dosing at 0, 2, 4 weeks then 4 weeks thereafter (intravenous) within 3 months headache, upper respiratory symptoms Anakinra (Kineret ) blocks the interleukin-1 receptor to inhibit inflammatory reactions 1 to 2 mg/kg daily; may titrate to 4 mg/kg (subcutaneous) within 1-3 weeks injection site reaction Canakinumab (Ilaris ) binds interleukin-1 beta to inhibit inflammatory reactions 4 mg/kg every 4 weeks (subcutaneous) within 1 week headache, nausea, diarrhea, influenza Tocilizumab (Actemra ) blocks the interleukin-6 receptor to inhibit inflammatory reactions 8 to 12 mg/kg every 2 to 4 weeks based on weight and severity (intravenous) within 2 weeks upper respiratory tract infections, headache, hypertension, injection site reaction, tuberculosis, hyperlipidemia Black box warnings are noted in bold Abatacept [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; Anakinra [package insert]. Stockholm, Sweden: Swedish Orphan Biovitrum; Tocilizumab [package insert]. South San Francisco, CA: Genentech, Inc; Canakinumab [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; Health maintenance Nutrition Physical therapy Vaccinations Should receive age appropriate vaccines Should NOT receive live vaccines Tuberculosis screening with biologics Prior to initiation Anytime risk of TB changes to moderate or high 12

13 Transition to adulthood Image: Role of the pharmacist Medication review Ensure medication list is complete and accurate Optimization of treatment with routine follow-up Adherence tools Co-pay assistance programs Education on medication therapies Dose calculation Associated adverse effects Administration techniques Dosing during illnesses or infections Encouragement of general health maintenance Facilitate communication between patients and the rest of the care team Questions? Brittany A. Bruch, PharmD 13