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Giant-Cell Arteritis: What's the evidence for steroid-sparing therapies? (Case Presentation)


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Provided to the pharmacy staff at Lions Gate Hospital, North Vancouver, British Columbia on December 5, 2013.

Provided to the pharmacy staff at Lions Gate Hospital, North Vancouver, British Columbia on December 5, 2013.

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  • 1. Giant-Cell Arteritis: What’s the Evidence for Steroid-the Evidence for Steroid- Sparing Therapies? Joan Ng, Pharmacy Resident Medicine Rotation – Case Presentation December 5, 2013 1
  • 2. Learning Objectives 1. To understand and describe the pathophysiology, etiology, clinical manifestations, diagnosis, and treatment for giant-cell arteritis.giant-cell arteritis. 2. To become familiar with the evidence of steroid-sparing options in the treatment of giant-cell arteritis. 2
  • 3. My Patient, CA 60 yo female, NKDA Admitted to Lions Gate Hospital (LGH): November 17, 2013 CC Facial pain and headache HPI -Bifrontal facial pain and headache x3/52, right worse than left -Jaw claudication, scalp tenderness, and fever 39.4°C (resolved) -Initially treated in Squamish General (SGH) for ?sinus infection-Initially treated in Squamish General (SGH) for ?sinus infection -Transferred to LGH for ENT consult PMH CVA (2008, 2010), giant-cell arteritis (GCA; 2012), polymyalgia rheumatica (PMR; 2012), syncope NYD, hypertension, dyslipidemia, cholecystectomy, hysterectomy, right eye total blindness from retinal artery occlusion (2012), insomnia Fam Hx Father (deceased) and sister diagnosed with lupus and PMR/GCA 3
  • 4. Review of Systems Vitals BP = 141/67 T = 37.1 (oral) HR = 80 RR = 16 PO2 = 95% RA CNS/Neuro/ψ Bifrontal headache/facial pain; Quality: aching, heavy, persistent - Severity: 10/10 without analgesia; 3-5/10 with analgesia -Location: submandibular, peri-facial, peri-orbital CT head: normal; no abscess, infection, CVA, or tumor HEENT Right eye blind, Left eye vision intact but impaired with diplopia CVS, RESP, GI, GU Unremarkable (ECG = NSR)CVS, RESP, GI, GU Unremarkable (ECG = NSR) Liver/Renal Cr = 75 eGFR = 68 ALP = 128 GGT = 96 ALT = 75 AST = 76 LDH = 220 Lytes/Heme WBC = 6.7 ESR = 96 Hgb = 115 Plts = 310 Endocrine Random BG = 7.2 MSK/Derm Unremarkable ID Unremarkable 4
  • 5. Medications PTA to LGH Medication (regimen, dates) Indication Clindamycin 300 mg tid x10/7 (Nov 13, cont’d at SGH) ?Sinus Infection Ciprofloxacin 500 mg bid x10/7 (Nov 13, D/C’d at SGH) ?Sinus Infection Ceftriaxone IV (dose unknown) x3 doses at SGH ?Sinus Infection Prednisone 20 mg PO daily (D/C’d at SGH) GCA/PMR Ramipril 10 mg PO daily HypertensionRamipril 10 mg PO daily Hypertension Clopidogrel 75 mg PO daily 2° Stroke Prevention Simvastatin 40 mg PO daily 2° Stroke Prevention Dyslipidemia Zopiclone 7.5 mg PO at bedtime Insomnia Tramadol LA 100 mg PO daily PMR (chronic pain) Vitamin D 2000 IU PO daily Osteoporosis Prev 5
  • 6. Medication in Hospital (LGH) Medication (regimen) Indication Prednisone 60 mg PO daily GCA Azathioprine 50 mg PO daily GCA Ramipril 10 mg PO twice daily Hypertension Clopidogrel 75 mg PO daily 2° Stroke Prevention Atorvastatin 20 mg PO daily (therapeutic substitution) 2° Stroke PreventionAtorvastatin 20 mg PO daily (therapeutic substitution) 2° Stroke Prevention Dyslipidemia Zopiclone 7.5 mg PO at bedtime Insomnia Tramadol LA 100 mg PO daily PMR (chronic pain) Vitamin D 2000 IU PO daily Osteoporosis Prevention Hydromorphone 2-4 mg PO q4h prn Pain Ibuprofen 200-400 mg PO q6h prn Pain Acetaminophen 325-650 mg PO q4-6h prn Pain 6
  • 7. Hmm… • Initial question: is azathioprine (AZA) indicated? Medication (regimen) Indication Prednisone 60 mg PO daily GCA Azathioprine 50 mg PO daily GCA • Initial question: is azathioprine (AZA) indicated? • Initial Google Scholar manual search: – Only 1 small study from 1986 (will discuss later) – 2008 Lancet summary/review on GCA/PMR • No compelling evidence that AZA is beneficial. 71,2
  • 8. DRPs 1. CA is at risk of experiencing unwanted side effects from receiving azathioprine, which may not be indicated/effective in the treatment of GCA, and requires reassessment of therapy. 2. CA is experiencing dyspepsia and at risk of gastritis/ulceration secondary to prednisone therapy 2. CA is experiencing dyspepsia and at risk of gastritis/ulceration secondary to prednisone therapy and neglect to continue her PTA esomeprazole, and would benefit from reassessment. 3. CA is at risk of experiencing osteoporotic fracture secondary to being post-menopausal and continuing long-term therapy with prednisone, and would benefit from reassessment of therapy. 8
  • 9. GCA: Pathophysiology • Giant-cell arteritis, a.k.a. temporal arteritis • Inflammation in large- and medium-sized muscular arteries with prominent internal elasticwith prominent internal elastic membrane and vasa vasorum 9 Salvarani et al. Lancet 2008 Image from: • Activated dendritic cells in artery walls produce chemokines, recruit CD4+ T-cells and macrophages, and activate CD4+ T cells – Activated CD4+ T cells secrete cytokines INF-γ – Macrophages produce IL-1, IL6, metalloproteinases, ROS
  • 10. 10 Image from:
  • 11. GCA: Etiology • Cause unknown • Highest incidence in Scandinavian countries • Possible risk factors: genetics, viral infections, smoking, atherosclerotic diseasesmoking, atherosclerotic disease • Women are 2-3x more commonly affected by GCA (or PMR) than men 11 Salvarani et al. Lancet 2008
  • 12. GCA: Clinical Manifestations • Fever, malaise, anorexia, weight loss • New-onset headache (temporal/occipital) • Jaw claudication (ischemia of muscles of mastication)mastication) • Scalp tenderness, transient diplopia • Visual loss due to anterior ischemic optic neuropathy or retinal artery occlusion • Cerebrovascular accidents, aortic arch syndrome 12 Salvarani et al. Lancet 2008
  • 13. GCA: Diagnostic Criteria 13 Salvarani et al. Lancet 2008
  • 14. GCA: Treatment • Glucocorticosteroids = treatment of choice – Prednisone 40-60mg/day initially (or equivalent) – If recent visual loss, methylprednisolone 1000mg IV daily x3d – Continue for 2-4 weeks until reversible signs and symptoms resolved, and acute phase reactants decreased – Slow taper every 1-2 weeks by max 10% of total daily dose – Necessary duration of therapy varies • Long-term steroid use adverse effects related to cumulative dose and age – Bone fractures, diabetes mellitus, infections, GI bleeding, hypertension, cataracts 14 Salvarani et al. Lancet 2008
  • 15. Clinical Question P 60 year-old female with current active giant-cell arteritis and history of polymyalgia rheumatica I Prednisone + steroid-sparing agent 15 C Prednisone + placebo O Disease relapse, cumulative corticosteroid dose, side effects
  • 16. Literature Search Database EMBASE, Medline, Web of Science, CENTRAL, Google Scholar Search Terms EMBASE: (exp *giant cell arteritis/ OR exp *temporal arteritis/ OR exp *rheumatic polymyalgia/) AND (exp *azathioprine/ OR exp *methotrexate/ OR exp *tumor necrosis factor inhibitor/ OR exp *infliximab/ OR exp *etanercept/ OR exp *adalimumab/) Medline: (exp *giant cell arteritis/ OR exp *temoral arteritis/ OR Polymyalgia Rheumatica/) AND (exp *azathioprine/ OR exp *methotrexate/ OR exp *Tumor Necrosis Factor-alpha) 16 OR exp *Tumor Necrosis Factor-alpha) Web of Science: TS=(“temporal arteritis” OR “giant cell arteritis” OR “polymyalgia rheumatica”) AND TS=(“azathioprine” OR “methotrexate” OR “tumor necrosis”) Results EMBASE 156, Medline 59, WoS 304 (a lot of overlap) --Manual review for relevance, set aside PMR studies— AZA (1 RCT), MTX (1 Meta-analysis, 4 RCT), IFX (1 RCT, 1 PS, 3 CR) Adalimumab, etanercept, rituximab, tocilizumab, cyclophosphamide, and leflunomide (various CR to RCTs)
  • 17. 17
  • 18. De Silva, Hazleman 1986 [Azathioprine] Randomized, double-blinded, placebo-controlled study P N = 31 (Mean age 70, female 77%, disease duration 2.4 years) - Patients with PMR or GCA or both who fulfilled Jones and Hazleman criteria - Stable prednisolone dose ≥5 mg daily for ≥3 months, at a minimum sufficient to control symptoms - 17 concomitant PMR and GCA, 12 hypertension, 2 osteoporosis, 1 thyrotoxicosis, 1 heart failure, 1 peptic esophagitis (all present for ≥1 year) 18 thyrotoxicosis, 1 heart failure, 1 peptic esophagitis (all present for ≥1 year) I Prednisolone + azathioprine (AZA) 50mg tablets tid after meals - Prednisolone dose altered by 1mg/day based on clinical and hematological assessment every 4 weeks C Prednisolone + placebo tid after meals (matching tablets) O Patients assessed at start of study, then every 4 weeks to 52 weeks total - “steroid-sparing effect of azathioprine”: change in dose of trial medication, occurrence of side effects, and laboratory assessment (ESR, CRP, liver function)
  • 19. Results (De Silva) • 44% vs 27% withdrawal rate (?significance) • Withdrawals from AZA: nausea, vomiting, diarrhea, collapse, non-compliance • Withdrawals from Placebo: nausea, diarrhea, d/c beforenausea, diarrhea, d/c before surgery • At 52 weeks: 5 patients could take 150mg AZA/d, 4 patients 100mg AZA/d • Reduction in mean steroid use became significant at week 52. 19
  • 20. Limitations (De Silva) • Small sample size (N=31) • Patients were on prednisolone – most patients now are maintained on prednisone • Doses of AZA based on subjective patient tolerance • “randomized” – no sequence generation or allocation• “randomized” – no sequence generation or allocation concealment details • Outcomes ill-defined • No power calculation • Significant percentage withdrawal (44% and 27%) 20
  • 21. Bottom Line (De Silva) • Authors’ conclusion: – “This steroid-sparing effect of azathioprine may be used to advantage particularly in those patients suffering from concomitant diseases which may be adversely affected by steroids and to reduce the side effects of long term steroid therapy in those patients with PMR/GCA syndrome who require large doses of steroids not only for initial control of the disease but also for maintenance therapy.”maintenance therapy.” • Joan’s conclusion: – Possible steroid-sparing effect when AZA used in conjunction with prednisolone for treatment of PMR/GCA, but cannot base practice on this old, dated trial with questionable methods – Larger scale, better quality studies required 21
  • 22. 22
  • 23. Mahr et al. 2007 [Methotrexate] Meta-analysis with individual patient data from 3 RCTs P N = 161 (Mean age 74.6, female 70%) -Patients from 3 RCTs assessing E/S of methotrexate (MTX) in newly diagnosed GCA -All patients received prednisone (initial dosage 1 mg/kg/d or 60 mg/d) I Prednisone + MTX (mean starting dose 9.4 ± 1.6 mg/week; mean dosage 23 I Prednisone + MTX (mean starting dose 9.4 ± 1.6 mg/week; mean dosage over total period of intake 11.1 ± 2.5 mg/week) - Prednisone duration ~6 months C Prednisone + Placebo O Time to first relapse, time to second relapse, NNT to prevent first or second relapse, cumulative dose of corticosteroids, time to sustained discontinuation of corticosteroids (≥24 weeks), and adverse events. Duration of follow-up 54.7 ± 39.2 weeks
  • 24. Results (Mahr et al.) • 25% withdrawal (but all patients included in ITT analysis) • Risk of 1st relapse: HR 0.65 (p = 0.04); NNT = 3.6 • Risk of 2nd relapse: HR 0.49 (p = 0.02); NNT = 4.7 • Sensitivity analysis (only patients who completed treatment) – Risk of 1st relapse: HR 0.65 (0.42-0.99, p = 0.04); Risk 2nd relapse: HR 0.52 (0.28-0.95, p = 0.03) 24
  • 25. Results (Mahr et al.) 25
  • 26. Results (Mahr et al.) • Mean cumulative corticosteroid dose: – MTX reduced dose by 1101mg (308-1894), p=0.007, by week 96. • Sustained discontinuation of corticosteroids for ≥24 weeks:for ≥24 weeks: – HR 2.84 (1.52-5.28, p = 0.001) • Adverse Events: – No significant differences between treatment groups 26
  • 27. Results (Mahr et al.) 27
  • 28. Strengths • Sensitivity analysis completed, and results for MTX effect on risk of relapse similar to initial analysis • No statistical heterogeneity was found in models that analyzed outcomes Limitations 28 Limitations • Number of patients relatively small (may lack power) • Between-trial heterogeneity: criteria for GCA, treatment regimens, difference in length of follow-up • Follow-up from studies likely too short to show differences in side effects
  • 29. Bottom Line (Mahr et al.) • Authors’ conclusion: – “To summarize, this individual patient data meta-analysis supports low-dose MTX as an effective corticosteroid-sparing agent, which should be considered as a therapeutic option for patients with GCA. Further studies are warranted to clarify the benefits conferred by MTX in terms of reductions in side effects, and to assess the efficacy and safety of higher doses of MTX for GCA.” • Joan’s conclusion:• Joan’s conclusion: – MTX may be indeed have moderate benefit in preventing relapse, and has steroid-sparing effect, so it may be a consideration at time of diagnosis , and/or for patients with comorbidities (diabetes, severe hypertension, severe osteoporosis, older age) – Hypothesis-generating for future longer-term studies 29
  • 30. 30
  • 31. Hoffman et al. 2007 [Infliximab] Randomized, double-blinded, placebo-controlled trial P 22 sites in US, UK, Belgium, Italy, Spain; N = 44 (mean age ~70, female 80%) - Patients with newly diagnosed GCA (within 4 weeks), clinically remissed -Stable dose of prednisone/prednisolone of 40-60mg/d at least 1 week prior -Exclusion: received other forms of immunosuppressants within 3 months before screening, hematologic abnormalities, LFTs >3xULN -Randomized in 2:1 ratio to receive infliximab or placebo 31 -Randomized in 2:1 ratio to receive infliximab or placebo I Glucocorticosteroid + Infliximab (5mg/kg, infused at weeks 0, 2, 6, and every 8 weeks thereafter) - Glucocorticosteroid dosage tapered according to predefined schedule C Glucocorticosteroid + Placebo O Primary: proportion of patients who remained relapse-free through week 22, and incidence of adverse events Secondary: cumulative dose of glucocorticosteroid (+ others)
  • 32. Results (Hoffman et al.) Patients who remained relapse-free at 22 weeks Placebo (N=16) IFX (N=28) Significance? 8 (50%) 12 (43%) P = 0.658 (50%) 12 (43%) P = 0.65 32 Cumulative glucocorticosteroid dose at 22 weeks Placebo (N=16) Infliximab (N=28) Significance? 3049.56 ± 769.54 mg 3154.10 ± 968.50 mg P = 0.95
  • 33. Results (Hoffman et al.) • No difference in frequency of adverse events or serious adverse events • Incidence of• Incidence of infections higher in infliximab patients (71% vs. 56%), but not statistically significant 33
  • 34. Limitations • Sample size small (N = 44) – Not powered to detect modest effects of infliximab added to glucocorticoid therapy • Interim analysis by steering committee at• Interim analysis by steering committee at week 22: infusions discontinued due to no apparent therapeutic benefit of infliximab 34
  • 35. Bottom Line (Hoffman et al.) • Author’s conclusions: – “This trial is too small to draw definitive conclusions, but it provides evidence that using infliximab as maintenance therapy in patients in glucocorticoid-induced remission of newly diagnosed giant cell arteritis is of no benefit and may be harmful. If infliximab has benefit, it is unlikely to be great.”it is unlikely to be great.” • Joan’s conclusion: – Cannot recommend IFX for adjunctive treatment of GCA 35
  • 36. Other Drugs • Adalimumab • Etanercept • Rituximab • Tocilizumab• Tocilizumab • Cyclophosphamide • Leflunomide 36
  • 37. Recommendation • Continue prednisone 60 mg daily – to be tapered gradually based on clinical improvement as assessed by physician • Discontinue AZA – No good evidence of benefit– No good evidence of benefit • ? MTX 7.5mg/week + folic acid 1mg/day – Patient is not part of population studied (not newly diagnosed), but she strongly supported any steroid-sparing options (father died of GI perforation complications due to long-term glucocorticosteroid use) – Suggested this to physician for consideration 37
  • 38. Monitoring Efficacy Toxicity Frequency CNS Insomnia, mood Daily by patient, at each physician visit HEENT Headache/ head pain JawJaw claudication Transient diplopia CVS Hypertension GI Mucositis, GI upset GI perforation 38
  • 39. Monitoring (cont’d) E Toxicity Frequency Liver Hepatotoxicity (elevated ALT, AST, ALP) LFTs at baseline, then every 2-4 weeks for first 3 months, then every 8- 12 weeks thereafter12 weeks thereafter Endo Diabetes mellitus FPG at each physician visit Heme Leukopenia, thrombocytopenia CBC-Differential and platelets (same as above) MSK Osteoporosis/fract ure Daily by patient 39
  • 40. What Happened? • CA’s liver enzymes suddenly elevated on Nov 25 – GGT = 235, ALT = 203, AST = 146 • AZA was discontinued (statin was also held) • Physician noted my suggestion of MTX, but did not consider it at that time given patient’s liver dysfunctionconsider it at that time given patient’s liver dysfunction • CA’s condition stabilized, so she was discharged on November 28 with prescription for prednisone 60mg daily or as directed, hydromorphone for pain prn (and alendronate 70mg weekly) • To be followed up by neurologist and opthalmologist 40
  • 41. References 1. Salvarani C, Cantini F, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. Lancet. 2008 Jul 19;372(9634):234–45. 2. Silva MD, Hazleman BL. Azathioprine in giant cell arteritis/polymyalgia rheumatica: a double-blind study. Ann Rheum Dis. 1986 Feb 1;45(2):136–8. 3. Mahr AD, Jover JA, Spiera RF, Hernández-García C, Fernández-Gutiérrez B, LaValley MP, et al. Adjunctive methotrexate for treatment of giant cell arteritis: An individual patient data meta-analysis. Arthritis Rheum. 2007;56(8):2789–97. 4. Hoffman GS, Cid MC, Hellmann DB, Guillevin L, Stone JH, Schousboe J, et al. A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum. 2002;46(5):1309–18.Arthritis Rheum. 2002;46(5):1309–18. 5. Jover JA, Hernández-García C, Morado IC, Vargas E, Bañares A, Fernández-Guérrez B. Combined Treatment of Giant-Cell Arteritis with Methotrexate and PrednisoneA Randomized, Double-Blind, Placebo-Controlled Trial. Ann Intern Med. 2001 Jan 16;134(2):106–14. 6. Spiera RF, Mitnick HJ, Kupersmith M, Richmond M, Spiera H, Peterson MG, et al. A prospective, double- blind, randomized, placebo controlled trial of methotrexate in the treatment of giant cell arteritis (GCA). Clin Exp Rheumatol. 2001 Oct;19(5):495–501. 7. Hoffman GS, Cid MC, Rendt-Zagar KE, Merkel PA, Weyand CM, Stone JH, et al. Infliximab for Maintenance of Glucocorticosteroid-Induced Remission of Giant Cell ArteritisA Randomized Trial. Ann Intern Med. 2007 May 1;146(9):621–30. 41