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

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: www.sinaiem.org
• 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:
www.intechopen.com

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