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

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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.

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My Patient, CA60 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

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Review of SystemsVitals 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

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Medications PTA to LGHMedication (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

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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

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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.

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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.

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GCA: Pathophysiology

• Giant-cell arteritis, a.k.a. temporal

arteritis

• Inflammation in large- and

medium-sized muscular arteries

with prominent internal elastic with prominent internal elastic

membrane and vasa vasorum

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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

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Image from:

www.intechopen.com

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

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Salvarani et al. Lancet 2008

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

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Salvarani et al. Lancet 2008

GCA: Diagnostic Criteria

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Salvarani et al. Lancet 2008

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

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Salvarani et al. Lancet 2008

Clinical Question

P60 year-old female with current active giant-cell

arteritis and history of polymyalgia rheumatica

I Prednisone + steroid-sparing agent

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C Prednisone + placebo

ODisease relapse, cumulative corticosteroid dose,

side effects

Literature SearchDatabase 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)

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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)

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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)

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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)

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 before nausea, 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.

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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%)

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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

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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

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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

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)

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Results (Mahr et al.)

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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

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Results (Mahr et al.)

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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

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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

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

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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

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-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)

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

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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

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

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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

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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

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Other Drugs

• Adalimumab

• Etanercept

• Rituximab

• Tocilizumab• Tocilizumab

• Cyclophosphamide

• Leflunomide

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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

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MonitoringEfficacy Toxicity Frequency

CNS Insomnia, mood Daily by

patient, at

each physician

visit

HEENT Headache/

head pain

Jaw Jaw

claudication

Transient

diplopia

CVS Hypertension

GI Mucositis, GI upset

GI perforation

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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

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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

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References1. 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-GuZérrez 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.

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