6. • any type of lupus nephritis patient
(class 3/4/5)
• received only 500 mg of IV mPSL and
rituximab on days 1 and 15
• as well as mycophenolate mofetil 500 mg
bid, titrated up according to trough levels.
• NO oral steroids.
7. 1. Glucocorticoid mecanisms of action overview
2. Adverse reaction
– Infection
– Osteoporosis
3. Clinical use overview
– Lupus and Vasculitis
– Inflammatory Arthritis
– Others
35. Pneumocystis jirovecii
– “One of the greatest errors in using CYC and
prednisone is the failure to use Pneumocystis
carinii (jiroveci) pneumonia (PCP) prophylaxis”
Rheum Dis Clin N Am 33 (2007) 691-739
44. • HIV
– CD4 countと発症リスクが比較的Linear
→ 「CD4陽性 helper T cell」の機能がCD4 countで良
好に近似できる
cf. ESPRIT study (IL-2 SQ injection for HIV pts)
45. HIV感染症患者とPcP
Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults
and Adolescents. Recommendations from the CDC, NIH, and HIVMA of the IDSA
47. Why AGAINST universal prophylaxis?
• ST合剤が広域抗菌薬であること
Infection with a fluconazole-resistant isolate was associated with
exposure to carbapenems, trimethoprim-sulfamethoxazole,
clindamycin, and colistin (odds ratio, 2.8; P = 0.01).
Antimicrob. Agents Chemother. 2012, 56(5):2518
56. ADVISORY COMMITTEE MEETING
TOFACITINIB FOR THE TREATMENT OF
RHEUMATOID ARTHRITIS
NDA 203214
BRIEFING DOCUMENT
May 9, 2012
• Two of the 3 Pneumocystis jirovecii
pneumonia cases occurred in Japan, a country
where pneumocystis is diagnosed 10 times
more frequently than in the United States.
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials
/Drugs/ArthritisAdvisoryCommittee/UCM302960.pdf
59. • A diagnosis of PcP was deemed definitive…
– if P jiroveci was found on microscopic analysis of respiratory samples with
concurrent clinical manifestations (fever, dry cough, or dyspnea), hypoxemia,
and radiologic findings indicative of PcP.
• The diagnosis of PcP was considered presumptive…
– if a patient fulfilled these conditions in the absence of evidence of bacterial
pneumonia and presence of either a positive polymerase chain reaction
(PCR) test for P jiroveci DNA or increased serum 1,3-D-glucan levels with
response to standard treatments for PcP .
• PcP確実例:PcPの臨床症状に加えてP.jiroveci菌体を同定
• PcP疑い例:PcPの臨床症状に加えてPneumocystis-PCR陽性、
あるいは β-Dグルカンの上昇を認め、通常治療に反応
• 「確実例 2例+疑い例 19例」の検討であることに留意
67. Glucocorticoids in ABT-LN trial
Daily dose of prednisone or prednisolone being taken for each week during taper
Week 1 2 3 4 5 6 7 8 9 10 11 12 13–52
Dose 90%
up to
max
55 mg
80%
up to
max
50 mg
70%
up to
max
40 mg
60%
up to
max
35 mg
50%
up to
max
30 mg
40%
up to
max
25 mg
35%
up to
max
20 mg
30%
up to
max
18 mg
25%
up to
max
15 mg
20%
up to
max
12 mg
15%
up to
max
10 mg
12%
up to
max
7 mg
8%
‡
up to
max
5 mg
ARTHRITIS & RHEUMATOLOGY
Vol. 66, No. 2, February 2014, pp 379–389
初期量を4週間(28日間)継続
その後減量(PSL 週5mg程度ずつ)
69. Ann Rheum Dis 2013;72:1280–1286
• Another problem with LUNAR and other
observational studies is the continued reliance on
long-term oral steroids.•
• In the LUNAR study the data suggest that patients
were failing to have their steroids cut according to
planned taper, highlighting how difficult it is to wean
steroids once started.
70. EXPLORER trial
• 腎炎・中枢神経病変「以外の」SLE臓器障害に対して
• Glucocorticoid + ( Rituximab vs Placebo )
• Primary Endpoint:
– 24週時点でのBILAGのClinical Response
Arthritis Rheumatism
Vol. 62, No. 1, January 2010, pp 222–233
71. Glucocorticoids in RAVE trial
ステロイドパルス(1000mgを1-3日)、
その後1mg/kg(最大 80mg/day)で
最大4週間
その後 40mgで2週間
30mgで2週間
15mgで2週間
10mgで2週間
7.5mgで2週間
5mgで2週間
2.5mgで2週間 → 中止
N Engl J Med 2013;369:417-27.
72. EUVAS trials
CYCAZAREM
(n=144)
NORAM
(n=100)
WGET
(n=180)
Prednisone dose
@ 6 months
10mg以上 7.5mg Off
Prednisone dose
@ 12months
7.5mg Off Off
Flare rate
(%)
15% 70% (MTX arm)
47% (CY arm)
51%
• CYCAZAREM: CYCとAzathioprineで寛解維持(18ヶ月後の再発)同等
• NORAM: Early Systemicの症例:CyclophosphamideとMTXは寛解率同等
CYC 94% vs MTX 90%
• WGET: Etanerceptによる寛解維持効果(-)
Goek CN, Stone J Curr Opin Rheumatol 2005; 17: 257-264
73. Glucocorticoid in AAV – pearl?
• Pearl: A little bit of prednisone goes a long way
toward sustaining disease remissions in AAV.
• 少量ステロイドによる「維持療法」で、
ANCA関連血管炎の再燃率が大幅に低下する。
Stone J “A Clinician’s Pearls and Myths in Rheumatology” p262
Springer 2009
76. ステロイド投与そのものの工夫
• As much as necessary, as little as possible.
• 隔日投与
Annals of Internal Medicine 1975: 82; 613-8
77. • biopsy-proven GCA(n=60)
• 60例とも「プレドニゾン 20mgを8時間間隔」で5日間治
療
• その後以下の3群にランダムに振り分けた。
1. Group A: prednisone 15mg q8hr
2. Group B: prednisone 45mg q24hr (朝8時に内服)
3. Group C: prednisone 90mg q48hr (朝8時に内服)
• エンドポイントとして、同regimenで1ヶ月治療した場合
の「効果」と「副作用」を検討した。
Annals of Internal Medicine 1975: 82; 613-8
78. • Group Aのうち18例は1ヶ月後にGCAに関連したすべて
の症状が消失した。
– 消失しなかった2例については、そもそもステロイド治療に
反応性ではなかった可能性はある。
• Group Bのうち16例で上記と同様の反応が得られた。
• Group C 20例のうち、4週間継続して動脈炎のコント
ロール良好であったのは、6例のみであった。
• "Hypercortisonism"に関連した副作用が認められたの
はGroup Aで9名、Bで7名、Cで0名であった
Annals of Internal Medicine 1975: 82; 613-8
79. ステロイド・免疫抑制剤以外の工夫
• ACE阻害薬
• ARB
• Spironolactone
• Statin
• ? 尿酸降下剤
Kidney Int 2000: 57; 274-81
Am J Med 2006: 119; 912-919
Rheumatology 2008: 47; 1093-96