TNF抑制剂在适应症以外的应用PPT
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• Quintos-Macasa AM, et al. Enbrel-induced interstitial lung disease. South Med J 2006;99:783–4.
• Hagiwara K, et al. Acute exacerbation of preexisting interstitial lung disease after administration of etanercept for rheumatoid arthritis. J Rheumatol 2007;34:1151–4.
• Ostör AJ, et al. Pulmonary complications of infliximab therapy in patients with rheumatoid arthritis. J Rheumatol 2006;33:622–8.
• Kramer N, et al. Methotrexate pneumonitis after initiation of infliximab therapy for rheumatoid arthritis. Arthritis Rheum 2002;47:670–1.
Stop of biological therapy (%)
91
95
100
89
14.70 ±2.77
100
23.63 ±3.24
91
16.09 ±6.27
97
47.14 ±7.33
40
14.75 ±4.48
100
Corticosteroi ds/immunosu pp. (%)
50, 1846, 13ຫໍສະໝຸດ TNF抑制剂在适应症以外的应用
Infliximab 适应症
（美国 FDA 批准）
➢类风湿关节炎 ➢幼年型类风关 ➢强直性脊柱炎 ➢银屑病关节炎 ➢银屑病 ➢炎性肠病
Miscellaneous conditions in which tumor necrosis factor blockade appears promising
a) Systemic autoimmune diseases
Reported cases (n)
140
• drug-induced lupus
• Vasculitis
139
• APS/APS-like disease
42
• Sarcoidosis
38
b) Organ-specific autoimmune diseases
Peripheral neuropathies
Inflammatory ocular disease
Autoimmune hepatitis
Mean time of appearance ±S EM (weeks)
32.95 ±6.45
34.02 ±4.13
11.79 ±6.04
96.92 ±13.62
• Lindsay K, et al. Acute progression of interstitial lung disease: a complication of etanercept particularly in the presence of rheumatoid lung and methotrexate treatment. Rheumatology (Oxford) 2006;45:1048–9.
Autoimmune diseases induced by biological agents: A double-edged sword?
Autoimmunity Reviews，2010, 9（3）：188-193 BIOGEAS Study Group
Characteristics of the main autoimmune diseases associated with biological agents (update July 15, 2009).
SAPHO syndrome Aphthous stomatitis Multicentric reticulohistiocytosis Macrophage activation syndrome Myelodysplastic syndrome disc disease Pyoderma gangrenosum Sweet’s syndrome CINCA syndrome Hyper-IgD syndrome Familial Hibernian fever PAPA syndrome TRAPS Periodic fever
Influence of anti-TNF therapy on mortality in patients with rheumatoid arthritis-associated interstitial lung disease: results from the British Society for Rheumatology Biologics Register.
• Optical neuritis
123
• Interstitial lung disease
118
• Inflammatory ocular disease
87
• MS/MS-like
55
• Peripheral neuropathies
44
• Autoimmune hepatitis
19
Female (%)
• Ann Rheum Dis. 2010;69(6):1086-91. University of Manchester, Manchester, UK.
• METHODS: • 367 patients with pre-existing RA-ILD were identified (299 treated with anti-TNF therapy and 68
Biological agent: INF, ETA, ADA, other (%)
37, 33, 25, 6
43, 42, 7, 7 45, 41, 5, 9 26, 61, 10, 3
43, 49, 7, 1 43, 47, 3, 7 18, 79, 2, 0 20, 51, 27, 2 74, 12, 14, 0 79, 10, 10, 0
infliximab in sarcoidosis (99%), AOSD (90%), and polychondritis (86%); etanercept in BD (96%). Lack of efficacy: infliximab in SS etanercept in SS, WG, and sarcoidosis. In conclusion, current evidence on the use of biological therapies in patients with SAD is mainly based on uncontrolled, observational data.
• CONCLUSION:
• The mortality in patients with RA-ILD is not increased following treatment with anti-TNF therapy compared with traditional DMARDs. The proportion of deaths attributable to RA-ILD is higher in patients treated with anti-TNF therapy, although reporting bias may exist.
• Huggett MT, et al. Adalimumab-associated pulmonary fibrosis. Rheumatology (Oxford) 2006;45:1312–13.
• Schoe A, et al. Pulmonary fibrosis in a patient with rheumatoid arthritis treated with adalimumab. Arthritis Rheum 2006;55:157–9.
treated with traditional DMARDs).
• RESULTS: • 70/299 patients (23%) in the anti-TNF cohort died after a median follow-up of 3.8 years compared
with 14/68 (21%) in the DMARD cohort after a median follow-up of 2.1 years. The mortality was 68 deaths/1000 pyrs in the anti-TNF cohort and 92/1000 pyrs in the DMARD cohort, generating an age- and sex-adjusted mortality rate ratio (aMRR) of 1.26. After further adjustment for potential confounders, the aMRR fell to 0.81 for the anti-TNF cohort compared with the DMARD cohort. RA-ILD was the underlying cause of death in 15/70 (21%) and 1/14 (7%) patients in the anti-TNF and DMARD cohorts, respectively.
11, 7
42, 0
No resolution of induced AD (%)
9 1 11 11
Deaths (n)
2 (1.4%) 0 (0%) 1 (2.4%) 0 (0%)
70, 13
37
14 (12%)
42, 6
30
1 (0.4%)
21, 56
11
0 (0%)
28, 3
37
0 (0%)
42, 10
77
79 70 65
63 77 81 70 66 76
Underlying disease:
RA, Sp, IBD (%)
72, 7, 11
92, 7, 8 26, 11, 26 60, 37, 0
37, 17, 25 77, 6, 4 41, 48, 0
59, 17, 12 61, 16, 16 32, 47, 21
Amyloidosis SLE; PM/DM; SS Adult Still’s disease Relapsing polychondritis Systemic vasculitis Sarcoidosis Scleroderma
RA合并肺间质病变
• 以下为TNF抑制剂导致急性肺间质病变的文献
Medicine (Baltimore). 2008;87(6):345-64. 西班牙
Outcomes of the main autoimmune diseases associated with biological agents
Vasculitis
Lupus/lupus-like
APS/APS-like
Sarcoidosis
Interstitial lung disease
Demyelinating CNS disease
6
A systematic review of the off-label use of biological therapies in systemic autoimmune diseases.
1370 patients with 19 systemic autoimmune diseases （SAD） and 6 biological agents. Included SS, WG, sarcoidosis, SLE, BD, AOSD, cryoglobulinemia, et al. Higher rate response：
• Hagiwara K, et al. Acute exacerbation of preexisting interstitial lung disease after administration of etanercept for rheumatoid arthritis. J Rheumatol 2007;34:1151–4.
• Ostör AJ, et al. Pulmonary complications of infliximab therapy in patients with rheumatoid arthritis. J Rheumatol 2006;33:622–8.
• Kramer N, et al. Methotrexate pneumonitis after initiation of infliximab therapy for rheumatoid arthritis. Arthritis Rheum 2002;47:670–1.
Stop of biological therapy (%)
91
95
100
89
14.70 ±2.77
100
23.63 ±3.24
91
16.09 ±6.27
97
47.14 ±7.33
40
14.75 ±4.48
100
Corticosteroi ds/immunosu pp. (%)
50, 1846, 13ຫໍສະໝຸດ TNF抑制剂在适应症以外的应用
Infliximab 适应症
（美国 FDA 批准）
➢类风湿关节炎 ➢幼年型类风关 ➢强直性脊柱炎 ➢银屑病关节炎 ➢银屑病 ➢炎性肠病
Miscellaneous conditions in which tumor necrosis factor blockade appears promising
a) Systemic autoimmune diseases
Reported cases (n)
140
• drug-induced lupus
• Vasculitis
139
• APS/APS-like disease
42
• Sarcoidosis
38
b) Organ-specific autoimmune diseases
Peripheral neuropathies
Inflammatory ocular disease
Autoimmune hepatitis
Mean time of appearance ±S EM (weeks)
32.95 ±6.45
34.02 ±4.13
11.79 ±6.04
96.92 ±13.62
• Lindsay K, et al. Acute progression of interstitial lung disease: a complication of etanercept particularly in the presence of rheumatoid lung and methotrexate treatment. Rheumatology (Oxford) 2006;45:1048–9.
Autoimmune diseases induced by biological agents: A double-edged sword?
Autoimmunity Reviews，2010, 9（3）：188-193 BIOGEAS Study Group
Characteristics of the main autoimmune diseases associated with biological agents (update July 15, 2009).
SAPHO syndrome Aphthous stomatitis Multicentric reticulohistiocytosis Macrophage activation syndrome Myelodysplastic syndrome disc disease Pyoderma gangrenosum Sweet’s syndrome CINCA syndrome Hyper-IgD syndrome Familial Hibernian fever PAPA syndrome TRAPS Periodic fever
Influence of anti-TNF therapy on mortality in patients with rheumatoid arthritis-associated interstitial lung disease: results from the British Society for Rheumatology Biologics Register.
• Optical neuritis
123
• Interstitial lung disease
118
• Inflammatory ocular disease
87
• MS/MS-like
55
• Peripheral neuropathies
44
• Autoimmune hepatitis
19
Female (%)
• Ann Rheum Dis. 2010;69(6):1086-91. University of Manchester, Manchester, UK.
• METHODS: • 367 patients with pre-existing RA-ILD were identified (299 treated with anti-TNF therapy and 68
Biological agent: INF, ETA, ADA, other (%)
37, 33, 25, 6
43, 42, 7, 7 45, 41, 5, 9 26, 61, 10, 3
43, 49, 7, 1 43, 47, 3, 7 18, 79, 2, 0 20, 51, 27, 2 74, 12, 14, 0 79, 10, 10, 0
infliximab in sarcoidosis (99%), AOSD (90%), and polychondritis (86%); etanercept in BD (96%). Lack of efficacy: infliximab in SS etanercept in SS, WG, and sarcoidosis. In conclusion, current evidence on the use of biological therapies in patients with SAD is mainly based on uncontrolled, observational data.
• CONCLUSION:
• The mortality in patients with RA-ILD is not increased following treatment with anti-TNF therapy compared with traditional DMARDs. The proportion of deaths attributable to RA-ILD is higher in patients treated with anti-TNF therapy, although reporting bias may exist.
• Huggett MT, et al. Adalimumab-associated pulmonary fibrosis. Rheumatology (Oxford) 2006;45:1312–13.
• Schoe A, et al. Pulmonary fibrosis in a patient with rheumatoid arthritis treated with adalimumab. Arthritis Rheum 2006;55:157–9.
treated with traditional DMARDs).
• RESULTS: • 70/299 patients (23%) in the anti-TNF cohort died after a median follow-up of 3.8 years compared
with 14/68 (21%) in the DMARD cohort after a median follow-up of 2.1 years. The mortality was 68 deaths/1000 pyrs in the anti-TNF cohort and 92/1000 pyrs in the DMARD cohort, generating an age- and sex-adjusted mortality rate ratio (aMRR) of 1.26. After further adjustment for potential confounders, the aMRR fell to 0.81 for the anti-TNF cohort compared with the DMARD cohort. RA-ILD was the underlying cause of death in 15/70 (21%) and 1/14 (7%) patients in the anti-TNF and DMARD cohorts, respectively.
11, 7
42, 0
No resolution of induced AD (%)
9 1 11 11
Deaths (n)
2 (1.4%) 0 (0%) 1 (2.4%) 0 (0%)
70, 13
37
14 (12%)
42, 6
30
1 (0.4%)
21, 56
11
0 (0%)
28, 3
37
0 (0%)
42, 10
77
79 70 65
63 77 81 70 66 76
Underlying disease:
RA, Sp, IBD (%)
72, 7, 11
92, 7, 8 26, 11, 26 60, 37, 0
37, 17, 25 77, 6, 4 41, 48, 0
59, 17, 12 61, 16, 16 32, 47, 21
Amyloidosis SLE; PM/DM; SS Adult Still’s disease Relapsing polychondritis Systemic vasculitis Sarcoidosis Scleroderma
RA合并肺间质病变
• 以下为TNF抑制剂导致急性肺间质病变的文献
Medicine (Baltimore). 2008;87(6):345-64. 西班牙
Outcomes of the main autoimmune diseases associated with biological agents
Vasculitis
Lupus/lupus-like
APS/APS-like
Sarcoidosis
Interstitial lung disease
Demyelinating CNS disease
6
A systematic review of the off-label use of biological therapies in systemic autoimmune diseases.
1370 patients with 19 systemic autoimmune diseases （SAD） and 6 biological agents. Included SS, WG, sarcoidosis, SLE, BD, AOSD, cryoglobulinemia, et al. Higher rate response：