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1. Extrahepatic Manifestations of Hepatitis C Virus Infection Service de Médecine Interne, et CNRS UMR 7087 Université Pierre et Marie Curie Centre National de Référence Maladies Autoimmunes Hôpital La Pitié-Salpêtrière, Paris, FRANCE Pr. Patrice CACOUB
10. HCV Mixed Cryoglobulinemia & Digestive Tract Mesenteric artery stenosis Intestinal wall thickening Terrier B et al, GUT 2011
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12. - important peri-vascular infiltrate of lymphocyte - around small vessels i.e. venules, capillaries - no PMN, no destruction of the vascular wall Mixed Cryoglobulin and Distal Polyneuropathy Peripheral Nerve Biopsy
16. Central Nervous System Involvement in HCV-Cryoglobulinemia Vasculitis HCV-vasculitis HCV Controls (n=40) (n=11) (n=36) -------------------------------------------------------------------------------------- Gender (F/M) 23/17 6/5 20/16 Age (yrs) 59 ± 13 56 ± 10 58 ± 12 WMHS 7.0 ± 9.9 0.9 ± 1.8 * 2.0 ± 3.1 PVHS 2.5 ± 3.1 0.4 ± 0.5 * 0.8 ± 1.4 NCFD 2.2 ± 1.8 0.9 ± 0.8 * - -------------------------------------------------------------------------------------- * P<0.01 WMHS: White Matter Hypersignals PVHS: Periventricular Hypersignals NCFD: Number of Cognitive Function Deficiency Casato M et al, J Hepatol 2004
17. Demographic & Clinical Features of 250 Mixed Cryoglobulinemic Patients Ferri C, Mascia MT, Saadoun D, Cacoub P. 2009 Age at disease onset 54 ± 13 (29-72) Female/Male ratio 3 Purpura 98% Weakness 98% Arthralgias 91% Arthritis (non-erosive) 8% Raynaud's phenomenon 32% Sicca syndrome 51% Peripheral neuropathy 81% Renal involvement 31% B-cell non-Hodgkin's lymphoma 11% Hepatocellular carcinoma 3%
18. Cellular Infiltrate in HCV-Vasculitis HCV Core Protein in Skin Vascular Structures Who’s the culprit ?
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21. Quantitative Deficit in Treg Lymphocytes ( CD4 + CD25 + ) in HCV-Systemic Vasculitis Boyer O, Saadoun D et al, Blood 2004
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23. Complete clinical response of HCV-vasculitis to anti-viral treatment is associated with an increase in CD4 + CD25 high levels CD25high (% of CD4+) 4 4 5 6 Before treat. On Treat. Early F/U Late F/U . ** † ** † -CR -NR/PR After Treat . A
24. Correlation between Immune Response and Treg Lymphocytes in HCV MC Vasculitis 0 20 40 60 80 100 0 1 2 3 CD 25 high ( cells / μ l) Cryoglobulins ( g/l ) R ² - 0 . 1 , p< 0 . 005 0 20 40 60 80 100 0.0 0.2 0.4 CD 25 high ( cells / μ l) C 4 ( g/l ) R ² - 0 . 16 , p< 0 . 005
32. HCV Vasculitis: a Two-Faces Disease … Needs a Two Faces Treatment Strategy Rituximab PegIFN plus Ribavirin
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34. R ituximab plus Peg-IFNα2b-Ribavirin in Refractory HCV-Related Systemic Vasculitis RITUXIMAB (375 mg/m²) Time (months) 0 1 RIBAVIRIN (600-1200 mg/d) PEGYLATED INTERFERON 2b (1.5 μ g/Kg/wk) 12 2 Saadoun D et al, Ann Rheum Dis 2008
35. Saadoun D, Ann Rheum Dis, 2008 Response rate of HCV-cryoglobulinemia vasculitis during Rituximab & Peg-IFNα2b + Ribavirin.
36. Effects of rituximab on VH1-69 clonal B cells MC pre-Rx MC post-Rx VH1-69+ B Cells Total B Cells p=0.01 A B A patient with HCV-MC-vasculitis demonstrating staining with anti-Vh1-69 gene product mAb (MC pre-Rx) and disappearance of VH1-69+ B cells following rituximab (MC post-Rx). VH1-69+ cells among CD19+ B cells in patients with HCV-MC vasculitis (n=11) before and after rituximab 73 27 30 4 37 29 97 3 91 2 5 1
41. Antiviral therapy alone decreases the memory B cells Antiviral therapy plus Rituximab decrease naive B-cells Saadoun D et al, Blood 2010
42. Saadoun D et al, Ann Rheum Dis 2008 Réponse clinique complète P<0.05 Mais 77.3 vs 66.6% RC clinique et virologique + RP immunologique Dammacco, Blood, 2010
43. Dammacco F et al, Blood 2010 Maintien de la Réponse clinique complète
44. Time Course of HCV Viral Load Terrier B et al. Arthritis Rheum 2009
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48. Overall Survival of 151 HCV-Vasculitis Patients Terrier B et al. Arthritis Rheum 2010 Years Overall survivall
55. Reversible Quantitative Deficit in Treg Lymphocytes ( CD4+CD25+) in HCV-Systemic Vasculitis CD25high (% of CD4+) 4 4 5 6 Before treat. On Treat. Early F/U Late F/U . ** † ** † -CR -NR/PR After Treat . A 0 20 40 60 80 100 0 1 2 3 CD 25 high ( cells / μ l) Cryoglobulins ( g/l ) R ² - 0 . 1 , p< 0 . 005 0 20 40 60 80 100 0.0 0.2 0.4 CD 25 high ( cells / μ l) C 4 ( g/l ) R ² - 0 . 16 , p< 0 . 005
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57. Effects of Low-Dose Interleukin-2 on Levels of CD4-Treg (c) and CD8-Treg (sq) in Patients with HCV-Vasculitis, According to Treatment Course.
58. Effects of Low-Dose Interleukin-2 on Levels on the Ratio of Treg Cells to the sum of Effector T Cells CD4 + CD8 in Patients with HCV-Vasculitis, According to Treatment Course.
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60. Effects of Low-Dose Interleukin-2 on Levels on CD19+ total B Cells (c) and Marginal-Zone B Cells (sq) in Patients with HCV-Vasculitis, According to Treatment Course.
61. Temporal Effects of Low-Dose Interleukin-2 on Clinical Features, Levels of Regulatory T Cells, and Cryoglobulin for Each Study Patient
62. Saadoun D et al. NEJM 2011 Anti-inflammatory Effects of Low-Dose Interleukin-2 Revealed through Unsupervised Transcriptome Analyses of PBMCs. BEFORE IL-2 AFTER IL-2 CCL3 CCL3L1 CCL3L3 IL1A CCL20 IL6 CLECL1 CD79A BLK CCL4L2 EBF1 CCL4L1 CXCR5 IER3 CXCR7 OLR1 PDE48 PTGS2 IL1B BAFFR 4-1BBL PLAUR NLRP3 RIPK2 ATF3 NAMPT-PBEF1 TNFRSF21-DR6 ETS2 MAPK3K8-COT GOS2 CD83 Up Down Khi2 test Inflammation 0 251 1,30E-40 Immune Response 16 684 3,40E-94 Lymphocyte 77 555 7,00E-49 Cell Cycle 1701 208 1,50E-138 Control 226 343 2,50E-01 Autoimmune & transplantation pathologies 0 46 7,60E-09 Inflammatory infectious diseases 6 242 7,60E-36 Other diseases 190 211 4,15E-02
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64. The Yin and Yang of IL-2-Mediated Immunotherapy Balance of Pathogenic Effector T Cells and Regulatory T Cells Bluestone JA, NEJM 2011
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66. Association between fatigue, depression and clinical extrahepatic manifestations (EM) Poynard T et al. J Viral Hep, 2002
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68. Prevalence of fatigue at baseline and at 18 months follow-up in treated and untreated patients Poynard T et al. J Viral Hep, 2002
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70. Impact of Treatment on Extra hepatic Manifestations in HCVpatients. At Baseline and 18 months Follow-up in Responders. Cacoub P et al. J Hepatol 2002
71. Impact of Treatment on Extra hepatic Manifestations in HCVpatients. At Baseline and 18 months Follow-up in Responders. Cacoub P et al. J Hepatol 2002
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73. Auto-antibody production in chronic HCV infection. Pawlotsky JM, Hepatology 1994. Pawlotsky JM, Ann Intern Med 1994. Prieto J, Hepatology 1996. Cacoub P, J Rheumatol 1997. Cacoub P, Medicine 2000.
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Editor's Notes
Diagnosis of neuropathic pain requires identifying the nerve structures that are involved. Pattern recognition is a common means of identifying the location of the deficit. Once the pattern of involvement is recognized, the next step is to identify the etiology. Mononeuropathies are usually posttraumatic or caused by entrapment neuropathies. 1 Occasionally systemic disease (eg, diabetes or vasculitis) can produce a mononeuropathy. 2 Mononeuropathy multiplex means that a patient has multiple mononeuropathies, usually asymmetric and involving multiple parts of the body. Causes include vasculitis, sarcoidosis, and inflammatory polyneuropathies. 2 Involvement of most of an extremity in the neuropathic process suggests involvement of the plexus, or a plexopathy. 2,3 Common causes include trauma, cancer, radiation, and some systemic illnesses. 3 Peripheral polyneuropathy, resulting in a “stocking-and-glove” pattern, is perhaps the pattern most easily recognized. 4 It is always the result of a systemic process, such as a toxic exposure, diabetes, or alcohol. 1 1. Boulton AJM, Malik RA. Diabetic neuropathy. Med Clin North Am . 1998;82:909-929. 2. Portenoy RK. Neuropathic Pain. In: Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice . Philadelphia, Pa: FA Davis Company; 1996:108-113. 3. Katz N. Neuropathic pain in cancer and AIDS. Clin J Pain . 2000;16:S41-S48. 4. Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain . Minneapolis, Minn: McGraw-Hill Companies Inc; 2000:100.
Diagnosis of neuropathic pain requires identifying the nerve structures that are involved. Pattern recognition is a common means of identifying the location of the deficit. Once the pattern of involvement is recognized, the next step is to identify the etiology. Mononeuropathies are usually posttraumatic or caused by entrapment neuropathies. 1 Occasionally systemic disease (eg, diabetes or vasculitis) can produce a mononeuropathy. 2 Mononeuropathy multiplex means that a patient has multiple mononeuropathies, usually asymmetric and involving multiple parts of the body. Causes include vasculitis, sarcoidosis, and inflammatory polyneuropathies. 2 Involvement of most of an extremity in the neuropathic process suggests involvement of the plexus, or a plexopathy. 2,3 Common causes include trauma, cancer, radiation, and some systemic illnesses. 3 Peripheral polyneuropathy, resulting in a “stocking-and-glove” pattern, is perhaps the pattern most easily recognized. 4 It is always the result of a systemic process, such as a toxic exposure, diabetes, or alcohol. 1 1. Boulton AJM, Malik RA. Diabetic neuropathy. Med Clin North Am . 1998;82:909-929. 2. Portenoy RK. Neuropathic Pain. In: Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice . Philadelphia, Pa: FA Davis Company; 1996:108-113. 3. Katz N. Neuropathic pain in cancer and AIDS. Clin J Pain . 2000;16:S41-S48. 4. Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain . Minneapolis, Minn: McGraw-Hill Companies Inc; 2000:100.
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