Methods of treating inflammatory and autoimmune diseases with natalizumab

Abstract

Natalizumab is a safe and efficacious treatment for inflammatory and autoimmune diseases, such as multiple sclerosis, Crohn's Disease, and rheumatoid arthritis. Rare occurrences of progressive multifocal leucoencephalopathy during treatment suggest the possibility that it may be related to natalizumab treatment. Monitoring for JCV and informing caregivers and patients about the manifestations of progressive multifocal leucoencephalopathy can improve the safety of natalizumab therapy.

1 . A method of using natalizumab to treat a patient with an inflammatory or autoimmune disease comprising: 
 (a) administering a pharmaceutically effective amount of natalizumab;    (b) monitoring the patient for indicators of progressive multifocal leukoencephalopathy; and    (c) discontinuing the administration of natalizumab in the presence of indicators of progressive multifocal leukoencephalopathy;    wherein the monitoring improves the safety of the treatment.    
   
   
       2 . The method of  claim 1 , wherein the disease is multiple sclerosis.  
   
   
       3 . The method of  claim 2 , wherein the multiple sclerosis is selected from relapsing remitting, secondary progressive, primary progressive, and chronic progressive multiple sclerosis.  
   
   
       4 . The method of  claim 1 , wherein the disease is inflammatory bowel disease or rheumatoid arthritis.  
   
   
       5 . The method of  claim 4 , wherein the inflammatory bowel disease is Crohn's Disease.  
   
   
       6 . The method of  claim 1 , wherein the monitoring detects JCV in the patient's urine, blood, and/or cerebrospinal fluid.  
   
   
       7 . The method of  claim 6 , wherein the monitoring comprises serially removing samples of the patient's blood, measuring the amount of IgG antibodies to JCV in the samples, and comparing the amount of the antibodies in the samples.  
   
   
       8 . The method of  claim 7 , wherein the monitoring further comprises measuring the amount of IgM antibodies to JCV in the samples, and comparing the amount of the IgM and IgG antibodies in the samples.  
   
   
       9 . The method of  claim 7 , wherein the monitoring detects seroconversion and/or an increasing titer of JCV in the patient's urine and/or blood, and further comprises 
 (a) removing a sample of the patient's cerebrospinal fluid when the comparison of the serial urine and/or blood samples detect seroconversion and/or an increasing titer of JCV; and    (b) testing the cerebrospinal fluid for the presence of JCV.    
   
   
       10 . The method of  claim 1 , wherein the monitoring comprises testing for clinical and/or radiologic symptoms of progressive multifocal leukoencephalopathy.  
   
   
       11 . The method of  claim 10 , wherein the testing for clinical symptoms comprises testing for new or worsening neurological symptoms.  
   
   
       12 . The method of  claim 11 , wherein the neurological symptoms comprise one or more of central blindness, mental confusion, personality change, and dyskinesia.  
   
   
       13 . The method of  claim 11 , wherein the testing for radiologic symptoms comprises performing a Gd-enhanced magnetic resonance imaging scan.  
   
   
       14 . The method of  claim 1 , further comprising, in the presence of indicators of progressive multifocal leukoencephalopathy, providing at least one treatment selected from intravenous immunoglobulin therapy, plasmapheresis, and antiviral therapy.  
   
   
       15 . The method of  claim 14 , wherein the antiviral therapy comprises the administration of at least one therapeutically effective dose of an antiviral agent selected from cytosine arabinoside (cytarabine), cidofovir, and a serotonin antagonist.  
   
   
       16 . The method of  claim 15 , wherein the serotonin antagonist is a 5HT2a antagonist.  
   
   
       17 . The method of  claim 1 , wherein the patient is not treated simultaneously with natalizumab and an immunosuppressive or antineoplastic agent.  
   
   
       18 . The method of  claim 17  wherein the immunosuppressive or antineoplastic agent is selected from one or more of chlorambucil, melphalan, 6-mercaptopurine, thiotepa, ifodfamide, dacarbazine, procarbazine, temozolomide, hexamethylmelamine, doxorubicine, daunarubicine, idarubicin, epirubicin, irinotecan, methotrexate, etoposide, vincristine, vinblastine, vinorelbine, cytarabine, busulfan, amonifide, 5-fluorouracil, topotecan, mustargen, bleomycin, lomustine, semustine, mitomycin C, mutamycin, cisplatin, carboplatin, oxaliplatin, methotrexate, trimetrexate, raltitrexid, flurorodeoxyuridine, capecitabine, ftorafur, 5-ethynyluracil, 6-thioguanine, cladribine, pentostatin, teniposide, mitoxantrone, losoxantrone, actinomycin D, vindesine, docetaxel, amifostine, interferon alpha, tamoxefen, medroxyprogesterone, megestrol, raloxifene, letrozole, anastrzole, flutamide, bicalutamide, retinoic acids, arsenic trioxide, rituximab, CAMPATH-1, mylotarg, mycophenolic acid, tacrolimus, glucocorticoids, sulfasalazine, glatiramer, fumarate, laquinimod, FTY-720, interferon tau, daclizumab, infliximab, IL10, anti-IL2 receptor antibody, anti-IL-12 antibody, anti-IL6 receptor antibody, CDP-571, adalimumab, entaneracept, leflunomide, anti-interferon gamma antibody, abatacept, fludarabine, cyclophosphamide, azathioprine, cyclosporine, intravenous immunoglobulin, 5-ASA (mesalamine), and a β-interferon.  
   
   
       19 . The method of  claim 18 , wherein the immunosuppressive agent is a β-interferon.  
   
   
       20 . A method of using natalizumab to treat a patient with an inflammatory or autoimmune disease comprising: 
 (a) removing a sample of blood from the patient;    (b) testing the serum or plasma of the sample for the presence of IgQ antibodies to JCV;    (c) initiating treatment of the patient with natalizumab in the event the sample is negative for IgG antibodies to JCV;    (d) monitoring the patient for indicators of progressive multifocal leukoencephalopathy; and    (e) discontinuing the administration of natalizumab in the presence of indicators of progressive multifocal leukoencephalopathy;    wherein the testing and monitoring improve the safety of the treatment.    
   
   
       21 . The method of  claim 20 , wherein the disease is multiple sclerosis.  
   
   
       22 . The method of  claim 21 , wherein the multiple sclerosis is selected from relapsing remitting, secondary progressive, primary progressive, and chronic progressive multiple sclerosis.  
   
   
       23 . The method of  claim 20 , wherein the disease is inflammatory bowel disease or rheumatoid arthritis.  
   
   
       24 . The method of  claim 23 , wherein the inflammatory bowel disease is Crohn's Disease.  
   
   
       25 . The method of  claim 20 , further comprising testing the serum or plasma of the sample for IgM antibodies to JCV and initiating treatment if the serum or plasma is negative for both IgG and IgM antibodies to JCV.  
   
   
       26 . The method of  claim 20 , wherein the monitoring detects JCV in the patient's urine, blood, and/or cerebrospinal fluid.  
   
   
       27 . The method of  claim 26 , wherein the monitoring comprises serially removing samples of the patient's blood, measuring the amount of IgG antibodies to JCV in the samples, and comparing the amount of the antibodies in the samples.  
   
   
       28 . The method of  claim 26 , wherein the monitoring further comprises measuring the amount of IgM antibodies to JCV in the samples, and comparing the amount of the IgM and IgG antibodies in the samples.  
   
   
       29 . The method of  claim 27 , wherein the monitoring detects seroconversion and/or an increasing titer of JCV in the patient's urine and/or blood, and further comprises 
 (a) removing a sample of the patient's cerebrospinal fluid when the comparison of the serial urine and/or blood samples detect seroconversion and/or an increasing titer of JCV; and    (b) testing the cerebrospinal fluid for the presence of JCV.    
   
   
       30 . The method of  claim 20 , wherein the monitoring comprises testing for clinical and/or radiologic symptoms of progressive multifocal leukoencephalopathy.  
   
   
       31 . The method of  claim 30 , wherein the testing for clinical symptons comprises testing for new or worsening neurological symptoms.  
   
   
       32 . The method of  claim 31 , wherein the neurological symptoms comprise one or more of central blindness, mental confusion, personality change, and dyskinesia.  
   
   
       33 . The method of  claim 30 , wherein the testing for radiologic symptoms comprises performing a Gd-enhanced magnetic resonance imaging scan.  
   
   
       34 . The method of  claim 20 , further comprising, in the presence of indicators of progressive multifocal leukoencephalopathy, providing at least one treatment selected from intravenous immunoglobulin therapy, plasmapheresis, and antiviral therapy.  
   
   
       35 . The method of  claim 34 , wherein the antiviral therapy comprises the administration of at least one therapeutically effective dose of an antiviral agent selected from cytosine arabinoside (cytarabine), cidofovir, and a serotonin antagonist.  
   
   
       36 . The method of  claim 35 , wherein the serotonin antagonist is a 5HT2a antagonist.  
   
   
       37 . The method of  claim 20 , wherein the patient is not treated simultaneously with natalizumab and an immunosuppressive or antineoplastic agent.  
   
   
       38 . The method of  claim 37  wherein the immunosuppressive or antineoplastic agent is selected from one or more of chlorambucil, melphalan, 6-mercaptopurine, thiotepa, ifodfamide, dacarbazine, procarbazine, temozolomide, hexamethylmelamine, doxorubicine, daunarubicine, idarubicin, epirubicin, irinotecan, methotrexate, etoposide, vincristine, vinblastine, vinorelbine, cytarabine, busulfan, amonifide, 5-fluorouracil, topotecan, mustargen, bleomycin, lomustine, semustine, mitomycin C, mutamycin, cisplatin, carboplatin, oxaliplatin, methotrexate, trimetrexate, raltitrexid, flurorodeoxyuridine, capecitabine, ftorafur, 5-ethynyluracil, 6-thioguanine, cladribine, pentostatin, teniposide, mitoxantrone, losoxantrone, actinomycin D, vindesine, docetaxel, arnifostine, interferon alpha, tamoxefen, medroxyprogesterone, megestrol, raloxifene, letrozole, anastrzole, flutamide, bicalutamide, retinoic acids, arsenic trioxide, rituximab, CAMPATH-1, mylotarg, mycophenolic acid, tacrolimus, glucocorticoids, sulfasalazine, glatiramer, fumarate, laquinimod, FTY-720, interferon tau, daclizumab, infliximab, IL10, anti-IL2 receptor antibody, anti-IL-12 antibody, anti-IL6 receptor antibody, CDP-571, adalimumab, entaneracept, leflunomide, anti-interfeton gamma antibody, abatacept, fludarabine, cyclophosphamide, azathioprine, cyclosporine, intravenous immunoglobulin, 5-ASA (mesalamine), and a β-interferon.  
   
   
       39 . The method of  claim 38 , wherein the immunosuppressive agent is a β-interferon.  
   
   
       40 . A method of using natalizumab to treat a patient with an inflammatory or autoimmune disease comprising: 
 (a) removing a sample of blood from the patient;    (b) testing the serum or plasma of the sample for the presence of IgG antibodies to JCV;    (c) initiating treatment of the patient with natalizumab in the event the sample is positive for IgG antibodies to JCV;    (d) monitoring the patient for indicators of progressive multifocal leukoencephalopathy; and    (e) discontinuing the administration of natalizumab in the presence of indicators of progressive multifocal leukoencephalopathy;    wherein the testing and monitoring improves the safety of the treatment.    
   
   
       41 . The method of  claim 40 , wherein the disease is multiple sclerosis.  
   
   
       42 . The method of  claim 41 , wherein the multiple sclerosis is selected from relapsing remitting, secondary progressive, primary progressive, and chronic progressive multiple sclerosis.  
   
   
       43 . The method of  claim 40 , wherein the disease is inflammatory bowel disease or rheumatoid arthritis.  
   
   
       44 . The method of  claim 43 , wherein the inflammatory bowel disease is Crohn's Disease.  
   
   
       45 . The method of  claim 40 , wherein the monitoring detects JCV in the patient's urine, blood, and/or cerebrospinal fluid.  
   
   
       46 . The method of  claim 45 , wherein the monitoring comprises serially removing samples of the patient's blood, measuring the amount of IgG antibodies to JCV in the samples, and comparing the amount of the antibodies in the samples.  
   
   
       47 . The method of  claim 46 , wherein the monitoring detects an increasing titer of JCV in the patient's urine and/or blood, and further comprises: 
 (a) removing a sample of the patient's cerebrospinal fluid when the comparison of the serial urine and/or blood samples detect an increasing titer of JCV; and    (b) testing the cerebrospinal fluid for the presence of JCV.    
   
   
       48 . The method of  claim 40 , wherein the monitoring comprises testing for clinical and/or radiologic symptoms of progressive multifocal leukoencephalopathy.  
   
   
       49 . The method of  claim 48 , wherein the testing for clinical symptoms comprises testing for new or worsening neurological symptoms.  
   
   
       50 . The method of  claim 49 , wherein the neurological symptoms comprise one or more of central blindness, mental confusion, personality change, and dyskinesia.  
   
   
       51 . The method of  claim 50 , wherein the testing for radiologic symptoms comprises performing a Gd-enhanced magnetic resonance imaging scan.  
   
   
       52 . The method of  claim 40 , further comprising, in the presence of indicators of progressive multifocal leukoencephalopathy, providing at least one treatment selected from intravenous immunoglobulin therapy, plasmapheresis, and antiviral therapy.  
   
   
       53 . The method of  claim 52 , wherein the antiviral therapy comprises the administration of at least one therapeutically effective dose of an antiviral agent selected from cytosine arabinoside (cytarabine), cidofovir, and a serotonin antagonist.  
   
   
       54 . The method of  claim 53 , wherein the serotonin antagonist is a 5HT2a antagonist.  
   
   
       55 . The method of  claim 50 , wherein the patient is not treated simultaneously with natalizumab and an immunosuppressive or antineoplastic agent.  
   
   
       56 . The method of  claim 55  wherein the immunosuppressive or antineoplastic agent is selected from one or more of chlorambucil, melphalan, 6-mercaptopurine, thiotepa, ifodfamide, dacarbazine, procarbazine, temozolomide, hexamethylmelamine, doxorubicine, daunarubicine, idarubicin, epirubicin, irinotecan, methotrexate, etoposide, vincristine, vinblastine, vinorelbine, cytarabine, busulfan, amonifide, 5-fluorouracil, topotecan, mustargen, bleomycin, lomustine semustine, mitomycin C, mutamycin, cisplatin, carboplatin, oxaliplatin, methotrexate, trimetrexate, raltitrexid, flurorodeoxyuridine, capecitabine, ftorafur, 5-ethynyluracil, 6-thioguanine, cladribine, pentostatin, teniposide, mitoxantrone, losoxantrone, actinomycin D, vindesine, docetaxel, amifostine, interferon alpha, tamoxefen, medroxyprogesterone, megestrol, raloxifene, letrozole, anastrzole, flutamide, bicalutamide, retinoic acids, arsenic trioxide, rituximab, CAMPATH-1, mylotarg, mycophenolic acid, tacrolimus, glucocorticoids, sulfasalazine, glatiramer, fumarate, laquinimod, FTY-720, interferon tau, daclizumab, infliximab, IL10, anti-IL2 receptor antibody, anti-IL-12 antibody, anti-IL6 receptor antibody, CDP-571, adalimumab, entanercept, leflunomide, anti-interferon gamma antibody, abatacept, fludarabine, cyclophosphamide, azathioprine, cyclosporine, intravenous immunoglobulin, 5-ASA (mesalamine), and a β-interferon.  
   
   
       57 . The method of  claim 56 , wherein the immunosuppressive agent is a β-interferon.  
   
   
       58 . A method of using natalizumab to treat a patient with an inflammatory or autoimmune disease comprising: 
 (a) removing a sample of blood from the patient;    (b) testing the sample for the presence of IgG antibodies to JCV;    (c) initiating treatment of the patient with natalizumab;    (d) informing the prescribing physician about the mental and physical symptoms of progressive multifocal leukoencephalopathy;    (e) informing the patient about the mental and physical symptoms of progressive multifocal leukoencephalopathy and instructing the patient to report to the physician in the presence of at least one symptom;    (f) monitoring the patient for indicators of progressive multifocal leukoencephalopathy; and    (g) discontinuing the administration of natalizumab in the presence of indicators of progressive multifocal leukoencephalopathy;    wherein the testing, information, and monitoring improve the safety of the treatment.    
   
   
       59 . The method of  claim 58 , wherein the disease is multiple sclerosis.  
   
   
       60 . The method of  claim 59 , wherein the multiple sclerosis is selected from relapsing remitting, secondary progressive, primary progressive, and chronic progressive multiple sclerosis.  
   
   
       61 . The method of  claim 58 , wherein the disease is inflammatory bowel disease or rheumatoid arthritis.  
   
   
       62 . The method of  claim 61 , wherein the inflammatory bowel disease is Crohn's Disease.  
   
   
       63 . The method of  claim 58 , wherein the monitoring detects JCV in the patient's urine, blood, and/or cerebrospinal fluid.  
   
   
       64 . The method of  claim 63 , wherein the monitoring comprises serially removing samples of the patient's blood, measuring the amount of IgG antibodies to JCV in the samples, and comparing the amount of the antibodies in the samples.  
   
   
       65 . The method of  claim 64 , wherein the monitoring further comprises measuring the amount of IgM antibodies to JCV in the samples, and comparing the amount of the IgM and IgG antibodies in the samples.  
   
   
       66 . The method of  claim 65 , wherein the monitoring detects seroconversion and/or an increasing titer of JCV in the patient's urine and/or blood, and further comprises 
 (a) removing a sample of the patient's cerebrospinal fluid when the comparison of the serial urine and/or blood samples detect seroconversion and/or an increasing titer of JCV; and    (b) testing the cerebrospinal fluid for the presence of JCV.    
   
   
       67 . The method of  claim 58 , wherein the monitoring comprises testing for clinical and/or radiologic symptoms of progressive multifocal leukoencephalopathy.  
   
   
       68 . The method of  claim 67 , wherein the testing for clinical symptoms comprises testing for new or worsening neurological symptoms.  
   
   
       69 . The method of  claim 68 , wherein the neurological symptoms comprise one or more of central blindness, mental confusion, personality change, and dyskinesia.  
   
   
       70 . The method of  claim 67 , wherein the testing for radiologic symptoms comprises performing a Gd-enhanced magnetic resonance imaging scan.  
   
   
       71 . The method of  claim 58 , further comprising, in the presence of indicators of progressive multifocal leukoencephalopathy, providing at least one treatment selected from intravenous immunoglobulin therapy, plasmapheresis, and antiviral therapy.  
   
   
       72 . The method of  claim 71 , wherein the antiviral therapy comprises the administration of at least one therapeutically effective dose of an antiviral agent selected from cytosine arabinoside (cytarabine), cidofovir, and a serotonin antagonist.  
   
   
       73 . The method of  claim 72 , wherein the serotonin antagonist is a 5HT2a antagonist.  
   
   
       74 . The method of  claim 58 , wherein the patient is not treated simultaneously with natalizumab and an immunosuppressive or antineoplastic agent.  
   
   
       75 . The method of  claim 74  wherein the immunosuppressive or antineoplastic agent is selected from one or more of chlorambucil, melphalan, 6-mercaptopurine, thiotepa, ifodfamide, dacarbazine, procarbazine, temozolomide, hexamethylmelamine, doxorubicine, daunarubicine, idarubicin, epirubicin, irinotecan, methotrexate, etoposide, vincristine, vinblastine, vinorelbine, cytarabine, busulfan, amonifide, 5-fluorouracil, topotecan, mustargen, bleomycin, lomustine, semustine, mitomycin C, mutamycin, cisplatin, carboplatin, oxaliplatin, methotrexate, trimetrexate, raltitrexid, flurorodeoxyuridine, capecitabine, ftorafur, 5-ethynyluracil, 6-thioguanine, cladribine, pentostatin, teniposide, mitoxantrone, losoxantrone, actinomycin D, vindesine, docetaxel, amifostine, interferon alpha, tamoxefen, medroxyprogesterone, megestrol, raloxifene, letrozole, anastrzole, flutamide, bicalutamide, retinoic acids, arsenic trioxide, rituximab, CAMPATH-1, mylotarg, mycophenolic acid, tacrolimus, glucocorticoids, sulfasalazine, glatiramer, fumarate, laquinimod, FTY-720, interferon tau, daclizumab, infliximab, IL10, anti-IL2 receptor antibody, anti-IL-12 antibody; anti-IL6 receptor antibody, CDP-571, adalimumab, entaneracept, leflunomide, anti-interferon gamma antibody, abatacept, fludarabine, cyclophosphamide, azathioprine, cyclosporine, intravenous immunoglobulin, 5-ASA (mesalamine), and a β-interferon.  
   
   
       76 . The method of  claim 75 , wherein the immunosuppressive agent is a β-interferon.