Method for treating joint damage

Abstract

Methods of treating joint damage in a subject eligible for treatment are provided involving administering an antagonist that binds to a B-cell surface marker, such as CD20 antibody, to the subject in an amount effective to slow progression of the joint damage as measured by radiography. Further provided are articles of manufacture useful for such methods.

What is claimed is: 
     
         1 . A method for treating joint damage in a subject comprising administering a CD20 antibody to the subject, and giving the subject, at least about one month after the administration, a radiographic test that measures a reduction in the joint damage as compared to baseline prior to the administration, wherein the amount of CD20 antibody administered is effective in achieving a reduction in the joint damage. 
     
     
         2 . The method of  claim 1  wherein the radiographic testing after administering the CD20 antibody occurs at least about two months after administering the antibody. 
     
     
         3 . The method of  claim 1  wherein the radiographic testing after administering the CD20 antibody occurs at least about 10 weeks after administering the antibody. 
     
     
         4 . The method of  claim 1  wherein the radiographic testing after administering the CD20 antibody occurs at least about three months after administering the antibody. 
     
     
         5 . The method of  claim 1  wherein the radiographic testing after administering the CD20 antibody occurs at least about four months after administering the antibody. 
     
     
         6 . The method of  claim 1  wherein the radiographic testing after administering the CD20 antibody occurs at least about five months after administering the antibody. 
     
     
         7 . The method of  claim 1  wherein the radiographic testing after administering the CD20 antibody occurs at least about 24 weeks after administering the antibody. 
     
     
         8 . The method of  claim 1  wherein the radiographic testing after administering the CD20 antibody occurs at least about 52 weeks after administering the antibody. 
     
     
         9 . The method of any one of  claims 1 - 8  further comprising an additional administration to the subject of a CD20 antibody in an amount effective to achieve a continued or maintained reduction in joint damage as compared to the effect of a prior administration of CD20 antibody. 
     
     
         10 . The method of  claim 9  wherein the CD20 antibody is additionally administered to the subject even if there is no clinical improvement in the subject at the time of the radiographic testing after a prior administration. 
     
     
         11 . The method of  claim 10  wherein the clinical improvement is determined by assessing the number of tender or swollen joints, the Psoriasis Assessment Severity Index, a global clinical assessment of the subject, assessing erythrocyte sedimentation rate, or assessing the amount of C-reactive protein level. 
     
     
         12 . The method of  claim 1  wherein the test measures a total modified Sharp score. 
     
     
         13 . The method of  claim 1  wherein the antibody is rituximab. 
     
     
         14 . The method of  claim 1  wherein the antibody is humanized 2H7 comprising the variable domain sequences in SEQ ID Nos. 2 and 8. 
     
     
         15 . The method of  claim 1  wherein the antibody is humanized 2H7 comprising the variable domain sequences in SEQ ID NOS:39 and 40. 
     
     
         16 . The method of  claim 1  wherein the antibody is humanized 2H7 comprising the variable domain sequences in SEQ ID NOS:32 and 33. 
     
     
         17 . The method of  claim 1  wherein the antibody is humanized 2H7 comprising a variable heavy-chain domain with alteration N100A, or D56A and N100A, or D56A, N100Y, and S100aR in SEQ ID NO:8 and a variable light-chain domain with alteration M32L, or S92A, or M32L and S92A in SEQ ID NO:2. 
     
     
         18 . The method any  claim 1  wherein the joint damage is caused by arthritis, aseptic joint loosening of orthopedic implants, non-union of a fracture, spondyloarthropathies, psoriasis, or Crohn's disease. 
     
     
         19 . The method of  claim 18  wherein the joint damage is caused by arthritis. 
     
     
         20 . The method of  claim 19  wherein the joint damage is caused by rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and psoriatic arthritis. 
     
     
         21 . The method of  claim 1  wherein the antibody is administered intravenously. 
     
     
         22 . The method of  claim 1  wherein the antibody is administered subcutaneously. 
     
     
         23 . The method of  claim 1  wherein the subject has never been previously treated with a CD20 antibody. 
     
     
         24 . The method of  claim 1  wherein the subject is a methotrexate-naïve patient. 
     
     
         25 . The method of  claim 24  wherein the methotrexate-naïve patient has active rheumatoid arthritis. 
     
     
         26 . The method of  claim 1  wherein the antibody is a naked antibody. 
     
     
         27 . The method of  claim 1  wherein the antibody is conjugated with another molecule. 
     
     
         28 . The method of  claim 1  wherein the antibody is administered in a dose of about 0.4 to 4 grams. 
     
     
         29 . The method of  claim 26  wherein the antibody is administered in a dose of about 0.4 to 1.3 grams. 
     
     
         30 . The method of  claim 29  wherein the dose is about 1.5 to 3.5 grams. 
     
     
         31 . The method of acclaim  30  wherein the dose is about 1.5 to 2.5 grams. 
     
     
         32 . The method of  claim 1  wherein the antibody is administered at a frequency of one to four doses within a period of about one month. 
     
     
         33 . The method of  claim 32  wherein the dose is about 500 mg to 1.2 grams. 
     
     
         34 . The method of  claim 33  wherein the dose is about 750 mg to 1.1 grams. 
     
     
         35 . The method of  claim 1  wherein the antibody is administered in two to three doses. 
     
     
         36 . The method of  claim 1  wherein the antibody is administered within a period of about 2 to 3 weeks. 
     
     
         37 . The method of  claim 1  wherein no other medicament than the CD20 antibody is administered to the subject to treat the joint damage. 
     
     
         38 . The method of  claim 1  wherein a second medicament is administered in an effective amount, wherein the CD20 antibody is a first medicament. 
     
     
         39 . The method of  claim 38  wherein the second medicament is more than one medicament. 
     
     
         40 . The method of  claim 38  or  39  wherein the second medicament is an antibiotic, an immunosuppressive agent, a disease-modifying anti-rheumatic drug (DMARD), a pain-control agent, an integrin antagonist, a non-steroidal anti-inflammatory drug (NSAID), a cytokine antagonist, a bisphosphonate, or a hormone, or a combination thereof. 
     
     
         41 . The method of  claim 40  wherein the second medicament is a DMARD. 
     
     
         42 . The method of  claim 41  wherein the DMARD is selected from the group consisting of auranofin, chloroquine, D-penicillamine, injectable gold, oral gold, hydroxychloroquine, sulfasalazine, myocrisin and methotrexate. 
     
     
         43 . The method of  claim 40  wherein the second medicament is a NSAID. 
     
     
         44 . The method of  claim 43  wherein the NSAID is selected from the group consisting of: pentasa, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac, indomethacin, aspirin and ibuprofen. 
     
     
         45 . The method of  claim 40  wherein the second medicament is a pain-control agent. 
     
     
         46 . The method of  claim 45  wherein the pain-control agent is selected from the group consisting of: paracetamol and dextropropoxyphene. 
     
     
         47 . The method of  claim 40  wherein the immunosuppressive agent is selected from the group consisting of etanercept, infliximab, adalimumab, leflunomide, anakinra, azathioprine, and cyclophosphamide. 
     
     
         48 . The method of  claim 40  wherein the second medicament is selected from the group consisting of OPG, etanercept, infliximab, etanercept, adalimumab, kinaret, raptiva, osteoprotegerin (OPG), RANKFc, anti-RANKL, pamidronate, alendronate, actonel, zolendronate, clodronate, methotrexate, azulfidine, hydroxychloroquine, doxycycline, leflunomide, sulfasalazine (SSZ), prednisolone, interleukin-1 receptor antagonist, prednisone and methylprednisolone. 
     
     
         49 . The method of  claim 40  wherein the second medicament is selected from the group consisting of infliximab, an infliximab/methotrexate (MTX) combination, MTX, etanercept, a corticosteroid, cyclosporin A, azathioprine, auranofin, hydroxychloroquine (HCQ), combination of prednisolone, MTX, and SSZ, combinations of MTX, SSZ, and HCQ, the combination of cyclophosphamide, azathioprine, and HCQ, and the combination of adalimumab with MTX. 
     
     
         50 . The method of  claim 49  wherein the corticosteroid is prednisone, prednisolone, methylprednisolone, hydrocortisone, or dexamethasone. 
     
     
         51 . The method of  claim 49  wherein the second medicament is MTX. 
     
     
         52 . The method of  claim 1  wherein the subject is rheumatoid factor negative. 
     
     
         53 . The method of  claim 1  wherein the subject is rheumatoid factor positive. 
     
     
         54 . The method of  claim 1  wherein the subject was administered methotrexate prior to the baseline. 
     
     
         55 . The method of  claim 54  wherein the methotrexate was administered at a dose of about 10-25 mg/week. 
     
     
         56 . The method of  claim 54  or  55  wherein the methotrexate was administered for at least about 12 weeks prior to the baseline. 
     
     
         57 . The method of  claim 56  wherein the methotrexate was administered at a stable dose the last four weeks prior to the baseline. 
     
     
         58 . The method of  claim 54  wherein the methotrexate was administered perorally or parenterally. 
     
     
         59 . The method of  claim 1  wherein the joint damage is caused by rheumatoid arthritis and the subject has exhibited an inadequate response to one or more anti-tumor necrosis factor (TNF) inhibitors. 
     
     
         60 . The method of  claim 59  wherein concomitant methotrexate is administered to the subject along with the CD20 antibody. 
     
     
         61 . The method of  claim 60  wherein the CD20 antibody is administered at a dose of about 1000 mg×2 on days 1 and 15 intravenously at the start of the treatment. 
     
     
         62 . A method of monitoring the treatment of joint damage in a subject comprising administering an effective amount of a CD20 antibody to the subject and measuring by radiography after at least about one month from the administration whether the joint damage has been reduced over baseline prior to the administration, wherein a decrease versus baseline in the subject after treatment indicates the CD20 antibody is having an effect on the joint damage. 
     
     
         63 . The method of  claim 62  wherein the degree of reduction versus baseline is measured a second time after the administration of the CD20 antibody. 
     
     
         64 . The method of  claim 62  or  claim 63  wherein the measurement is after at least about 24 weeks. 
     
     
         65 . An article of manufacture comprising:
 a. a container comprising a CD20 antibody; and   b. a package insert with instructions for treating joint damage in a subject, wherein the instructions indicate that the subject is administered the CD20 antibody and is then subjected, at least about one month after the administration, to a radiographic test that measures a reduction in the joint damage as compared to baseline prior to the administration, wherein the amount of CD20 antibody administered is effective in achieving a reduction in the joint damage.   
     
     
         66 . The article of  claim 65  further comprising a container comprising a second medicament, wherein the CD20 antibody is a first medicament, further comprising instructions on the package insert for treating the subject with an effective amount of the second medicament. 
     
     
         67 . A method for treating joint damage in a subject comprising administering a CD20 antibody to the subject, and giving the subject, at least about 52 weeks after the administration, a radiographic test that measures a reduction in the joint damage as compared to baseline prior to the administration, wherein the amount of CD20 antibody administered is effective in achieving a reduction in the joint damage. 
     
     
         68 . The method of  claim 67  wherein the test measures a total modified Sharp score. 
     
     
         69 . The method of  claim 67  wherein the antibody is rituximab. 
     
     
         70 . The method of  claim 67  wherein the antibody is humanized 2H7 comprising the variable domain sequences in SEQ ID NOS:2 and 8. 
     
     
         71 . The method of  claim 67  wherein the antibody is humanized 2H7 comprising the variable domain sequences in SEQ ID NOS:39 and 40. 
     
     
         72 . The method of  claim 67  wherein the antibody is humanized 2H7 comprising the variable domain sequences in SEQ ID NOS:32 and 33. 
     
     
         73 . The method of  claim 67  wherein the antibody is humanized 2H7 comprising a variable heavy-chain domain with alteration N100A, or D56A and N100A, or D56A, N100Y, and S100aR in SEQ ID NO:8 and a variable light-chain domain with alteration M32L, or S92A, or M32L and S92A in SEQ ID NO:2. 
     
     
         74 . The method of  claim 67  wherein the joint damage is caused by arthritis. 
     
     
         75 . The method of  claim 74  wherein the arthritis is rheumatoid arthritis. 
     
     
         76 . The method of  claim 75  wherein the arthritis is early active rheumatoid arthritis. 
     
     
         77 . The method of  claim 67  wherein the subject has not been previously treated with an immunosuppressive agent before the administration of a first dose of CD20 antibody in the treatment method. 
     
     
         78 . The method of  claim 67  wherein the antibody is administered in a dose of about 0.4 to 4 grams. 
     
     
         79 . The method of  claim 67  wherein the antibody is administered in a dose of about 0.4 to 1.3 grams at a frequency of one to four doses within a period of about one month. 
     
     
         80 . The method of  claim 79  wherein the dose is about 500 mg to 1.2 grams. 
     
     
         81 . The method of  claim 80  wherein the dose is about 750 mg to 1.1 grams. 
     
     
         82 . The method of  claim 67  wherein the antibody is administered in two to three doses. 
     
     
         83 . The method of  claim 67  wherein the antibody is administered within a period of about 2 to 3 weeks. 
     
     
         84 . The method of  claim 67  further comprising re-treating the subject by administering an effective amount of the CD20 antibody to the subject. 
     
     
         85 . The method of  claim 84  wherein the re-treatment is commenced at at least about 24 weeks after the first administration of the CD20 antibody. 
     
     
         86 . The method of  claim 85  wherein a further re-treatment is commenced. 
     
     
         87 . The method of  claim 86  wherein the further re-treatment is commenced at at least about 24 weeks after the second administration of the CD20 antibody. 
     
     
         88 . The method of  claim 84  wherein joint damage has been reduced after the re-treatment. 
     
     
         89 . The method of  claim 84  wherein no clinical improvement is observed in the subject at the time of the radiographic testing after the re-treatment. 
     
     
         90 . The method of  claim 89  wherein the clinical improvement is determined by assessing the number of tender or swollen joints, the Psoriasis Assessment Severity Index, a global clinical assessment of the subject, assessing erythrocyte sedimentation rate, or assessing the amount of C-reactive protein level. 
     
     
         91 . The method of  claim 67  wherein a second medicament is administered in an effective amount, wherein the CD20 antibody is a first medicament. 
     
     
         92 . The method of  claim 91  wherein the second medicament is more than one medicament. 
     
     
         93 . The method of  claim 91  wherein the second medicament is an antibiotic, an immunosuppressive agent, a disease-modifying anti-rheumatic drug (DMARD), a pain-control agent, an integrin antagonist, a non-steroidal anti-inflammatory drug (NSAID), a cytokine antagonist, a bisphosphonate, or a hormone, or a combination thereof. 
     
     
         94 . The method of  claim 93  wherein the second medicament is methotrexate. 
     
     
         95 . The method of  claim 67  wherein the subject is rheumatoid factor negative. 
     
     
         96 . The method of  claim 67  wherein the subject is rheumatoid factor positive. 
     
     
         97 . The method of  claim 67  wherein the CD20 antibody is administered intravenously. 
     
     
         98 . The method of  claim 67  wherein the CD20 antibody is administered subcutaneously. 
     
     
         99 . A method of monitoring the treatment of joint damage in a subject comprising administering an effective amount of a CD20 antibody to the subject and measuring by radiography after at least about 52 weeks from the administration whether the joint damage has been reduced over baseline prior to the administration, wherein a decrease versus baseline in the subject after treatment indicates the CD20 antibody is having an effect on the joint damage. 
     
     
         100 . The method of  claim 99  wherein the degree of reduction versus baseline is measured a second time after the administration of the CD20 antibody. 
     
     
         101 . An article of manufacture comprising:
 (a) a container comprising a CD20 antibody; and   (b) a package insert with instructions for treating joint damage in a subject, wherein the instructions indicate that the subject is administered an effective amount of the CD20 antibody and is then subjected, at least about 52 weeks after the administration, to a radiographic test that measures a reduction in the joint damage as compared to baseline prior to the administration, wherein the amount of CD20 antibody administered is effective in achieving a reduction in the joint damage.   
     
     
         102 . The article of  claim 101  further comprising a container comprising a second medicament, wherein the CD20 antibody is a first medicament, further comprising instructions on the package insert for treating the subject with an effective amount of the second medicament. 
     
     
         103 . The article of  claim 102  wherein the second medicament is methotrexate. 
     
     
         104 . A method for the treatment of joint damage in a subject, wherein (a) the subject has exhibited an inadequate response to one or more anti-tumor necrosis factor (TNF) inhibitors; (b) the subject received at least one prior course of treatment with a CD20 antibody, and (c) the treatment comprises administering at least one further course of treatment with a CD20 antibody. 
     
     
         105 . The method of  claim 104  wherein the subject responded to at least one prior course of treatment with anti-CD20 antibody. 
     
     
         106 . The method of  claim 104  wherein the joint damage is caused by arthritis. 
     
     
         107 . The method of  claim 106  wherein the arthritis is rheumatoid arthritis. 
     
     
         108 . The method of  claim 104  wherein the antibody is rituximab. 
     
     
         109 . The method of  claim 104  wherein the antibody is humanized 2H7 comprising the variable domain sequences in SEQ ID Nos. 2 and 8. 
     
     
         110 . The method of  claim 104  wherein the antibody is humanized 2H7 comprising the variable domain sequences in SEQ ID NOS:39 and 40. 
     
     
         111 . The method of  claim 104  wherein the antibody is humanized 2H7 comprising the variable domain sequences in SEQ ID NOS:32 and 33. 
     
     
         112 . The method of  claim 104  wherein the antibody is humanized 2H7 comprising a variable heavy-chain domain with alteration N100A, or D56A and N100A, or D56A, N100Y, and S100aR in SEQ ID NO:8 and a variable light-chain domain with alteration M32L, or S92A, or M32L and S92A in SEQ ID NO:2.