Treating and evaluating inflammatory disorders

Abstract

Methods of treating inflammatory disorders, such as rheumatoid arthritis, by modulating TWEAK and TNF-α are disclosed, as are other methods.

1 . A method comprising:
 administering, to a human subject who has rheumatoid arthritis, a TWEAK blocking agent in combination with a TNF-α blocking agent, in amounts and for a time to provide a therapeutic effect.   
     
     
         2 . The method of  claim 1  wherein the TWEAK blocking agent and the TNF-α blocking agent are administered in an amount effective to inhibit TWEAK and TNF-α in synoviocytes, chondrocytes, osteoclasts, or osteoblasts. 
     
     
         3 . The method of  claim 1  wherein the TWEAK blocking agent and the TNF-α blocking agent are administered in an amount effective to reduce transcription of a set of genes induced by TWEAK and TNF-α cellular programs in synoviocytes, chondrocytes, osteoclasts, or osteoblasts. 
     
     
         4 . The method of  claim 1  wherein the TWEAK blocking agent and the TNF-α blocking agent are administered in an amount effective to reduce transcription of one or more genes list in Table 1 in synoviocytes, chondrocytes, osteoclasts, or osteoblasts. 
     
     
         5 . The method of  claim 1  wherein the TWEAK blocking agent is administered in an amount that is at least 20% less than standard dosages for TWEAK blocking agent monotherapy for treating an adult subject for rheumatoid arthritis. 
     
     
         6 . The method of  claim 1  or  5  wherein the TNF-α blocking agent is administered in an amount that is at least 20% less than standard dosages for TNF-α blocking agent monotherapy for treating an adult subject for rheumatoid arthritis. 
     
     
         7 . The method of  claim 1  wherein the subject is not receiving methotrexate. 
     
     
         8 . The method of  claim 1  wherein the subject is not receiving any other disease modifying anti-rheumatic drug (DMARD). 
     
     
         9 . The method of  claim 1  wherein the amounts result in a statistically significant reduction in joint damage as measured by the Sharp erosion score. 
     
     
         10 . The method of  claim 1  wherein the TWEAK blocking agent reduces the ability of TWEAK to bind to a TWEAK receptor. 
     
     
         11 . The method of  claim 1  wherein the TWEAK blocking agent is an antibody that binds to TWEAK. 
     
     
         12 . The method of  claim 1  wherein the TWEAK blocking agent comprises an antibody that binds to a TWEAK receptor. 
     
     
         13 . The method of  claim 1  wherein the TWEAK blocking agent comprises a soluble form of a TWEAK receptor. 
     
     
         14 . The method of  claim 1  wherein the TWEAK blocking soluble form of the TWEAK receptor is fused with an antibody Fc region. 
     
     
         15 . The method of  claim 1  wherein the TNF-α blocking agent reduces the ability of TNF-α to bind to a TNF-α receptor. 
     
     
         16 . The method of  claim 1  wherein the TNF-α blocking agent comprises an antibody that binds to TNF-α, TNFR-I, or TNFR-II. 
     
     
         17 . The method of  claim 16  wherein the TNF-α blocking agent is infliximab or adalimumab. 
     
     
         18 . The method of  claim 1  wherein the TNF-α blocking agent comprises a soluble form of a TNF-α receptor. 
     
     
         19 . The method of  claim 1  wherein the TNF-α blocking agent is etanercept. 
     
     
         20 . The method of  claim 1  further comprising: evaluating the subject using a total Sharp score (TSS), Sharp erosion score, HAQ disability index, or radiologic method. 
     
     
         21 . A method comprising:
 administering, to a human subject who has rheumatoid arthritis, a TWEAK blocking agent in combination with another biologic DMARD, in amounts and for a time to provide a therapeutic effect.   
     
     
         22 . A kit that comprises a TWEAK blocking agent and a TNF-α blocking agent, wherein the agents are provided as separate pharmaceutical compositions or a single pharmaceutical composition. 
     
     
         23 . The kit of  claim 22  further comprising instructions for administration to treat rheumatoid arthritis. 
     
     
         24 . A pharmaceutical composition that includes:
 a TWEAK blocking agent; and   a TNF-α blocking agent.   
     
     
         25 . A method comprising:
 identifying a subject who has TWEAK and TNF-α mediated inflammation; and   administering to the subject: (i) a TWEAK blocking agent; (ii) a TNF-α blocking agent; or (iii) a combination of (i) and (ii).   
     
     
         26 . The method of  claim 25  wherein the subject is identified by evaluating expression of one or more genes in synoviocytes from the subject. 
     
     
         27 . The method of  claim 26  wherein the evaluated one or more genes include one or more genes selected from Table 1. 
     
     
         28 . The method of  claim 26  wherein the evaluating comprises obtaining a sample of cells or tissue from the subject. 
     
     
         29 . The method of  claim 25  wherein the identifying further comprises detecting symptoms of rheumatoid arthritis in the subject. 
     
     
         30 . A method comprising:
 administering, to a human subject who has rheumatoid arthritis, and who is being or has been withdrawn from a TNF-α blocking agent, a TWEAK blocking agent in an amount and for a time effective to provide a therapeutic effect.   
     
     
         31 . The method of  claim 30  wherein the TNF-α blocking agent causes toxicity, induces an immune-compromised state, or lacks efficacy. 
     
     
         32 . The method of  claim 30  wherein the subject is refractory to therapy with the TNF-α blocking agent. 
     
     
         33 . The method of  claim 30  wherein the subject has tuberculosis, an opportunistic infection, or a pathogenic bacterial infection. 
     
     
         34 . The method of  claim 30  wherein the subject has glomerulonephritis. 
     
     
         35 . The method of  claim 30  wherein the subject has a demyelinating syndrome. 
     
     
         36 . The method of  claim 30  wherein the subject has a lupus-like reaction. 
     
     
         37 . A method comprising:
 detecting an adverse event in a human subject who has rheumatoid arthritis, wherein the subject is being treated with a TNF-α blocking agent, but not a TWEAK blocking agent; and   administering, to the subject, a TWEAK blocking agent in an amount and for a time effective to provide an overall therapeutic effect.   
     
     
         38 . The method of  claim 37  further comprising withdrawing the TNF-α blocking agent. 
     
     
         39 . The method of  claim 37  wherein the adverse event comprises a lupus-like reaction. 
     
     
         40 . The method of  claim 37  wherein the adverse event comprises a bacterial or opportunistic infection. 
     
     
         41 . The method of  claim 37  wherein the adverse event comprises tuberculosis. 
     
     
         42 . A method comprising:
 administering, to a human subject who has rheumatoid arthritis, and who is being or has been withdrawn from a DMARD other than a TWEAK blocking agent, a TWEAK blocking agent in an amount and for a time to provide a therapeutic effect.   
     
     
         43 . The method of  claim 42  wherein the DMARD is methotrexate, parenteral gold, sulphasalazine, or hydroxychloroquinone. 
     
     
         44 . The method of  claim 42  wherein the DMARD is other than a TNF-α blocking agent. 
     
     
         45 . The method of  claim 42  wherein the DMARD is withdrawn due to toxicity or to lack of efficacy. 
     
     
         46 . A method comprising:
 administering, to a human subject who has an inflammatory disorder, a TWEAK blocking agent in combination with a TNF-α blocking agent, in amounts and for a time to provide a therapeutic effect, wherein the inflammatory disorder is one that a TNF-α blocking agent does not exacerbate.   
     
     
         47 . The method of  claim 46  wherein the inflammatory disorder is psoriatic arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, or inflammatory myositis. 
     
     
         48 . The method of  claim 46  wherein the subject is less than 17 years of age, and the disorder is juvenile rheumatoid arthritis or pediatric psoriasis. 
     
     
         49 . A method of reducing joint inflammation, the method comprising identifying a subject having joint inflammation, and administering to the subject a TWEAK blocking agent in combination with a TNF-α blocking agent. 
     
     
         50 . The method of  claim 49  wherein the subject has rheumatoid arthritis. 
     
     
         51 . The method of  claim 49  wherein the TWEAK blocking agent is an antibody that binds to TWEAK. 
     
     
         52 . The method of  claim 49  wherein the TWEAK blocking agent comprises an antibody that binds to a TWEAK receptor. 
     
     
         53 . The method of  claim 49  wherein the TWEAK blocking agent comprises a soluble form of a TWEAK receptor. 
     
     
         54 . The method of  claim 53  wherein the soluble form of the TWEAK receptor is fused with an antibody Fc region.