Medscape Rheumatology article on TNF A drugs

[Mike Bartolatz]

Ask the Experts about New Therapies for Rheumatic Disease
From Medscape Rheumatology

Failing Response to Infliximab

Question
I have a 29-year-old male patient with psoriatic arthritis and skin involvement. He has been treated with infliximab since August 2003 with excellent response. He responded poorly to the last infusion at 3 mg/kg, and also at 2 week 2 mg/kg. Is there an explanation for this lack of response, and what is your expert advice for my next course of action?

Vicente Juarez


Response from Stephen A. Paget, MD, FACP, FACR
Physician-in-Chief, Chairman of the Division of Rheumatology, the Joseph P. Routh Professor of Medicine and Rheumatic Disease, Hospital for Special Surgery, New York Presbyterian Hospital and the Weill Medical College of Cornell University, New York, NY.




All 3 anti-TNF medications (etanercept [ Enbrel ], adalimumab [ Humira ], and infliximab [ Remicade ]) have been shown to be amazingly effective and safe in the treatment of psoriasis and psoriatic arthritis. However, a few important anti-tumor necrosis factor (TNF) realities must be appreciated, all gleaned from a worldwide experience with these wonderful new medications over these past 5 years:

All anti-TNFs are not created equal.


Etanercept is given subcutaneously twice a week or weekly and has a short half-life of 4-5 days. Unlike adalimumab and infliximab, etanercept is not a monoclonal antibody and works in a very different manner employing a receptor decoy action. Although the 2 monoclonal antibody preparations have been effective in Crohn's disease, Wegener's granulomatosis, and likely other granulomatous disorders, etanercept has not because it probably does not have optimal tissue penetration. Etanercept does not need to be administered in combination with methotrexate because it is fully human in structure; however, the best clinical and radiologic results occur when it is combined with methotrexate.


Adalimumab is given subcutaneously every other week or weekly, has a long half-life of 12-14 days, and is a fully human monoclonal protein. It works best in rheumatoid arthritis when given along with methotrexate, although this combination is not mandatory.


Infliximab is given intravenously at weeks 0, 2, and 6 and then every 8 weeks at a dose of 3 mg/kg. It is a chimeric monoclonal antibody, one quarter mouse. Thus, in order to control the development of neutralizing antibodies to the mouse moiety, it must be given along with methotrexate. Its half-life is 9 days. Dose adjustments over time with infliximab are common and, in some centers, half of the patients with rheumatoid arthritis are treated with 5-10 mg/kg, every 4 weeks, in order to maintain the clinical response.


Only 60% to 70% of patients taking any one of the anti-TNFs have a clinical response, from moderately good to excellent. The rest do not have a response and need to be switched to an alternative TNF-blocker. These switches are commonly helpful and each of the anti-TNFs has been switched to one of the others with good results. Why these medications do not work in everyone is not known but probably relates to the genetically defined, immunologic processes that cause that specific person's arthritis.


All of the anti-TNFs may "run out of gas" to one degree or another after 2-3 years, and some type of medication switch or dose change is needed. With adalimumab you can move from injection every other week to weekly, and with infliximab you can raise both the dose or frequency of dosage. Why this may happen is not known but may reflect a switch by the immune system to another dominant cytokine than TNF or to antibodies that are developed by the immune system and neutralize the biologic agent.


So, your next course of action for this patient is to either raise the dose of infliximab (ie, 5-10 mg/kg every 6-8 weeks) or switch to an alternative anti-TNF medication.



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Disclosure: Stephen A. Paget, MD, FACP, FACR, has disclosed no relevant financial relationships.




Medscape Rheumatology. 2005; 6 (1): ©2005 Medscape

[Guest]

Brilliant stuff whats it called? ^

[Mike Bartolatz]

All 3 anti-TNF medications (etanercept [ Enbrel ], adalimumab [ Humira ], and infliximab [ Remicade ]) have been shown to be amazingly effective and safe in the treatment of psoriasis and psoriatic arthritis. However, a few important anti-tumor necrosis factor (TNF) realities must be appreciated, all gleaned from a worldwide experience with these wonderful new medications over these past 5 years:

All anti-TNFs are not created equal.