Antibodies concomitant therapy

Whereas initially the focus on antibody-based therapies was on cancer, anti-TNFa antibodies in particular have recently proven powerful in the therapy of chronic inflammatory diseases such as inflammatory bowel disease and rhemnatoid arthritis [71], These antibodies complex serum TNFa, the clinical benefit to RA patients most likely being the reduction of pro-inflammatory IL-6 and acute phase protein levels [9], Although they are directed against soluble proteins and as such will not serve as a drug carrier, they do show that targeted, i.e. selective, interference with a specific molecule or process can have a powerful effect without significant concomitant toxicity. 

Antibodies to the antibody (ATA) may develop with all three agents. These antibodies may attenuate or eliminate the clinical response and increase the likelihood of developing acute or delayed infusion or injection reactions. Antibody formation is much more likely in patients given episodic anti-TNF therapy than regular scheduled injections. In patients on chronic maintenance therapy, the prevalence of ATA with infliximab is 10%, certolizumab 8%, and adalimumab 3%. Antibody development also is less likely in patients who receive concomitant therapy with immunomodulators (ie, 6-MP or methotrexate). However, there are increasing concerns that concomitant treatment with anti-TNF agents and immunomodulators may increase the risk of lymphoma. 

Keystone, E. C., Kavanaugh, A. E., Sharp, J. T., et al. (2004) Radiographic, cUnical, and functional outcomes of treatment with adaUmumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy a randomized, placebo-controUed, 52-week trial. Arthritis and Rheumatism. 50, 1400-1411. 

Treatment with available anti-TN F-a inhibitors can be associated with the development of antibodies to the administered biologies [10]. The incidence is reported to be higher in patients receiving infliximab (13 to 60%), the chimeric monoclonal antibody containing a murine variable region, compared with the incidences reported for the fusion protein etanercept (<5 %) or the fully human antibody, adalimumab (-12% as monotherapy). The observed incidence of antibody formation is reduced by concomitant immunosuppressive therapies, such as methotrexate. Lower efficacy and higher incidences of infusion-related reactions have been reported in antibody-positive patients receiving infliximab [80]. 

Chickenpox in infancy and shingles in adults are caused by the same varicella-zoster virus. Very rarely and almost exclusively in immunosuppressed patients, concomitant hepatitis can occur with pronounced (mainly focal) hepatocellular necrosis, sometimes even with a fatal course. (37) Leucocytic portal and periportal infiltration can spread to the blood vessels and bile capillaries. Intranuclear inclusion bodies are present (s. fig. 23.2). Diagnosis is based on increased GPT, GOT, GDH and y-GT values as well as the presence of varicella IgM antibodies alternatively, pathogens can also be demonstrated in cultures. In children, a differential diagnosis of Reye s syndrome must be considered. As therapy in a severe course, aciclovir is indicated. (38-43)... 

The clinical significance of antibodies to infliximab has also been explored in 125 patients with Crohn s disease who were given infliximab, of whom 61% had antibodies after the fifth infusion however, there was no further increase in incidence after subsequent treatment (21). The presence of antibodies was associated with a 2.4-fold increase in the risk of infusion reactions, lower serum infliximab concentrations, and a shorter duration of clinical response, compared with patients with no infliximab antibodies. Patients who received concomitant immunosuppressive therapy had a lower incidence of infliximab antibodies, higher infliximab serum concentrations, and a longer duration of clinical response. Pretreatment with glucocorticoids may reduce the risk of antibody formation, but it is not known whether a pretreatment test for human antichimeric antibodies has a predictive value for adverse reactions (22). However, there were technical issues relating to the antibody assay and definition of clinically relevant antibody titers in this study. 

Because of the lipase deficiency, fat-soluble vitamin (A, D, E, and K) deficiencies may occur. Whether lipase activity or bile acids (e.g., in micelle formation) are involved in fat-soluble vitamin absorption with steatorrhea is unclear. Vitamin and zinc deficiencies also may occur as aresult of pancreatic enzyme deficiency. Although pancreatic involvement is predominantly exocrine in nature, insulin deficiency with glucose intolerance also occurs in CF patients, especially as they advance in age. Carbohydrate intolerance is characterized by low insulin concentrations and enhanced peripheral sensitivity to insulin but not by the presence of islet cell or anti-insulin antibodies. Carbohydrate intolerance in CF is not usually associated with the ketosis as commonly occurs in type 1 diabetes. This complication involves an increase in the number of insulin receptors with decreased affinity for insulin. Despite a concomitant increase in tissue affinity for insulin, 8% of CF children over 12 years of age require insulin therapy. 

All cases of Legionella IE have had an extended febrile course over months and high mAi-Legionella antibody titers and have occurred in patients with prosthetic valves." When special media are used, blood cultures will reveal this organism. Prolonged parenteral therapy with either doxycycline or erythromycin, with prolonged oral therapy (e.g., 6 to 17 months), has elicited cure in some patients." Most patients require concomitant valve replacement. 

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