**7. Impact of TCZ on the treatment strategy for rheumatoid arthritis**

Examination by MRI of RA patients has revealed that in approximately half of the patients, bone destruction in joints had begun within 4 months of the onset of inflammation (McQueen et al., 1998). It is, therefore, important to achieve remission within 4 months of the onset of RA to reduce the chances of bone destruction. In treatment with the conventional DMRADs including MTX and with TNF inhibitors, patients who do not respond or who show insufficient response are often encountered. In these patients, bone destruction often progresses whilst disease activity remains uncontrolled. Medically, there is no reason why MTX or TNF inhibitors must be used initially. Therefore, to achieve tight control, and to reduce the number of such unfortunate patients, TCZ monotherapy is recommended from the beginning in new onset patients because it shows high efficacy and response rates. After tight control is achieved, how long to continue TCZ treatment and what treatment to use after completion of TCZ treatment are topics for future study.

#### **8. References**

Atarashi, K, Nishimura, J, Shima, T, Umesaki, Y, Yamamoto, M, Onoue, M, Yagita, H, Ishii, N, Evans, R, Honda, K, & Takeda, K. (2008). ATP drives lamina propria T(H)17 cell differentiation. *Nature*, Vol. 455, No. 7214, pp. 808-812, ISSN 0028-0836

Australian Government Department of Health and Ageing. (2011). Australian Public Assessment Report for Tocilizumab. pp. 1-107

Changes in laboratory findings are shown in figure 2. CRP virtually normalized in all patients after the first dose of TCZ (1.61 ± 0.16 → 0.20 ± 0.03 mg/dL) (Fig. 2a). Erythrocyte sedimentation rate (ESR) likewise normalized quickly after the first dose (37.9 ± 2.47 → 8.8 ± 0.85 mm/h) (Fig. 2b). Both followed a normal course afterwards as well. The level of matrix metalloproteinase-3 (MMP-3) gradually decreased from 207.7 ng/ml at baseline to 88.4 ± 8.79 ng/ml at 51 weeks (Fig. 2c). The mean leukocyte count was 8260 ± 278 /mL at baseline; however, this decreased to approximately 5500 /mL after the first dose. There was no progressive fall as seen in myelosuppression and no significant increase in infections (Fig. 2d). Likewise, the mean platelet count of 328000 ± 9100 /mL at baseline decreased to approximately 220000 /mL after the first dose (Fig.2e). The hemoglobin (Hb) level rose gradually and anemia improved after treatment with TCZ began (Fig. 2f). Figure 2g shows changes over time in AST and ALT as an index of liver function. Even though abnormal values for AST or ALT were seen, these were transient and all were of grade I based on the National Cancer Institute Common Toxicity Criteria. Mean total T-cho at baseline was 201.7 ± 3.46 mg/dL. Upon treatment with TCZ, it rose to approximately 220 mg/dL and then decreased to 210 mg/dL (Fig. 2h). I provided lifestyle guidance and monitored the clinical course without administering drug treatment at least until dose 3. Several patients whose level nevertheless exceeded 280 mg/dL were treated with a HMG-CoA reductase inhibitor. HDL and LDL at baseline were 58.4 ± 1.55 mg/dL and 123.5 ± 3.08 mg/dL, respectively. HDL rose to approximately 65 mg/dL. LDL transiently rose to approximately 130 mg/dL but returned to baseline thereafter (Fig. 2h). I encountered no laboratory test abnormalities so severe that treatment with TCZ could not continue. TCZ was generally well tolerated, as

**7. Impact of TCZ on the treatment strategy for rheumatoid arthritis** 

what treatment to use after completion of TCZ treatment are topics for future study.

Atarashi, K, Nishimura, J, Shima, T, Umesaki, Y, Yamamoto, M, Onoue, M, Yagita, H, Ishii,

differentiation. *Nature*, Vol. 455, No. 7214, pp. 808-812, ISSN 0028-0836 Australian Government Department of Health and Ageing. (2011). Australian Public

Assessment Report for Tocilizumab. pp. 1-107

N, Evans, R, Honda, K, & Takeda, K. (2008). ATP drives lamina propria T(H)17 cell

Examination by MRI of RA patients has revealed that in approximately half of the patients, bone destruction in joints had begun within 4 months of the onset of inflammation (McQueen et al., 1998). It is, therefore, important to achieve remission within 4 months of the onset of RA to reduce the chances of bone destruction. In treatment with the conventional DMRADs including MTX and with TNF inhibitors, patients who do not respond or who show insufficient response are often encountered. In these patients, bone destruction often progresses whilst disease activity remains uncontrolled. Medically, there is no reason why MTX or TNF inhibitors must be used initially. Therefore, to achieve tight control, and to reduce the number of such unfortunate patients, TCZ monotherapy is recommended from the beginning in new onset patients because it shows high efficacy and response rates. After tight control is achieved, how long to continue TCZ treatment and

was observed in clinical trials.

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**4** 

**Mycobacterial Infections Associated** 

Tumor necrosis factor (TNF) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis and other chronic inflammatory diseases. TNF also plays a critical role in host responses to intracellular pathogens and in granuloma formation and maintenance. The TNF-α inhibitors are a class of highly effective, targeted anti-inflammatory medications in widespread use for the treatment of rheumatoid arthritis. However, evidence has accumulated since the introduction of the TNF-antagonists that they are also associated with an increased risk of granulomatous infections, including tuberculosis and non-tuberculous

This chapter will review the literature on the role of TNF in response to mycobacterial infection, the various TNF-α inhibitors and their biological differences, and the indications for TNF-α inhibitors in the treatment of rheumatoid arthritis. We will also review the literature to date on the risk of tuberculosis associated with rheumatoid arthritis and TNFantagonist therapy. We will discuss the clinical evaluation and treatment of latent tuberculosis infection in the setting of proposed TNF-antagonist therapy, as well as the presentation and treatment of active tuberculosis. We will review the current literature on the risk of NTM disease associated with TNF-α inhibitor therapy, as well as the

TNF is produced primarily by activated monocytes/macrophages, T- and B-lymphocytes, and natural killer cells. It is made as a transmembrate protein (tmTNF), which is then cleaved to a soluble form (sTNF). Three monomers then associate to form trimeric TNF, which is biologically active. This trimeric TNF binds to cell-surface receptors TNFR1 and TNFR2. Both TNFR1 and TNFR2 can signal pro-inflammatory pathways and anti-apoptotic pathways. TNFR1 can also signal via death domain caspase-dependent pathways to induce

TNF plays a major role in the initial host response to infection. With respect to tuberculosis, TNF is involved in macrophage activation; it increases the phagocytic capacity of the macrophage and enhances its killing of intracellular bacteria, via the generation of reactive nitrogen and oxygen species (Bekker et al. 2001). TNF also stimulates macrophages and T-

presentation, treatment, and prevention of NTM disease in this setting.

**1. Introduction** 

mycobacterial (NTM) infections.

**2. TNF and TNF-α inhibitors** 

**2.1 TNF biology** 

apoptosis.

 **with TNF-α Inhibitors** 

*University of Toronto* 

*Canada* 

Sarah K. Brode and Theodore K. Marras

