**6.2.1 Patients**

58 Rheumatoid Arthritis – Treatment

The TNFα -/- mice or the IL-6 -/- mice demonstrated that TNF is critical for initiation of the granulomatous response, and IL-6 plays a key role in the granuloma maintenance response (Welsh et al., 2008). Unlike Il-6 -/- mice, TCZ does not completely inactivate the IL-6 system because TCZ works as a competitive inhibitor of IL-6. Moreover, TCZ, unlike TNF inhibitors, does not inhibit *M. tuberculosis* antigen-induced interferon gamma (IFN-γ) production (Ogata et al., 2010b). TNF inhibitors increase the risk of infection or reactivation of *M. tuberculosis* while TCZ does not in clinical practice. Of course, TCZ should not be used in the patients with active mycobacterium infection. However, TCZ may be a candidate for intractable RA patients with mycobacterium infection which is treated. A patient with intractable RA was treated with TCZ without aggravation of *M. avium* infection which had

IL-6 increases the production of hepcidin, which is an iron-regulatory peptide secreted from liver cells, inhibits the signal transduction of erythropoietin, and causes anemia (Ganz and Nemeth 2009). Therefore, inhibition of IL-6 signaling by TCZ significantly improves anemia caused by chronic inflammation and benefits patients'general physical condition (Song et al.,

Secondary amyloidosis is a life-threatening complication of RA. Mortality, amyloid burden, and renal prognosis significantly correlate with serum amyloid A (SAA) concentration. As amyloid deposits regressed in 60% of patients who had a median SAA concentration of less than 10 µg/ml, normalization of the SAA concentration not only prevents but also treats secondary amyloidosis (Lachmann et al., 2007). TCZ treatment almost completely normalizes the serum SAA level because IL-6 signal is essential for the expression of SAA (Hagihara et al., 2005). Therefore, TCZ is very useful for the treatment of secondary

IL-6 levels are significantly higher (30 to 1000-fold) in synovial fluid than in sera (Desgeorges et al., 1997), and IL-6 drives osteoclastgenesis (Le Goff et al., 2010). Since osteoclasts are primarily involved in bone resorption, reduction in their number would be anticipated to reduce bone loss. This expectation is supported by the results of Axmann et al (2009) who demonstrated that blockade of IL-6R dose dependently decreased the joint osteoclast count and the number of bone erosions. They concluded that the mechanism for this effect was that blockade of IL-6R negatively affects osteoclast differentiation (Axmann et

The response rate and the speed of improvement basically depend on the ratio between the target cytokine and the biological agent which traps the target cytokine. To lessen the amount of the target cytokine, it is very important that any comorbidity (e.g., infectious

**5.4 Mycobacterium infection** 

**5.5 Anemia** 

**5.6 Amyloidosis** 

**5.7 Osteoporosis** 

al., 2009).

2010).

been treated in advance (Nakahara et al., 2010).

amyloidosis (Sato et al., 2009; Inoue et al., 2010).

**6. Improving clinical outcomes** 

**6.1 Strategies for improving clinical outcomes** 

The subjects of this analysis were patients who met the 1987 revised criteria for the classification of RA from ACR. Patients were included in the analysis if they started treatment with TCZ for the first time after 16 April 2008 (the date of insurance approval in Japan) (Table 2). This is an extension of a previous study (Hirabayashi et al, 2010). Data were collected until 20 March 2010. More than 23 and 51 weeks had elapsed since the first administration of TCZ in all 101 and in 70 patients, respectively. To reduce adverse events, any comorbidity was treated or controlled as well as possible before giving TCZ. All patients had a thoracic CT scan and were tested for the tuberculin reaction (or QuantiFERON ®), anti-streptolysin O (ASO), anti-streptokinase (ASK), treponema pallidum haemagglutination (TPHA), hepatitis B surface antigen (and anti-hepatitis B core antigen antibody), anti-hepatitis C virus antibody, and -D-glucan in order to screen for infections. If tooth plaque or caries were present, I arranged for assessment and treatment by a dentist. If chronic rhinorrhea or nasal blockage was seen, the patient was assessed and treated by an otolaryngologist. Patients were asked whether they had hemorrhoids. Patients were required to abstain from smoking.

Among the various therapies being used by the patients in the three months before they received TCZ, infliximab was discontinued at least one month before, adalimumab at least one week before, and etanercept at least 4 days before the new treatment commenced. Salazosulfapyridine, bucillamine, sodium aurothiomalate and mizoribine were discontinued upon initiating TCZ. The patients continued on MTX, tacrolimus and steroids at the same dose levels as before at least until dose 3 of TCZ. Then, MTX and tacrolimus were tapered off until 6 months after. The steroid dose was decreased slowly to avoid steroid withdrawal syndrome. There were no users of auranofin, D-penicillamine, hydroxychloroquine, minocycline or lobenzarit disodium.

The Role of Tocilizumab in the Treatment of Rheumatoid Arthritis 61

a b

0

0 3 7 11 15 19 23 27 31 35 39 43 47 51

≧10years

<2years

2years≦,<10years

Week

2

4

DAS28-ESR

6

A total of 72 adverse events occurred in 64 of the 101 patients and these are listed in Table 3. The adverse events seen during infusion were transient bone pain (back pain, lumbar discomfort and ischial pain). These all appeared a few minutes into infusion and disappeared within a few minutes. Infections were the most frequent adverse events. Nasopharyngitis (common cold) was most frequent among the infections; however, the frequency was similar to that in normal individuals. A total of 10 serious adverse events requiring hospitalization occurred in 8 patients. Three patients developed pneumonia. A 60 year-old woman with old tuberculosis and bronchiectasis as comorbidities showed a slight rise over her previous level of hemosputum, and bacterial pneumonia appeared subsequently. An 80-year-old woman was suspected of having pneumonia due to *Chlamydia pneumoniae*. Both recovered with treatment. A 67-year-old man developed *pneumocystis carinii* pneumonia followed by cytomegalovirus pneumonia and died. MTX was administrated concurrently to only this person due to scleritis suggesting vasculitis. A 68 year-old man had chronic pancreatitis as a comorbidity with several episodes of acute exacerbations before exposure to TCZ. He died of an acute exacerbation of chronic pancreatitis. One patient who died due to cerebellar infarction was elderly, at 82 years of age, and had once suffered strokes in the past. A patient with malignant lymphoma discovered as a left axillary mass underwent PET-CT scan to assess the activity of interstitial pneumonia before being treated with TCZ. Accumulation was picked up in the left axillary lymph nodes. Tiny lymphadenopathy was found at the same site by CT scan. Retrospectively, it may be inferred that the accumulation seen by PET had been the early stages of malignant lymphoma. A patient who had developed colitis probably due to viral

Fig. 1. Change in DAS28ESR by disease activity at baseline (a) and by duration of disease (b). Mean values shown. The criteria for exclusion from the analysis set were as follows: (i) autoimmune disease comorbidities except Sjögren's syndrome and Hashimoto's disease, (ii) functional class IV based on the Steinbrocker criteria, (iii) presence of active infection, (iv) pregnancy, (v) drug poisoning, including alcohol, (vi) lymphocyte count £ 500 cells/mL, and (vii) positive serum β-D-glucan. The method of administering TCZ that has received insurance approval in Japan is continuous infusion of a dose of 8 mg/kg over a period of at least 1 hour once every 4 weeks. The interval between infusions was shortened to 3 weeks between the first and second infusions only, and an interval of 4 ± 1 weeks was used thereafter. Treatment was continued unless there were adverse events requiring

discontinuation or the patient requested that treatment be stopped.

0 3 7 11 15 19 23 27 31 35 39 43 47 51

>5.1 3.2~5.1 >2.6,<3.2 ≦2.6

Week

**6.2.3 Safety** 

DAS28-ESR

infection recovered quickly.

Patient Characteristics


Table 2. Patient demographics, clinical characteristics, and previous medications at baseline. SD: standard deviation. SE: standard error. 'Previous medications' denotes drugs used in the 3 months before administration of TCZ. IFX: Infliximab, ETA: etanercept, ADA: adalimumab. 'Other DMARDS' were sodium aurothiomalate, bucillamine, salazosulfapyridine, and mizoribine.

#### **6.2.2 Clinical efficacy**

The mean DAS28ESR at the start of TCZ treatment in all 101 patients was 4.60 ± 0.12 (mean ± standard error of the mean (SEM)). Mean DAS28ESR had fallen below the remission threshold (<2.6) to 2.20 ± 0.10 after two doses and had further improved to 1.61 ± 0.08 at 23 weeks (intention-to-treat with last observation carried forward (ITT-LOCF)) and 1.50 ± 0.09 at 51 weeks (ITT-LOCF). The clinical response was evaluated using the European League Against Rheumatism (EULAR) response criteria. At 51 weeks (ITT-LOCF), 64 out of 70 patients (91.4%) had achieved remission with treatment response of good in 91.4%, moderate in 7.1% and one case of no response. The no response seen beyond five doses was due to a rise in DAS28ESR associated with a temporary deterioration in symptoms due to factors other than RA and did not represent secondary non-response. To date, no patient has discontinued the treatment due to lack of response.

Next, the patients were classified based on DAS28ESR into a high-activity group at >5.1, a moderate-activity group at 3.2-5.1 and a low-activity group at <3.2. Although mean DAS28ESR had been 5.84 ± 0.13 (n=36) in the high-activity group before treatment with TCZ, this improved rapidly to below the remission threshold to 2.31 ± 0.20 after 3 doses (after 11-12 weeks; Fig. 1a). Mean DAS28ESR further improved to 1.92 ± 0.15 at 23 weeks and 1.66 ± 0.17 at 51 weeks. TCZ proved to be very effective regardless of baseline disease activity. Also, patients were classified based on disease duration into three groups (≥10 years, 2≤~<10, <2). Although mean DAS28ESR had been 4.57 ± 0.21 (n=30) in the ≥10 years group before treatment, this improved rapidly to below the remission threshold to 2.30 ± 0.17 after 2 doses (after 7 weeks; Fig. 1b). Mean DAS28ESR further improved to 1.60 ± 0.14 at 51 weeks. TCZ proved to be effective regardless of disease duration. However, in the ≥10 years group, the number of swelling joints rapidly decreased while the number of joints with tenderness decreased slowly, indicating that inflammation had subsided rapidly but that tenderness at the damaged joints was prolonged.

Fig. 1. Change in DAS28ESR by disease activity at baseline (a) and by duration of disease (b). Mean values shown. The criteria for exclusion from the analysis set were as follows: (i) autoimmune disease comorbidities except Sjögren's syndrome and Hashimoto's disease, (ii) functional class IV based on the Steinbrocker criteria, (iii) presence of active infection, (iv) pregnancy, (v) drug poisoning, including alcohol, (vi) lymphocyte count £ 500 cells/mL, and (vii) positive serum β-D-glucan. The method of administering TCZ that has received insurance approval in Japan is continuous infusion of a dose of 8 mg/kg over a period of at least 1 hour once every 4 weeks. The interval between infusions was shortened to 3 weeks between the first and second infusions only, and an interval of 4 ± 1 weeks was used thereafter. Treatment was continued unless there were adverse events requiring discontinuation or the patient requested that treatment be stopped.

#### **6.2.3 Safety**

60 Rheumatoid Arthritis – Treatment

Age, mean ± SD, median (min - max), years 60.6 ± 12.7, 61 (23 – 82)

Steinbrocker Class (I, II, III, IV) : Stage (I, II, III, IV) 37, 49, 15, 0 : 16, 19, 15, 53

Previous medications No. of patients treated Prednisolone 71 (mean dosage: 3.9 mg/day)

Table 2. Patient demographics, clinical characteristics, and previous medications at baseline. SD: standard deviation. SE: standard error. 'Previous medications' denotes drugs used in the 3 months before administration of TCZ. IFX: Infliximab, ETA: etanercept, ADA:

The mean DAS28ESR at the start of TCZ treatment in all 101 patients was 4.60 ± 0.12 (mean ± standard error of the mean (SEM)). Mean DAS28ESR had fallen below the remission threshold (<2.6) to 2.20 ± 0.10 after two doses and had further improved to 1.61 ± 0.08 at 23 weeks (intention-to-treat with last observation carried forward (ITT-LOCF)) and 1.50 ± 0.09 at 51 weeks (ITT-LOCF). The clinical response was evaluated using the European League Against Rheumatism (EULAR) response criteria. At 51 weeks (ITT-LOCF), 64 out of 70 patients (91.4%) had achieved remission with treatment response of good in 91.4%, moderate in 7.1% and one case of no response. The no response seen beyond five doses was due to a rise in DAS28ESR associated with a temporary deterioration in symptoms due to factors other than RA and did not represent secondary non-response. To date, no patient has

Next, the patients were classified based on DAS28ESR into a high-activity group at >5.1, a moderate-activity group at 3.2-5.1 and a low-activity group at <3.2. Although mean DAS28ESR had been 5.84 ± 0.13 (n=36) in the high-activity group before treatment with TCZ, this improved rapidly to below the remission threshold to 2.31 ± 0.20 after 3 doses (after 11-12 weeks; Fig. 1a). Mean DAS28ESR further improved to 1.92 ± 0.15 at 23 weeks and 1.66 ± 0.17 at 51 weeks. TCZ proved to be very effective regardless of baseline disease activity. Also, patients were classified based on disease duration into three groups (≥10 years, 2≤~<10, <2). Although mean DAS28ESR had been 4.57 ± 0.21 (n=30) in the ≥10 years group before treatment, this improved rapidly to below the remission threshold to 2.30 ± 0.17 after 2 doses (after 7 weeks; Fig. 1b). Mean DAS28ESR further improved to 1.60 ± 0.14 at 51 weeks. TCZ proved to be effective regardless of disease duration. However, in the ≥10 years group, the number of swelling joints rapidly decreased while the number of joints with tenderness decreased slowly, indicating that inflammation had subsided rapidly but

Male : Female 20 : 81 Duration of disease, mean, years 11.3

DAS28ESR, mean ± SE 4.60 ± 0.12

 TNF inhibitors (IFX, ETA, ADA) 11 (8, 2, 1) MTX 38 Tacrolimus 11 Other DMARDs 48 No DMARDs for 3 months prior to TCZ treatment 20

adalimumab. 'Other DMARDS' were sodium aurothiomalate, bucillamine,

Patient Characteristics

salazosulfapyridine, and mizoribine.

discontinued the treatment due to lack of response.

that tenderness at the damaged joints was prolonged.

**6.2.2 Clinical efficacy** 

A total of 72 adverse events occurred in 64 of the 101 patients and these are listed in Table 3. The adverse events seen during infusion were transient bone pain (back pain, lumbar discomfort and ischial pain). These all appeared a few minutes into infusion and disappeared within a few minutes. Infections were the most frequent adverse events. Nasopharyngitis (common cold) was most frequent among the infections; however, the frequency was similar to that in normal individuals. A total of 10 serious adverse events requiring hospitalization occurred in 8 patients. Three patients developed pneumonia. A 60 year-old woman with old tuberculosis and bronchiectasis as comorbidities showed a slight rise over her previous level of hemosputum, and bacterial pneumonia appeared subsequently. An 80-year-old woman was suspected of having pneumonia due to *Chlamydia pneumoniae*. Both recovered with treatment. A 67-year-old man developed *pneumocystis carinii* pneumonia followed by cytomegalovirus pneumonia and died. MTX was administrated concurrently to only this person due to scleritis suggesting vasculitis. A 68 year-old man had chronic pancreatitis as a comorbidity with several episodes of acute exacerbations before exposure to TCZ. He died of an acute exacerbation of chronic pancreatitis. One patient who died due to cerebellar infarction was elderly, at 82 years of age, and had once suffered strokes in the past. A patient with malignant lymphoma discovered as a left axillary mass underwent PET-CT scan to assess the activity of interstitial pneumonia before being treated with TCZ. Accumulation was picked up in the left axillary lymph nodes. Tiny lymphadenopathy was found at the same site by CT scan. Retrospectively, it may be inferred that the accumulation seen by PET had been the early stages of malignant lymphoma. A patient who had developed colitis probably due to viral infection recovered quickly.

The Role of Tocilizumab in the Treatment of Rheumatoid Arthritis 63

a e

0

10

20

AST,ALT (IU/L)

30

Hb(g/dL)

PLT(×104/

μL)

0 7 15 23 31 39 47

Week

0 7 15 23 31 39 47

0 7 15 23 31 39 47

Week

0 7 15 23 31 39 47

Week

AST ALT

T-cho

LDL

HDL

Week

0.0 0.5 1.0 1.5 2.0

ESR(mm/hr)

MMP-3(ng/mL)

WBC(102/

μL)

CRP(mg/dL)

0 7 15 23 31 39 47

0 7 15 23 31 39 47

Week

0 7 15 23 31 39 47

0 7 15 23 31 39 47

Week

Week

Week

b f

c g

Cho(mg/dL)

d h

Fig. 2. Change in laboratory findings. a: CRP, b: ESR. c: MMP-3, d: WBC, e: PLT, f: Hb, g:

AST and ALT, h: T-cho, HDL, and LDL. Mean values shown. Bars indicate SE.


Table 3. Adverse events. \*serious adverse events requiring hospitalization, a: No. of patients, b: No. of events. WBC: white blood cell.

PT (MedDRA Ver13.0) a b

Bone pain 2 5 Total 2 5

Nasopharyngitis 13 15 Sinusitis 4 4 Pneumonia\* 1 2 Cystitis 3 3 Periodontitis 2 2 Otitis media 3 3 Paronychia 1 1 Infection 1 1 Bronchitis 1 2

Gastroenteritis 1 1 Pneumonia chlamydial\* 1 1 Herpes zoster 1 1 Total 33 37

Rhinitis allergic 2 2 Diarrhoea 3 3 Haemorrhoids 2 2 Rash 2 2 Conjunctivitis allergic 1 1 Abdominal pain upper 1 1 Platelet count decreased 1 1 Asthma 1 1 Ileus 1 1 Pancreatitis acute\* 1 2 Cough 1 1 Colitis\* 1 1 Dizziness 1 1 Total 18 19

Liver disorder 3 3 WBC count decreased 1 1 Lymphoma\* 1 1 Cerebral infarction\* 2 2 Hypoglossal nerve disorder 1 1 Toxic skin eruption 1 1 Bowen's disease 1 1 Compression fracture 1 1 Total 11 11 Table 3. Adverse events. \*serious adverse events requiring hospitalization, a: No. of patients,

1 1

a b

Adverse drug reactions

Pneumocystis jiroveci

Events hardly related to TCZ

Events unrelated to TCZ

b: No. of events. WBC: white blood cell.

Pneumonia\*

Events possibly related to TCZ

Fig. 2. Change in laboratory findings. a: CRP, b: ESR. c: MMP-3, d: WBC, e: PLT, f: Hb, g: AST and ALT, h: T-cho, HDL, and LDL. Mean values shown. Bars indicate SE.

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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 was observed in clinical trials.
