**4.3 Tacrolimus**

148 Neuromuscular Disorders

Fig. 2. Correlation of AUC0-6 with C0, C2 and C4 of cyclosporine. C0 presents the serum trough concentration. C2 and C4 present the blood concentration at 2 and 4 hours after administration, respectively. *Closed* and *Open circles* represent patients with preprandial and postprandial administration, respectively. Reproduced with permission from Nagai K, et al., Therapeutic drug monitoring of cyclosporine microemulsion in interstitial pneumonia with

Fig. 3. Comparison of blood cyclosporine level between postprandial daily administration in two doses and preprandial, once daily administration; *Pre* preprandial, once daily before breakfast in a single dose; *Post* postprandial, twice daily in a divided dose. Reproduced with

microemulsion in interstitial pneumonia with dermatomyositis. *Mod Rheumatol*, 2010 (21):

Adverse events to cyclosporine include infection as well as renal disorders, hypertension, diabetes mellitus, and hepatic disorders. Because the onset of adverse events is concentration-dependent, the dose is adjusted so that the C0 is 200 ng/mL or less, but it may be impossible to reduce the dose because of the high activity of IP. Nagai et al. reported that when the C2 was 1222.6±523.8 ng/mL, the C0 was 157.3±41.4 ng/mL (Nagai, 2010), so cyclosporine can be used relatively safely if the C2 is maintained at about 1200 ng/mL. If cyclosporine is used for a long time, however, the serum creatinine value gradually increases. Thus, monitoring of both C2 and C0 are required for the assessment of immunosuppressive effects and adverse events. Moreover, because cyclosporine is metabolized at cytochrome P450 (CYP) 3A4, concomitant use with tacrolimus, bosentan, pitavastatin, and rosuvastatin is contraindicated, and it is also necessary to pay attention to concomitant use with aminoglycoside antibiotics and amphotericin B, which have been

permission from Nagai K, et al., Therapeutic drug monitoring of cyclosporine

dermatomyositis. *Mod Rheumatol*, 2010 (21): 32-36.

32-36.

known to induce renal disorders.

Tacrolimus is a metabolic product of an actinobacteria, *Streptomyces tsukubaensis*, and has a macrolide skeleton. When it is incorporated into T-lymphocytes, it forms a complex with the FK506-binding protein. As a cyclosporine, this complex shows immunosuppressive effects by inhibiting the activity of calcineurin. The activity of tacrolimus is 30- to 100-times higher than that of cyclosporine *in vitro,* and it inhibits mixed lymphocyte culture reaction, production of IL-2, expression of IL-2 receptor, and production of IFN-γ. Clinically, tacrolimus is used for inhibition of rejection after transplantation of kidneys, liver, heart, lung and pancreas and in rheumatic diseases such as systemic lupus erythematosus, rheumatoid arthritis, Behçet's disease, and myasthenia gravis.

Oddis et al. reported the utility of tacrolimus in 8 patients with refractory PM associated with IP (Oddis, 1999). When tacrolimus was orally administered to maintain the C0 at 5 to 20 ng/mL, recovery of muscle strength was observed in all 8 patients, and among 5 patients complicated with IP, 3 showed improvement, and 1 was stabilized. Thereafter, Wilkes et al. reported 13 patients with anti-tRNA synthase antibody-positive refractory DM/PM who were treated with tacrolimus (Wilkes, 2005). It was possible to rescue all the patients, to improve respiratory function, and to reduce the dose of corticosteroids administered. Takada et al. retrospectively examined the clinical effects of tacrolimus in 5 IP patients complicated with refractory DM/PM (Takada, 2005). As a result, they reported that all 5 patients could be rescued and that in 4 patients who could be evaluated by PFT before and after treatment, the PFT values were improved.

The treatment of DM/PM-complicated IP is conducted at a tacrolimus dose of 4 to 6 mg/day and a C0 of 5 to 10 ng/mL. Tacrolimus is also likely to be affected by food, and it is known that the AUC and the maximum blood concentration (Cmax) decrease with postprandial administration. For cyclosporine, C2 monitoring is required to evaluate immunosuppressive effects, but for tacrolimus, since both the blood concentrations before and at 0 to 7 hours after administration correlate well with the AUC, it is better to monitor C0 only. (Figure 4)

The adverse events of tacrolimus are infection as well as renal disorders, hypertension, diabetes mellitus, and hyperkalemia. The onset of adverse events depends on the concentration, and if the C0 is as high as 20 ng/mL for a long time, adverse reactions increase. Similar to cyclosporine, because tacrolimus is metabolized at CYP3A4, it is necessary to pay attention to concomitant drug use. Moreover, because hyperkalemia can be observed, attention must be paid to administration of potassium-conserving diuretics such as spironolactone and eplerenone.

Interstitial Pneumonia in Dermatomyositis 151

There are limitations in the treatment of DM/PM-complicated IP, and particularly RRIP, with corticosteroids alone; thus, immunosuppressive drugs should be introduced early and aggressively before remodeling of the lung tissues. Many challenges remain in determining what treatment should be started for which patient, how to perform maintenance therapy, and how to switch between immunosuppressive drugs. At this time, prospective clinical studies of various immunosuppressive drugs are ongoing, and the results are eagerly

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**5. Conclusion** 

anticipated.

**6. References** 

4967.

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Fig. 4. Correlation of AUC0-6 with C0, C2 and C4 of Tacrolimus. C0 presents the serum trough concentration. C2 and C4 present the blood concentration at 2 and 4 hours after administration, respectively.

#### **4.4 Cyclophosphamide**

Cyclophosphamide is an alkylating agent that is used to inhibit rejection after renal transplantation and for the treatment of malignant tumors. Cyclophosphamide itself has no alkylating effect, but many of its metabolites have activities that alkylate guanine and inhibit replication of DNA chains and transcription to mRNA. To exert their immunosuppressive effects, these metabolites inhibit differentiation and proliferation of T-cells and B-cells and suppress antigen processes of antigen-presenting cells such as macrophages.

DM/PM-complicated IP is treated by pulse intravenous infusion of cyclophosphamide (IV-CY, 500 to 2,000 mg) in combination with corticosteroids. In the initial case reports, the effects of IV-CY were variable. Yamasaki et al. administered IV-CY at doses of 300 to 800 mg/m2 6 times every 4 weeks in addition to steroids to 17 patients with DM/PMcomplicated IP (Yamasaki, 2007). Dyspnea improved in 11 patients, %VC improved by 10% or more in 8 patients, and the chest CT score improved in 9 patients. Moreover, the number of days from the start of initial treatment and the rate of improvement in %VC showed a negative correlation, indicating the utility of early concomitant treatment.

Cyclophosphamide exerts strong immunosuppressive effects but is also accompanied by a number of adverse events including myelosuppression and following infections, hemorrhagic cystitis, ovarian insufficiency, azoospermia, and secondary carcinogenesis. It is therefore problematic whether cyclophosphamide may be used continuously for a long time in relapsed patients after remission induction or in patients with chronic advanced disease. It is considered useful to conduct initial treatment with concomitant use of corticosteroids and cyclophosphamide and then to switch to other immunosuppressive drugs, but this requires further evaluation. A prospective comparative study in which corticosteroids and IV-CY were administered 6 times every 4 weeks and then switched to azathioprine (2.5 mg/kg/day) was conducted in IP patients complicated with scleroderma17), which may be helpful for the treatment of DM/PM-complicated IP.

#### **5. Conclusion**

150 Neuromuscular Disorders

Fig. 4. Correlation of AUC0-6 with C0, C2 and C4 of Tacrolimus. C0 presents the serum trough concentration. C2 and C4 present the blood concentration at 2 and 4 hours after

Cyclophosphamide is an alkylating agent that is used to inhibit rejection after renal transplantation and for the treatment of malignant tumors. Cyclophosphamide itself has no alkylating effect, but many of its metabolites have activities that alkylate guanine and inhibit replication of DNA chains and transcription to mRNA. To exert their immunosuppressive effects, these metabolites inhibit differentiation and proliferation of T-cells and B-cells and

DM/PM-complicated IP is treated by pulse intravenous infusion of cyclophosphamide (IV-CY, 500 to 2,000 mg) in combination with corticosteroids. In the initial case reports, the effects of IV-CY were variable. Yamasaki et al. administered IV-CY at doses of 300 to 800 mg/m2 6 times every 4 weeks in addition to steroids to 17 patients with DM/PMcomplicated IP (Yamasaki, 2007). Dyspnea improved in 11 patients, %VC improved by 10% or more in 8 patients, and the chest CT score improved in 9 patients. Moreover, the number of days from the start of initial treatment and the rate of improvement in %VC showed a

Cyclophosphamide exerts strong immunosuppressive effects but is also accompanied by a number of adverse events including myelosuppression and following infections, hemorrhagic cystitis, ovarian insufficiency, azoospermia, and secondary carcinogenesis. It is therefore problematic whether cyclophosphamide may be used continuously for a long time in relapsed patients after remission induction or in patients with chronic advanced disease. It is considered useful to conduct initial treatment with concomitant use of corticosteroids and cyclophosphamide and then to switch to other immunosuppressive drugs, but this requires further evaluation. A prospective comparative study in which corticosteroids and IV-CY were administered 6 times every 4 weeks and then switched to azathioprine (2.5 mg/kg/day) was conducted in IP patients complicated with scleroderma17), which may be

suppress antigen processes of antigen-presenting cells such as macrophages.

negative correlation, indicating the utility of early concomitant treatment.

helpful for the treatment of DM/PM-complicated IP.

administration, respectively.

**4.4 Cyclophosphamide** 

There are limitations in the treatment of DM/PM-complicated IP, and particularly RRIP, with corticosteroids alone; thus, immunosuppressive drugs should be introduced early and aggressively before remodeling of the lung tissues. Many challenges remain in determining what treatment should be started for which patient, how to perform maintenance therapy, and how to switch between immunosuppressive drugs. At this time, prospective clinical studies of various immunosuppressive drugs are ongoing, and the results are eagerly anticipated.

#### **6. References**


Interstitial Pneumonia in Dermatomyositis 153

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**9** 

*USA* 

**IBMPFD and p97,** 

Wai-Kwan Tang and Di Xia *Laboratory of Cell Biology,* 

**the Structural and Molecular** 

**Basis for Functional Disruption** 

*Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland,* 

Inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia (IBMPFD, OMIM 167320) is an inherited, autosomal dominant, adult onset multidisorder, which affects the muscle, bone and the brain (Watts et al., 2004). It is a rare condition with unknown worldwide prevalence. Affected individuals may display one or a combination of the following three symptoms which, however, are generally not recognized until patients are in their 40s or 50s (Weihl, 2011). (1) IBM (Inclusion body myopathy): About 90% of all patients develop proximal and distal muscle weakness initially with atrophy of the pelvic and shoulder girdle muscles (Kimonis et al., 2000; Kimonis et al., 2008b; Kovach et al., 2001; Watts et al., 2003). Cellular inclusion bodies and rimmed vacuoles are commonly found in these muscle tissues (Kimonis et al., 2008a; Kimonis et al., 2000; Watts et al., 2004). Characteristically, two proteins are most frequently found co-localized with the inclusion, ubiquitin and TDP-43 (TAR DNA binding protein-43) (Ritson et al., 2010; Weihl et al., 2008). Ubiquitin is a signaling molecule that directs protein substrates into a variety of cellular pathways, including protein degradation. Misfolded or unwanted proteins are labeled with ubiquitin, mostly in the form of polyubiquitin, and targeted for degradation (Clague and Urbe, 2010). TDP-43, on the other hand, is believed to be a substrate itself for either proteasome or autophagal degradation (Caccamo et al., 2009; Wang et al., 2010). Detection of these proteins in the inclusions suggests impairments in the protein degradation pathways. (2) PDB (Paget's disease of the bone): About half of IBMPFD patients develop PDB, which is caused by an imbalance in the activities between osteoblasts and osteoclasts. (3) FTD (Frontotemporal dementia): Only ~30% of patients develop FTD, which is characterized by language and/or behavioral dysfunction. Interestingly, clinical manifestation of these symptoms is rather random, and has no clear-cut correlation with family history or mutations. Even within isolated families bearing the same genetic mutation, individuals can exhibit different symptoms. These heterogeneities in clinical presentations cause frequent misdiagnoses of IBMPFD patients (van der Zee et al., 2009). Accurate diagnosis of IBMPFD often requires molecular genetic testing, in addition to a

combined clinical diagnosis of myopathy, PDB and FTD.

**1. Introduction** 

