The study was conducted on 209 patients with rheumatoid arthritis (RA) resistant to multiple disease-modifying anti-rheumatic drugs(DMARDs) including methotrexate (patients without response to these drugs, exhibiting adverse reactions requiring discontinuation of drugs, or exhibiting weaker than normal responses to drugs).There were 28 males and 181 females with a mean age of 58.9 years. Mean disease duration was 10.2 years. Tacrolimus tended to be administrated more often in advanced stage according to Steinbrocker’s classification (stage III in 106 cases and IV in 42 cases) in the present study. Of the 209 patients, 20 were treated with tacrolimus alone, while 189 received tacrolimus combined with other drugs (methotrexate in 119 cases, leflunomide in 60 cases, and other drugs in 10 cases). The initial tacrolimus dose was 0.5 mg in 11 cases, 1 mg in 181 cases, 1.5 mg in 1 case, 2 mg in 5 cases, and 3 mg in 11 cases. Responses to treatment were evaluated after 6 months of treatment, using the DAS28EULAR criteria.
    Evaluation of responses after 6 months of treatment was possible in 185 (88.5%) of the 209 patients who received tacrolimus. According to the DAS28EULAR criteria, 92 cases were rated as exhibiting a good response, 64 as exhibiting a moderate response, and 29 as exhibiting no response. The response rate (the percentage of patients exhibiting moderate or better response) was 74.6% (156/209). Adverse reactions were seen in 60 (33.7%) of the 209 patients, including eruption/itching (26 cases), gastric/abdominal pain (6 cases), alopecia (4 cases), general malaise (4 cases), and others. In 15 cases, treatment had to be discontinued due to adverse reactions. These findings suggest that tacrolimus is highly effective and safe in patients with RA resistant to multiple drugs (including methotrexate), and can be expected to be very useful for drug treatment of RA.

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    The reactivation of latent tuberculosis infection is a major problem of anti-TNF-alpha treatment. Although the use of a tuberculin skin test is controversial because of the high rate of false-negative results in immunosuppressed patients, screening for tuberculosis infection is highly recommended before anti-TNF-alpha therapy is conducted. The aim of this study is to evaluate the clinical utility of the QuantiFeron TB-2G (QFT-2G) test for patients with rheumatoid arthritis before the treatment. Fifty RA patients received both tuberculin skin tests and QFT-2G blood tests. None of the50patients were suspected of having tuberculosis. Nine patients showed a reaction of more than10mm x10mm erythema in tuberculin skin tests, but these patients’ QFT-2G tests were negative. Indeterminate results were detected in QFT-2G test for 3 cases.These cases showed negative results in QFT-2G test one year later. In conclusion, it was suggested that QFT-2G test might be useful if it would be positive for the screening in RA patients for anti-TNF therapy. Both tuberculin skin test and QFT-2G test are necessary for the screening of tuberculosis infection for the time being.

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    Overactive bladder (OAB) is described as urinary urgency, with or without urge incontinence, and is usually associated with urinary frequency and nocturia. We conducted an investigation of OAB in patients with collagen disease. Two hundred sixty-eight cases were available for the analysis: 235 with rheumatoid arthritis (RA group) and 33 without RA (non-RA group). At least one of four OAB symptoms (urinary urgency, daytime urinary frequency, nocturia, and urge incontinence) was observed in 86% of the 268 patients. A significantly higher frequency of daytime urination (≥15 times/day) was observed in the non-RA group than in the RA group (p＜0.01), and a significantly higher frequency (≥3 times/day) of nocturia was observed in the RA group than in the non-RA group (p＜0.05). Thirty percent of the patients had urinary urgency, and 18% of the patients had urge incontinence. On the basis of the OAB symptom score, 39 (15%) of the 268 patients had OAB. Of these 39 patients, 8 were taking an over-the-counter drugs, and 34% desired treatment for OAB. Rheumatologists should be aware that some patients withcollagen disease have OAB symptoms, and these patients should be treated accordingly to improve their quality of life.

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    Human serum amylase is mainly derived from the pancreas and salivary glands. The level of serum salivary amylase has been shown to be helpful in the diagnosis of sialadenitis. Serum pancreatic and salivary amylase activities in 32 Sjögren’s syndrome (SS) patients were examined to determine whether the rate of pancreatic (AAP) and salivary isoamylase (AAS) secretion levels were useful to determine the grade of disease state in SS. The level of Xerostomia and serum AAS were significantly correlated (p＜0.05) in the 32 SS patients.
    An early stage 34 year-old female SS patient showed markedly high AAS. On the other hand, progressive stage 61 year-old SS patient displayed the reverse phenomenon in serum AAP and AAS levels, in that AAP was higher than the AAS level. An end-stage 77 year-old female SS patient showed a markedly low serum AAS level. These results suggested that the AAS level will increase at the early stage and reverse phenomenon, AAS becoming lower than AAP, will occur in the moderate stage and AAS level will markedly decrease in the end stage. We tried making one of a treatment guideline for grand symptoms related to the rate of serum isoamylase level. The SS patients in the early-stage, high AAS period, glucocorticoid or immunosuppressive therapy are indicated. Further in the SJS patients in the moderate-stage, reversing period of the level of AAS and AAP, medicine acting as salivary stimulant was indicated. Finally, in the period of AAS level becoming markedly low, medicine aiding the salivary fluid indicated.
    We discussed that investigating the serum AA is useful for deciding suitable medication for gland symptoms in SS.

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    We described clinicopathological features of eight patients (six females and two males) with isolated polyarteritis nodosa (PN). The age range of the patients was from 22 to 85 years. Six patients presented with fever, skin involvement and/or peripheral neuropathy related to the vasculitis. One patient presented with appendicitis, and the other patient presented with ovarian cyst. Biopsy specimens were obtained from 5 patients with skin and/or peripheral nerve involvement, and surgically resected specimens were obtained from one patient with appendicitis and from one patient with ovarian cyst. Fibrinoid necrosis of small to medium sized arteries was observed in all specimens. After resection, a patient with necrotizing vasculitis of the vermis and a patient with necrotizing vasculitis of the genital tract have not developed systemic vasculitis during the follow-up years. Four patients with peripheral nerve involvement responded well to high dose prednisolone therapy, however, two patients with PN confined to the skin (cutaneous PN) had frequent relapses, indicating that cutaneous PN has not necessarily a benign course.

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    We describe two autopsy cases of tacrolimus-induced acute interstitial pneumonia.
Case 1: A 70-year-old woman with RA had been treated with prednisolone since 1972. In May 2007, we added tacrolimus 1.5 mg/day, however, she complained of shortness of breath in August 2007. Chest X-ray and CT scans showed bilateral ground-glass opacity in the lung fields, and acute interstitial pneumonia was diagnosed. We treated her with methylprednisolone pulse therapy, however, she died of respiratory failure. The autopsy revealed acute and organizing diffuse alveolar damage.
Case 2: A 71 year-old woman with RA had been treated with prednisolone since 2005. She developed interstitial pneumonia in 2007, and we started tacrolimus 1 mg/day in March 2008. In May, 2008 she complained of shortness of breath. Chest X-ray and CT scans showed aggravation of interstitial pneumonia. We treated her with methylprednisolone pulse therapy, however, she died of respiratory failure. The autopsy also revealed acute and organizing diffuse alveolar damage.
    In both cases, implication of tacrolimus in the pathogenesis of IP was suggested.
    Tacrolimus is often used for the treatment of rheumatoid arthritis, however, attention needs to be given for the onset/aggravation of acute interstitial pneumonia.

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    Polyarteritis nodosa is a necrotizing angitis that predominantly affects small and medium-sized arteries. We present a case of polyarteritis nodosa with intra-abdominal and intra-muscular hemorrhage due to rupture of multiple aneurysms. A 47-year-old man was admitted to our hospital because of sudden onset lower abdominal pain. Angiography revealed the presence of multiple aneurysms of superior mesenteric artery, bilateral renal arteries, and splenic artery. Transcatheter arterial embolization was performed along with the administration of prednisolone. However, emergency surgery was performed because of small intestinal perforation. Histopathological examination on the resected small intestine showed the disruption of the internal lamina elastica with fibrinoid necrosis in the small arteries, confirming the diagnosis of polyarteritis nodosa. Although he gradually recovered after the operation, he suddenly presented pain in right axillary and femoral regions while the dose of prednisolone was decreased. CT scan revealed intramuscular hematoma. Accordingly, multiple aneurysms were found in the bilateral axillary arteries, right femoral artery and right popliteal artery on angiography. After the combination therapy with increased dose of prednisolone and methotrexate, he recovered from the manifestations. Physicians should be aware of intra-muscular hemorrhage as possible complication of PN, since it sometimes results in serious complications, such as compartment syndrome.

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    A 50 year-old-woman had been receiving regular outpatient treatment because of hypertension and glomerulonephritis. She was admitted to our hospital because of fever in May 2008. Initial examination showed WBC 12900/μl, CRP 16.39 mg/dl. Later, pleural effusion appeared rapidly. The property was exudative. She was treated with various antibiotics due to a diagnosis of infectious pleuritis. However, the treatment was not effective. Blood culture, pleural effusion culture, and pleural effusion cytology were negative. Her renal function gradually decreased. The level of serum MPO-ANCA was markedly elevated (48.0 U/ml). Although we could not examine histopathologically because of her bad condition, we diagnosed MPO-ANCA-associated glomerulonephrotis, especially microscopic polyangitis (MPA), secondary renal failure and pleuritis. She was treated with steroid pulse therapy followed by oral prednisolone (40 mg/day). Although she started hemodialysis, the fever subsided immediately. Her condition and laboratorydata were improved. Pleural effusion decreased gradually. Although she became complicated by candida esophagitis, it was resolved with syrup containing amphotericin B. After rehabilitation was performed for loss of muscle strength, she returned home in July 2008. This was a unique case of MPA with only pleuritis and without interstitial pneumonia or alveolar hemorrhage.

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    A 59 year-old woman with rheumatoid arthritis (RA) treated with 8 mg/week of methotrexate (MTX) for 4 years visited the department of otolaryngology of our hospital for swelling of her left parotid gland in June 2006. Diagnostic imaging including PET-scans revealed a tumor in the gland. The tumor adhered to the superficial layer of the parotid gland was resected by operation under general anesthesia in July 2006. Pathological diagnosis of the tumor was B cell non-Hodgkin’s lymphoma of low-grade malignancy. Two weeks after MTX was withdrawn from the treatment of RA, arthritis flared and showed resistance to 7 mg/day oral prednisolone.
    Therefore, the patient was started on treatment with rituximab (375 mg/m²×4 times/cycle) in May 2007 for both B cell lymphoma and RA. One month after the first cycle of the treatment, the arthritis disappeared, however the symptoms flared up again 6 months later. The second cycle of treatment was started in Jan 2008 and RA has been under control for 6 months. Reoccurrence of lymphoma has not been observed. Rituximab, an anti-CD20 chimeric antibody approved for the treatment of B cell non-Hodgkin’s lymphoma but not for RA in Japan, is considered to be an effective therapy for RA complicated with B cell non-Hodgkin’s lymphoma.

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    Recently, the rheumatoid arthritis (RA) patient treated with biologic agents is increasing in Japan. Effectiveness of biologic therapy is remarkably excellent as compared with the existing RA treatment. However, biologic therapy has some problems, representative problems are serious adverse reactions and expensive medical fee. Expensive medical fee is the problem of both a patient and a clinic owner. As compared with the advanced nations, the prices of Japanese biological drugs except remicade are inexpensive, but copayment is expensive in Japan. Sincemedical fee is mostly covered by the medical insurance, a copayment is almost gratuitous or low price in advanced nations. On the other hand, there is compulsory insurance system in Japan and all the people is subscriber of medical insurance. However, the majority of insured patients have to pay 30% of medical fee as a copayment. Therefore, some Japanese patients cannot be treated with biologic agents, since expensive medical fee cannot be defraied. Although a biologic therapy requires extra costs, such as an exclusive drip infusion room and personnel expenses, only insufficient medical treatment fee is given to a clinic owner. The medical care system of the RA biologic therapy in outpatient clinic is still insufficient in Japan.

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    We established the Shizuoka Rheumatism Network in 2007. The network was made to improve medical circumstances for patients with rheumatoid arthritis (RA) in Shizuoka prefecture which has a population of 3.8 million. The purpose of the network is to give patients easy access to information on RA, to encourage better corporation between hospitals and clinics, to improve the clinical skills of physicians,and to explore new findings about Japanese RA patients. As of April 2009, the network’s membership consisted of 53 medical workers including 43 physicians and 10 comedicals, and 148 patients. The network website provides useful information concerning RA, including information from participating institutions, new medical information about RA, antidisaster measures etc. Annual meetings and open symposiums for patients are held on a regular basis. Several lecture materials about RA for patients were made by the members and distributed to the patient members for free. Through this activity, we have already encountered some problems, namely, difficulty in increasing the number of participating medical institutions, difference in motivation towards the network activities between members, weak financial basis, competition with other similar activities, receiving many personal inquiries from patients, and tendency toward doctor-oriented activity. Therefore, it is necessary to evaluate the significance of the activity for the future. In spite of these problems, the Shizuoka Rheumatism Network has already managed to help some of the RA patients in this region. We would like to receive comments and questions from readers of this article. The website ishttp://www.hama-med.ac.jp/rheumatism/index.html, and the email address is srn＠hama-med.ac.jp.

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    The Network Of Rheumatic Disease In Shinshu (NORDIS) was established in November 2007 under the principle that every patient with rheumatoid arthritis (RA) should be treated with the best possible therapy in all areas of Nagano prefecture. Eighty five medical institutes actively participate in NORDIS. According to an annual questionnaire performed since 2006, orthopaedic surgeons account for approximately 80 percent of NORDIS members, and 17 percent of all members treat a large number of RA patients. Survey data from 2008 revealed that only 35 percent of members used biologics to treat RA. However, 72 percent of respondents who did not use biologics responded that they would accept patients treated with these drugs with the assistance of a rheumatologist. This implies that cooperation is needed among clinics and hospitals when complications occur to assure the spread of biologic use. It was also evident from survey findings that most patients who participated in the extension course for citizens understood their treatment and wanted to receive better therapy. As treatments for RA improve, more doctors and patients are informing themselves about new options. Thus, doctors need to decide their role in RA therapy and medical treatment to promote better collaboration among healthcare facilities.

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