The autoinflammatory diseases are Mendelian-inherited monogenic diseases that cause systemicinflammation. Most of the responsible genes for the autoinflammatory diseases areinvolved with the innate immunity, especially pattern recognition receptors. Dr. Kastner inNational Institutes of Health has introduced the term “autoinflammatory diseases”for the firsttime in 1999 in the report that identifies the responsible gene for TRAPS, so the field of the autoinflammatory diseases is relatively new. Since the patients with the autoinflammatorydiseases suffer from fever of unknown origin, arthritis, arthralgia, and rash, rheumatologists haverelatively higher probabilities to see these patients. Although their prevalence are very low, appropriate therapies will change QOL of these patients so dramatically that the rheumatologistsshould know the clinical features of the autoinflammatory diseases. In Japan, the nationwidesurveys on the autoinflammatory diseases had been conducted from 2009, which helped us tounderstand the pictures of autoinflammatory diseases in Japan. In this review, I am going todescribe what we have learned from the surveys and what needs to be done in the field ofautoinflammatory diseases.

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【Background】For the evaluation of large joints in patients with rheumatoid arthritis (RA), Larsen grade is usually used. However, this grading system, composed of only6grades (0-5), has several limitations such as ceiling effect within the grade. Therefore, we developed a new radiographic scoring method for large joints in RA (Assessment of Rheumatoid Arthritis by Scoring of Large Joint Destruction and Healing in Radiographic Imaging: ARASHI.
【Objective】The purpose of this study is to evaluate the radiographic damage of hip and knee joints in RA during TNF-blocking therapies by this new radiographic scoring method, and to clarify the pattern of the progression of damage during 2year therapies.
【Patients and Methods】 ʻARASHI status scoreʼ consists of 4 categories; joint space narrowing (0～3points), erosion(0～3points), joint surface (0～6points), and stability (0～4points), (total score range 0-16 points). ʻARASHI change scoreʼ consists of 5 categories; porosis (－1～1 point), joint space narrowing (－1～2 points), erosion (－2～2 points), joint surface (－6～6 points), and stability (－1～1 point), (total score range －11～12 points). Increase in more than 1point of change score was considered as progression of joint damage. Fifty one consecutive patients (6males, 45women, mean age of59. 9 years old) were enrolled in this study. All patients fulfilled the ACR 1987 revised criteria. The joints with history of surgical intervention were excluded from this analysis. The radiographic findings of96hip joints and 86knee joints were evaluated at baseline using the ARASHI status score, and at 2 years after TNF-blocking therapies (infliximab, etanercept or adalimumab) using the ARASHI change score.
【Results】 There were 12 joints (4 hip joints, 8 knee joints) with 3and more points of the status score at baseline. All of these joints resulted in significant increase in the change score during 2-year TNF-blocking therapies. On the other hand, joints with pre-existing status score of 0-2 points showed progression of joint damage only in 6.5％ of the hip and knee joints during the follow-up period.
【Conclusion 】 ARASHI scoring method was useful for radiographic assessment of the status and the progression of damage in large weight-bearing joints. In this study, we demonstrated that hip and knee joints with pre-existing damage greater than2points of the status score were highly predisposed to progressive destruction even under TNF-blocking therapies. Therefore, it is prerequisite for the hip and knee joints to be radiographically evaluated not to exceed status score 2 before the start of TNF-blocking therapies.

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    Efficacy of low dose triple combination therapy on rheumatoid arthritis (RA) was studied. Salazosulfapyridine (SASP), bucillamine (Bc), and methotrexate (MTX) were employed. Three disease modifying anti-rheumatic drugs (DMARDs) were given to MRL/l mice and RA patients. The former paper had elucidated the evidences that the low dose triple combination therapy had beneficial effects on the joint lesions in MRL/l mice. The study was carried out with clinical and histopathological analysis. In this paper, the efficacy was evaluated by cytokine assay. Sixteen cytokines were studied in the serum from the animal experimental models and 29 patients with RA. The triple combination therapy reduced serum level of cytokines, i.e. IL-1β, IL-2, IL-6, IL-13, TNF-α and IFN-γ in the animals and RA patients. The triple combination therapy would be identified as multi-target therapy. The combined drugs SASP, Bc and MTX must be identified as multi-target anti-rheumatic drugs (MTARDs).

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    We examined the clinical effect of etanercept on rheumatoid arthritis and factors affecting treatment outcomes. This study included 40patients with active rheumatoid arthritis who had received treatment with etanercept for one year or more. The mean age of the patients was58.8 years, and the mean disease duration was 9.7 years. The rates of concomitant MTX and steroid use were 80% and 62.5%, respectively. The mean duration of etanercept treatment was 3.6 years. The retention rate was87.0% according to Kaplan-Meier analysis. At the time of the final follow-up, we observed high disease activity in 12.5%, moderate disease activity in 35.0%, low disease activity in 17.5%, and remission in 35.0% of the patients. DAS28, mHAQ-DI, CRP, and MMP-3 were significantly improved. The average dose and usage rate of oral steroids at the time of etanercept initiation were significantly lower in the group who achieved remission or low disease activity than in the group who did not. After six months, there was a significant difference in DAS28, EULAR response criteria, and MMP-3 between the two groups. Etanercept is a biological preparation, which has a high retention rate because there is little secondary loss of efficacy and few adverse events. However, it is less effective in patients receiving oral steroid treatment. Therefore, in the event of changing to another agent, it is recommended to wait for at least 6 months after administration and MMP-3 and DAS28 values should be taken into consideration.

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Objective: There are no reports concerning the usefulness of etanercept (ETN) used at doses of less than 25-mg weekly. Our hospital uses ETN at various doses, from 25-mg biweekly to 50-mg weekly, and the efficacy of ETN by dose and upon increasing from small doses was examined retrospectively.
Methods: Analysis 1: The efficacy was examined in 3 groups (25-mg biweekly, 25-mg weekly, and 50-mg weekly dosing groups) of 40 patients with rheumatoid arthritis who were started on treatment with ETN on or after February 2010. Doses were determined by author, considering about patientʼs characteristics. Analysis 2: The efficacy of dose increase was examined in 6 patients started on the drug at the dose of 25-mg biweekly before February 2010, in whom the dose was increased because of insufficient effects.
Results: Analysis 1: The age tended to be high (p＝0.006), duration of the disease long, and combined use of tacrolimus common in the 25-mg biweekly group. The changes in the DAS28-CRP values following ETN administration were: 25-mg biweekly group (pre-dose 3.76→24 weeks post-dose 2.61), 25-mg weekly group (pre-dose 4.02→24 weeks post-dose 2.28), and 50-mg weekly group (pre-dose 3.80→24 weeks post-dose 2.49), showing no difference in the drug efficacy among the groups. Analysis 2: The DAS28-CRP of 4 .28 prior to dose increase improved to 3.16 at 52 weeks following the dose increase.
Conclusion: Although it has to be noted that the effectiveness between 3 groups is not able to be evaluated precisely because the decision of ETN doses was biased strongly, in elderly patients who have been suffering rheumatoid arthritis for a long time, ETN combined with DMARD could induce low disease activity even at the dose of 25-mg biweekly, and if the effects are insufficient, increase of the dose is useful.

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Objectives: The aim of this study is to investigate clinical outcomes of patients with RA after switching from infliximab (IFX) to tocilizumab (TCZ) compared with etanercept (ETN).
Methods:We followed RA patients switching from IFX as the first line biologics to TCZ (TCZ group)or ETN (ETN group)as the second line biologics until 12 months. Twenty-one patients were in the TCZ group and 47 patients in the ETN group. CDAI, SDAI and 28-joint disease activity score using CRP (DAS28) were evaluated at base line, 3, 6, 9 and 12 months after TCZ or ETN treatment was started.
Results: The treatment terminations of IFX in the TCZ group and the ETN group were 10 (48%) and 16 (34%) for inefficacy, 5 (24%) and 11 (23%) for relapse, 4 (19%) and 12 (26%) for toxicity respectively. In the data of the base line, CRP was significantly lower in the TCZ group than the ETN group. In the TCZ group and the ETN group, the patients remaining were 16 (76%)and 40 (85%), the treatment terminations for inefficacy were 4 (19%)and 4 (9%), the treatment terminations for toxicity was 1 (5%) and 2 (4%) at 12 months respectively.
With regard to CDAI, SDAI, DAS28, any points were significantly lower than base line. There is no difference between TCZ group and ETN group except SDAI and DAS28 at 6 months.Conclusions: In RA patients refractory to IFX,TCZ and ETN provide significant improvement and have similar effects.

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Background: Biologics have dramatically changed the treatment of rheumatoid arthritis (RA). In recent years, several biologics have become available, and about half of these drugs are delivered by subcutaneous (s.c.) injections. However, the pain caused by s.c. injection may become a problem in some cases.
Methods: The visual analogue scale (VAS) scale was used to assess the impact of the s.c. injection-related pain. Each patient gave assessments for a maximum of 4 types of s.c. injections. Etanercept (ETN), adalimumab (ADA), and golimumab (GOL) were the selectable drugs that the patients received at present and / or in the past, and s.c. of influenza vaccination (Flu-V) was used as a control.
Results: A total of 123 RA patients (mean age, 59 years;range, 30-84 years) participated in this study. There were 104 women (84.6%). The numbers of patients who provided VAS scores for IV, ETN, ADA, and GOL injections were 123, 70, 60, and 17, respectively. The VAS scores (median, IQR) were as follows: Flu-V, 26, 15-46; ETN, 41, 22.5-57; ADA, 59, 30-82.7; and GOL, 35, 27-41. The VAS score of GOL was about the same as that of Flu-V, and s.c. injections of GOL seemed to be the least painful(GOL vs. ADA, p=0.0052 and ETN vs. ADA, p=0.0060). Conclusion: Patient-orientated evaluations of pain caused by s.c. injections showed that injec tions of GOL caused less pain than those of the other biologics. Although evaluations of injection-associated pain differ with each patient, more comfortable s.c. injections are necessary to improve patient convenience and increase compliance with RA treatment.

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［Objective］ To compare pain levels at subcutaneous injection of three biological drugs, golimumab (GLM), adalimumab (ADA), and etanercept (ETN), with that at influenza vaccin (Flu) inoculation employing numeric scoring.
［Subjects and Methods］ There were 6,5,and 17 patients in the GLM, ADA, and ETN groups, respectively. Each patient received Flu inoculation and also a biological drug injection on the same day at our departmentʼs outpatient service, and was subsequently questioned about the level of drug injection pain relative to that of Flu injection. The biological drug injection pain level was assessed as “pain during drug injection” and “pain at needle insertion” separately and rated by numeric scoring, e.g., a 2-fold or more severe pain level was expressed as 2.0 and a 20% or more severe pain level as 1.2.
［Results and Discussion ］The mean pain levels during drug injection were 6.10, 2.21, and 1.30 for the ADA, ETN, and GLM groups, respectively. Hence, pain was significantly greater in the ADA than in the other two groups. The mean pain level at needle insertion was 1.00 for the ADA and GLM groups and 1.04 for the ETN group, showing no significant differences among these three drugs. The sodium citrate buffer in the ADA injectable solution and the dosage volume of 0.8mL being greater than that of the other two biological drugs (0.5mL) might account for the greater pain level with ADA during drug injection.

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Objective: The London Fibromyalgia Epidemiology Study Screening Questionnaire (LFESSQ) is a 6-item fibromyalgia screening questionnaire originally developed in English by White KP et al. for use in general population surveys. For practical use of this simple questionnaire in Japan, the objective of the study was to develop a Japanese version of the LFESSQ.
Methods: The LFESSQ was translated into Japanese after permission for translation was granted. Subsequently, linguistic validation of the translated version was performed. The development was implemented according to the general cross-cultural adaption process: ⑴ forward-translation (English to Japanese), followed by ⑵ back-translation (Japanese to English) for conceptual equivalence, and ⑶ cognitive debriefing among target respondents for their comprehension of the questions and response scales.
Results: After two translators, native speakers of Japanese, independently conducted the forward-translation, a reconciled version of single forward-translation was produced by the translators. Next, another independent translator, a native English speaker, conducted backtranslation. The back-translation was then reviewed by the original developer of the LFESSQ. Finally, six Japanese (4 females,2 males, average age of 50.0 years old) participants responded to the preliminary translated questionnaire and were interviewed afterwards (cognitive debrief ing). The interview results indicated that the participants, overall, experienced no difficulties understanding the wording, and interpreted each question itemʼs meaning correctly.
Conclusion: A linguistically-validated Japanese version of the LFESSQ was developed via a standardized translation and adaptation process.

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