1 Bisphosphonates (BPs) are inhibitors of bone resorption, and many derivatives have been developed for the treatment of enhanced bone resorption. Aminobisphosphonates (aminoBPs) are particularly potent in this respect. We have shown previously that aminoBPs, such as 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (AHBuBP), induce histidine decarboxylase, the enzyme forming histamine, and increase macrophages, granulocytes and osteoclast numbers. Non-aminoBPs do not show this activity. 2 In the present study, an additional aminoBP, cycloheptyl-aminomethylene bisphosphonate (CHAMBP), was shown to have similar properties to AHBuBP suggesting that these actions are common among aminoBPs. 3 In experiments carried out to determine if aminoBPs affect immune responses, we found that CHAMBP and AHBuBP each exacerbated the arthritis induced in mice by the co-injection of type II collagen and an adjuvant, a model for rheumatoid arthritis. In contrast, dichloromethylene bisphosphonate (C12MBP), a typical non-aminoBP, did suppress the arthritis. 4 On the basis of these results, and those obtained previously, we propose that the exacerbating effects of CHAMBP and AHBuBP may be related to their ability to stimulate the synthesis of histamine and to increase macrophages and granulocytes. Conversely, we propose that the suppressive effect of C12MBP on arthritis is related to its cytotoxic action on macrophages or granulocytes.

for the Michinoku Tocilizumab Study Group (2016) Clinical and structural remission rates increased annually and radiographic progression was continuously inhibited during a 3-year administration of tocilizumab in patients with rheumatoid arthritis: A multi-center, prospective cohort study by the Michinoku Tocilizumab Study Group, Modern Rheumatology, 26:6, 828-835, DOI: 10.3109/14397595.2016.1160991 To link to this article: https://doi.org/10. 3109/14397595.2016 Abstract Objective: To evaluate the clinical and structural efficacy of tocilizumab (TCZ) during its longterm administration in patients with rheumatoid arthritis (RA). Methods: In total, 693 patients with RA who started TCZ therapy were followed for 3 years. Clinical efficacy was evaluated by DAS28-ESR and Boolean remission rates in 544 patients. Joint damage was assessed by calculating the modified total Sharp score (mTSS) in 50 patients. Results: When the reason for discontinuation was limited to inadequate response or adverse events, the 1-, 2-, and 3-year continuation rates were 84.0%, 76.8%, and 72.2%, respectively. The mean DAS28-ESR was initially 5.1 and decreased to 2.5 at 6 months and to 2.2 at 36 months. The Boolean remission rate was initially 0.9% and increased to 21.7% at 6 months and to 32.2% at 36 months. The structural remission rates (DmTSS/year 0.5) were 68.8%, 78.6%, and 88.9% within the first, second, and third years, respectively. The structural remission rate at 3 years (DmTSS 1.5) was 66.0%, and earlier achievement of swollen joint count (SJC) of 1 or less resulted in better outcomes. Conclusions: TCZ was highly efficacious, and bone destruction was strongly prevented. SJC was an easy-to-use indicator of joint destruction.

To clarify the base of in vivo biological activities of peptidoglycans of Gram-positive bacteria, the effects of a polysaccharide peptide of Staphylococcus epidermidis peptidoglycan (SEPS) on the synthesis of histamine and putrescine in BALB/c mice were examined and compared with those of a lipopolysaccharide (LPS or endotoxin) of Gram-negative bacteria. Within a few hours after its injection into BALB/c mice, SEPS induced histidine decarboxylase (HDC), the enzyme forming histamine, in the liver, lung, spleen and bone marrow, and ornithine decarboxylase (ODC), the enzyme forming putrescine, in the tissues except for the lung. SEPS induced HDC activity even in mast cell-deficient mice and in nude mice. These effects of SEPS were essentially the same as those of LPS. However, the dosage of SEPS capable of inducing HDC and ODC was much higher (100 to 1,000 times) than that of LPS. We have reported that C3H/HeN mice are resistant to SEPS in producing acute arthritis, and their productions of IL-1 and prostaglandin E2 are less than BALB/c mice sensitive to producing acute arthritis. In the present study, it was also found that C3H/HeN mice were markedly resistant to SEPS in inducing HDC activity.

Objectives:To determine the necessity of methotrexate (MTX) in patients with rheumatoid arthritis (RA) achieving clinical remission treated by tocilizumab (TCZ) and MTX (TCZ+MTX). Methods:A 3 year, multicenter, observational cohort study was performed. RA patients were treated by TCZ with or without MTX depending on the attending doctor's decision. Of the patients treated with TCZ+MTX, the patients who discontinued MTX after achieving clinical remission (discontinued group: DISC) were compared with those who maintained the same dose of MTX after achieving clinical remission (maintained group: MAIN). Results:The DISC and MAIN consisted of 33 patients and 37 patients, respectively. The mean DAS28-ESR was significantly lower in the DISC than in the MAIN at 3 months, 6 months and 9 months (3 months: 1.8 ± 0.8 and 2.4 ± 1.0, p=0.018, 6 months: 1.5 ± 0.7 and 2.2 ± 1.0, p=0.009 and 9 months: 1.4 ± 0.6 and 2.0 ± 1.0, p=0.008, respectively).The DAS28-ESR remission rate and Boolean remission rate were significantly higher in the DISC than in the MAIN (93.8% and 64.5%, respectively in the DAS28-RSR, p=0.04; 51.6% and 17.2%, respectively in the Boolean, p=0.005) at 6 months. Conclusions:RA patients treated by the combination of TCZ and MTX who achieved deep remission (DAS28-ESR ≤ 1.98) at as early as 3 months could discontinue taking MTX.

Objectives : Methotrexate (MTX) is associated with extensive side effects, including myelosuppression, interstitial pneumonia, and infection. It is, therefore, critical to establish whether its administration is required after achieving remission with tocilizumab (TCZ) and MTX combination therapy in patients with rheumatoid arthritis (RA). Therefore, the aim of this multicenter, observational, cohort study was to evaluate the feasibility of MTX discontinuation for the safety of these patients. Methods : Patients with RA were administered TCZ, with or without MTX, for 3 years ; those who received TCZ+MTX combination therapy were selected. After remission was achieved, MTX was discontinued without flare development in one group (discontinued [DISC] group, n = 33) and continued without flare development in another group (maintain [MAIN] group, n = 37). The clinical efficacy of TCZ+MTX therapy, patient background characteristics, and adverse events were compared between groups. Results : The disease activity score in 28 jointserythrocyte sedimentation rate (DAS28 -ESR) at 3, 6, and 9 months was significantly lower in the DISC group (P < .05, P < .01, and P < .01, respectively). Further, the DAS28 -ESR remission rate at 6 and 9 months and Boolean remission rate at 6 months were significantly higher in the DISC group (P < .01 for all). Disease duration was significantly longer in the DISC group (P < .05). Furthermore, the number of patients with stage 4 RA was significantly higher in the DISC group (P < .01). Conclusions : Once remission was achieved, MTX was discontinued in patients who responded favorably to TCZ+MTX therapy, despite the prolonged disease duration and stage progression.