Digital reconstructed radiography with multiple color image overlay for image-guided radiotherapy.

Registration of patient anatomical structures to the reference position is a basic part of the patient set-up procedure. Registration of anatomical structures between the site of beam entrance on the patient surface and the distal target position is particularly important. Here, to improve patient positional accuracy during set-up for particle beam treatment, we propose a new visualization methodology using digitally reconstructed radiographs (DRRs), overlaid DRRs, and evaluation of overlaid DRR images in clinical cases. The overlaid method overlays two DRR images in different colors by dividing the CT image into two CT sections at the distal edge of the target along the treatment beam direction. Since our hospital uses fixed beam ports, the treatment beam angles for this study were set at 0 and 90 degrees. The DRR calculation direction was from the X-ray tube to the imaging device, and set to 180/270 degrees and 135/225 degrees, based on the installation of our X-ray imaging system. Original and overlaid DRRs were calculated using CT data for two patients, one with a parotid gland tumor and the other with prostate cancer. The original and overlaid DRR images were compared. Since the overlaid DRR image was completely separated into two regions when the DRR calculation angle was the same as the treatment beam angle, the overlaid DRR visualization technique was able to provide rich information for aiding recognition of the relationship between anatomical structures and the target position. This method will also be useful in patient set-up procedures for fixed irradiation ports.

[A practical procedure to improve the accuracy of radiochromic film dosimetry: a integration with a correction method of uniformity correction and a red/blue correction method].

It has been reported that the light scattering could worsen the accuracy of dose distribution measurement using a radiochromic film. The purpose of this study was to investigate the accuracy of two different films, EDR2 and EBT2, as film dosimetry tools. The effectiveness of a correction method for the non-uniformity caused from EBT2 film and the light scattering was also evaluated. In addition the efficacy of this correction method integrated with the red/blue correction method was assessed. EDR2 and EBT2 films were read using a flatbed charge-coupled device scanner (EPSON 10000G). Dose differences on the axis perpendicular to the scanner lamp movement axis were within 1% with EDR2, but exceeded 3% (Maximum: +8%) with EBT2. The non-uniformity correction method, after a single film exposure, was applied to the readout of the films. A corrected dose distribution data was subsequently created. The correction method showed more than 10%-better pass ratios in dose difference evaluation than when the correction method was not applied. The red/blue correction method resulted in 5%-improvement compared with the standard procedure that employed red color only. The correction method with EBT2 proved to be able to rapidly correct non-uniformity, and has potential for routine clinical IMRT dose verification if the accuracy of EBT2 is required to be similar to that of EDR2. The use of red/blue correction method may improve the accuracy, but we recommend we should use the red/blue correction method carefully and understand the characteristics of EBT2 for red color only and the red/blue correction method.

Induction of pulmonary thromboembolism by neutrophil elastase in collagen-induced arthritis mice and effect of recombinant human soluble thrombomodulin.

We previously reported that during total knee arthroplasty in rheumatoid arthritis (RA) patients, the use of tourniquet might promote local release of neutrophil elastase (NE) from neutrophils, which may contribute to the development of pulmonary thromboembolism (PTE) and tissue injury. The aim of this study was to develop PTE by the use of NE in a mouse model of collagen-induced arthritis (CIA) and investigate the relationship between thrombus and endothelial cells as well as the effect of recombinant human soluble thrombomodulin (rhs-TM) in reducing the risk of PTE. Male DBA/1J mice were injected intracutaneously at several sites with an emulsion containing bovine collagen and later a booster shot to produce CIA mice. Subsequently, NE was injected intravenously 2 times a day for 3 days and after a further 4 days, mice were sacrificed. A group of mice received rhs-TM injections prior to NE injections. We divided the mice into four groups of normal, CIA control, CIA + NE, and CIA + rhs-TM + NE mice and evaluated thrombus formation status. All CIA + NE mice developed PTE. In contrast, no thrombosis was found in normal control, CIA control and CIA + rhs-TM + NE mice. Plasma thrombin level, fibrinogen expression and neutrophil count were increased in CIA + NE mice. Double staining for anticoagulant TM and procoagulant von Willebrand factor (vWF) in pulmonary endothelial cells in normal mice showed a TM-dominant expression while in both CIA control and CIA + NE mice a vWF-dominant expression compatible with coagulant status was observed. Injection of rhs-TM into CIA + NE mice resulted in a phenotypic conversion of endothelial cells from vWF-dominant to TM-dominant expression and a reduction in fibrinogen deposition. These findings demonstrate that by repeated use of NE in CIA mice, it is feasible to produce PTE and to study its pathogenesis and that rhs-TM reduces the risk of PTE. We suggest that in surgical operations of upper and lower extremities in RA patients, the use of a tourniquet should be avoided as it may trigger NE release.

Postoperative results and complications of total elbow arthroplasty in patients with rheumatoid arthritis: three types of nonconstrained arthroplasty.

Postoperative results and complications of total elbow arthroplasty (TEA) conducted for rheumatoid arthritis (RA) patients at our institute were studied. Primary TEAs were performed in 72 patients. The mean follow-up period was 3.5 years. Three types of prostheses were implanted: JACE prosthesis in 34 elbows, STABLE prosthesis in 13 elbows, and KUDO prosthesis (type 5) in 32 elbows. The outcome was evaluated by the change in the range of motion and the Japanese Orthopaedic Association functional evaluation score for the elbow joint (JOA score). The arc of motion and the JOA score at discharge and at final examination significantly improved in patients with the three types of prosthesis. The loosening rates for the JACE, STABLE and KUDO prostheses were 15, 23, and 0%, respectively, although the follow-up periods were different. The loosening rate decreased to 2.5% when the humeral component was fixed with cement. Intraoperative fractures occurred in eight (10.1%) elbows and ulnar nerve palsy in six. Deep infection developed in three (4.8%) elbows and was treated by removing the prosthesis. Although there were considerable complications, the marked improvements in pain and function favor TEA in patients with rheumatoid elbow.

Efficacy and safety of iguratimod compared with placebo and salazosulfapyridine in active rheumatoid arthritis: a controlled, multicenter, double-blind, parallel-group study.

We conducted a 28-week, randomized, double-blind, parallel-group study of iguratimod in 376 Japanese patients with active rheumatoid arthritis to compare the efficacy and safety of the drug with those of placebo and salazosulfapyridine. In the American College of Rheumatology (ACR) 20 response rate, iguratimod was superior to placebo (53.8% versus 17.2%; Fisher's exact test, P < 0.001) and was not inferior to salazosulfapyridine (63.1% versus 57.7%, 95% confidence interval for the rate difference, -7.9% to 18.7%). Iguratimod began exhibiting its therapeutic effect within 8 weeks after the initiation of treatment and was effective even in patients who had a poor response to previous treatment with disease-modifying antirheumatic drugs. No statistically significant difference was noted in the incidence of adverse reactions between iguratimod and salazosulfapyridine. The study results suggest that iguratimod could become a new option for the treatment of rheumatoid arthritis.

Long-term safety study of iguratimod in patients with rheumatoid arthritis.

We conducted a 52-week clinical study of iguratimod in 394 Japanese patients with rheumatoid arthritis to evaluate the long-term safety of the drug. Iguratimod was administered orally at a daily dose of 25 mg for the first 4 weeks and 50 mg for the subsequent 48 weeks. Some of the patients continued the treatment for 100 weeks for their benefit. The cumulative incidence of adverse events for 100 weeks was 97.6%. The cumulative incidence of adverse reactions was 65.3%; unfavorable symptoms and signs (excluding abnormal laboratory data changes) accounted for 33.2% of the reactions, and abnormal laboratory data changes accounted for 50.4%. The continued treatment rate was 66.8% at week 28 and 53.6% at week 52. For reference, the American College of Rheumatology (ACR) 20 response rate was calculated for the patients who had assessable disease activity, who did not violate the study protocol, and who continued the study treatment at weeks 28 and 52. The rate was 46.9% at week 28 and 41.0% at week 52. To use iguratimod safely for a long time, patients should be observed closely for adverse reactions such as increased hepatic enzymes.

[Examination of formula for enhanced dynamic wedge factors in symmetric and asymmetric fields].

We proposed a formula for the enhanced dynamic wedge (EDW) factor in the half-field (HF) that combined the formula proposed by Liu et al. in 1998 and their formula in 2003. When the EDW was used for irradiation to the tangent line of the HF breast, the values calculated by our formula and the measured values were consistent within 0.5%. We showed that our proposed formula was useful, easy to use, and more accurate than the conventional formula. The purpose of this study was to examine the available range of the wedge factor of symmetrical and asymmetric EDW calculated by our formula. As a result of the examination, the values calculated by our formula and the measured values were consistent within 2% except for highly asymmetric EDW. We created a spreadsheet to calculate the wedge factor easily and accurately. We will examine the reason why the calculated and measured values were greater than 2%, and improve our formula so that it can be used in a wider range.

Critical roles of capillary endothelial cells for alveolar remodeling in nonspecific and usual interstitial pneumonias.

To characterize the relationship between angiogenesis factors and alveolar remodeling in interstitial lung diseases, we examined alveolar capillary endothelial cells in the normal lung (n=5) and in lungs with nonspecific interstitial pneumonia (NSIP) (n=4) or usual interstitial pneumonia (UIP) (n=6) using immunofluorescence staining for thrombmodulin and von Willebrand factor (vWF). With three-dimensional images of alveolar capillaries, the diameter of capillary tubes and their branching frequency per unit length were determined to define rearrangement of the capillary meshwork. Alveolar capillary endothelial cells in normal lungs expressed surface thrombomodulin, and those in lungs with cellular NSIP often showed coexpression of surface thrombmodulin and cytoplasmic vWF. In the alveolar septa of fibrotic NSIP and UIP, capillary endothelial cells demonstrated vWF in only the cytoplasm. Capillary branching frequencies in NSIP and UIP were decreased to 45% and 22%, respectively, of the normal level (p<0.002). Compared with normal lungs, in NSIP and UIP lungs alveolar capillaries containing TUNEL-positive endothelial cells (p<0.05) showed increases of 3.6-fold and 4.3-fold, respectively, indicating a close correlation between endothelial cell apoptosis and remodeling of alveolar capillary frameworks. The analysis of mRNA expression of vascular endothelial growth factors (VEGF) and their receptors (VEGFR1 and VEGFR2) showed a significant decrease in each VEGF isoform and in VEGFR2 mRNA in representative alveolar wall tissues microdissected from the normal, NSIP, and UIP lungs. These results suggest that decreased expression of VEGF mRNA is associated with a reduction in the number of capillary tubes via endothelial cell apoptosis that possibly results in alveolar remodeling in NSIP and UIP. However, whether VEGF is related to fibroblastic activation in the interstitial matrix remains unclear.

Modeling and cost-effectiveness analysis of etanercept in adults with rheumatoid arthritis in Japan: a preliminary analysis.

The tumor necrosis factor (TNF) antagonist etanercept is an antirheumatic agent which was approved by Japanese regulatory authorities in January 2005. In Japan, the cost-effectiveness of this therapy for patients with rheumatoid arthritis (RA) has not previously been evaluated. This study models the cost-utility of etanercept in comparison with standard therapy with disease-modifying antirheumatic drugs (DMARDs) among adult Japanese RA patients who have failed a previous course of the DMARD bucillamine. A Markov model with 6-month cycles was constructed to compare two therapeutic strategies: etanercept versus standard therapy. For each cycle, one of three options was possible: a patient could (i) remain on current therapy if American College of Rheumatology criteria for 20% clinical improvement (ACR20) were achieved, (ii) switch to another drug in the therapeutic pathway if ACR20 was not achieved or if side effects severe enough to cause treatment discontinuation occurred, or (iii) they could die. The therapeutic pathway for the etanercept strategy was etanercept, methotrexate (MTX), sulfasalazine (SSZ), combination therapy (MTX + SSZ) and, finally, no DMARD. The pathway for standard therapy was identical except the initial therapy was MTX (etanercept was excluded). Results from clinical trials in U.S. and European patient populations were used to derive model probabilities for disease progression, response to drug therapy, and relationships between ACR20 response and functional improvement as measured by the Health Assessment Questionnaire (HAQ) disability index. An equation was developed to predict utility from HAQ scores of Japanese patients. Costs for drugs and medical services in Japan were obtained for April 2003. Analysis was conducted from a societal perspective, including lost productivity costs due to RA disability and premature mortality. Costs were discounted at 6% annually, and quality-adjusted life years (QALYs) at 1.5% annually. Model parameters were varied by 20% above and below base-case values in sensitivity analyses. Compared to standard therapy, the etanercept strategy was yen6.39 million more costly per patient but yielded an additional 2.56 QALYs. The incremental cost-utility ratio was yen 2.50 million/QALY. Sensitivity analyses revealed that cost-utility was most strongly influenced by the acquisition cost of etanercept and the percentage of etanercept recipients who achieved ACR20. Using commonly applied thresholds for acceptable cost-effectiveness in the United States ($50 000 = yen 5.5 million/QALY) and the United Kingdom (pound 30 000 = yen 5.7 million/QALY), etanercept therapy in Japan can be considered cost-effective. Cost-utility ratios did not exceed these thresholds in any sensitivity analysis. Further analyses should be conducted once clinical and epidemiologic data for Japanese patients become available.

Inhibitory effect of bone resorption and inflammation with etidronate therapy in patients with rheumatoid arthritis for 3 years and in vitro assay in arthritis models.

This study was conducted to identify bone resorption and anti-inflammatory effects with intermittent cyclical etidronate therapy (ICET) in patients with rheumatoid arthritis, and anti-inflammatory effect of etidronate in vitro. We compared bone mineral density (BMD), urinary deoxypyridinoline (DPD) level, bone alkaline phosphatase (BAP) level and Larsen damage scores between the ICET and the non-ICET groups for 3 years. The levels of interleukin-6 (IL-6), prostaglandin E2 (PGE2), substance P and vascular endothelial growth factor (VEGF) in synovial cells from arthritis models were measured following the addition of etidronate. In the ICET group, BMD and BAP levels increased. Urinary DPD level and the Larsen damage score were significantly lower than that in the non-ICET group. In the in vitro study, the production of IL-6, PGE2, substance P and VEGF were inhibited in a dose-dependent manner. Bone resorption and destruction inhibition effect of etidronate remained for 3 years. In vitro study showed that the production of inflammatory cytokines and an angiogenesis factor were inhibited.

Correlation between dry eye and rheumatoid arthritis activity.

PURPOSE: To evaluate the incidence of dry eye in rheumatoid arthritis (RA) patients with or without Sjögren syndrome (SS), and to investigate the correlation between dry eye and RA activity. DESIGN: Prospective case-control study. METHODS: In 72 RA patients, the severity of dry eye was assessed by the Schirmer test, tear break-up time, rose bengal staining, and fluorescein staining. The RA activity was evaluated by the Lansbury index (LI), which is based on the duration of morning stiffness, erythrocyte sedimentation rate (ESR), grip strength, and joint score. RESULTS: Ten percent of patients met the Japanese criteria for SS. No difference in dry eye tests or LI was observed between SS patients and non-SS patients. Even in the non-SS group, 90% of patients were diagnosed with probable dry eye. In SS patients, positive correlations were observed between LI and Schirmer test (P = .048), ESR and Schirmer test (P = .035), ESR and rose bengal staining (P = .001), and grip strength and rose bengal staining (P = .047). No such correlations were observed in the non-SS patients. CONCLUSIONS: Dry eye is common in RA patients, including those without SS. We found that there was a correlation between LI and Schirmer test in RA patients with SS, but no correlation when the entire group was analyzed. Dry eye always should be taken into consideration regardless of the RA activity, because the severity of dry eye is independent of RA activity.

Inhibitory effect of mizoribine on matrix metalloproteinase-1 production in synovial fibroblasts and THP-1 macrophages.

To investigate the mechanism of antirheumatic action of mizoribine (MZR), we examined the expression of matrix metalloproteinase-1 (MMP-1) and MMP-3 utilizing THP-1 derived macrophage-like cells (THP-1 macrophages) and human synovial fibroblasts (SFs). The cells were respectively stimulated with lipopolysaccharide (LPS) and interleukin-1beta in the presence or absence of MZR in vitro. The concentrations of MMP-1 and MMP-3 in the supernatant were measured by enzyme-linked immunosorbent assay. The secretion of MMP-1 from SFs, as well as THP-1 macrophages, was inhibited by MZR in a dose-dependent manner. Furthermore, a quantitative real-time polymerase chain reaction revealed that MZR decreased the expression of MMP-1 messenger RNA. These findings may be an explanation for the clinical effect of MZR in patients with rheumatoid arthritis.

Follow-up study of ankle arthrodesis in severe hind foot deformity in patients with rheumatoid arthritis using an intramedullary nail with fins.

We report herein a retrospective study of 25 cases of ankle arthrodesis performed in 23 patients with rheumatoid arthritis (RA) using an intramedullary nail with fins, developed in 1994. Surgical treatment, postoperative management, and clinical evaluation are described. Clinical evaluation, at an average follow-up period of 7 years 1 month, was based on foot disease scores from the Japanese Orthopedic Association; we compared these scores pre- and postoperatively, and during follow-up. These parameters showed a significant difference between preoperation and the follow-up period. However, instability only significantly improved when compared between pre- and postoperation. Arthrodesis using an intramedullary nail with fins was effective for the treatment of severe deformity of the hind foot. Nonunion was not observed and no remarkable changes of the Chopart joint were recognized between preoperation and the follow-up period. In our series, delayed wound healing was recognized in 6 of 25 joints. However, infection or neuropathy and other complications were not found. Arthrodesis using an intramedullary nail with fins is a viable treatment option for severe deformity of the hind foot in RA patients, because nonunion was not recognized and the clinical results over an average 7-year follow-up period were good or satisfactory.

Human immunodeficiency virus vector-mediated intra-articular expression of angiostatin inhibits progression of collagen-induced arthritis in mice.

We examined the feasibility of the human immunodeficiency virus (HIV) vector-mediated local expression of angiostatin in the treatment of murine collagen-induced arthritis in a mouse model generated by immunization with bovine type II collagen and Freund's complete adjuvant. The HIV vector containing the murine angiostatin expression unit (HIV-angiostatin) was injected into right knee joints after arthritis development; the HIV vector containing the enhanced green fluorescein protein (EGFP) marker gene (HIV-EGFP) was injected into the left joints. Quantitative histological evaluation demonstrated that synovial cell hyperplasia and pannus formation were significantly reduced in the right knee joints as determined by this protocol. Suppression of radiographical changes in the ipsilateral paws was also observed. These results indicate that the HIV vector-mediated expression of angiostatin efficiently inhibits the progression of collagen-induced arthritis. Angiostatic gene therapy may provide a new approach to the effective treatment of rheumatoid arthritis.

Granulocyte adsorptive apheresis for leg ulcers complicated by rheumatoid arthritis: a report on three successfully treated cases.

BACKGROUND: The treatment of inflammatory leg ulcers complicated by rheumatoid arthritis (RA), which are unresponsive to conventional care, can be frustrating. Furthermore, as granulocytes and monocytes (GM) are major sources of inflammatory cytokines, they have the potential to initiate and perpetuate inflammatory skin lesions. Accordingly, a recent study reported the remission of pyoderma gangrenosum following the reduction of activated peripheral blood GM by adsorptive apheresis (GMA). METHODS: In this clinical study, we applied GMA to three cases, each with one leg ulcer below the knee and RA. The ulcers had not responded to conventional therapy, including disinfection, dressing, and antimicrobials, and therefore were thought to represent inflammatory vasculitic lesions. GMA was performed using a column with a capacity of 335 mL, filled with cellulose acetate beads that selectively adsorb granulocytes and monocytes/macrophages (Adacolumn). Each patient received one GMA session/week for five consecutive weeks. The duration of one session was 60 min, with a flow rate of 30 mL/min. RESULTS: The ulcers began to recede after two GMA sessions and, by the end of the fifth session, the ulcers in all three patients had healed. No recurrence has been observed up to the time of this report. The treatment was well tolerated and no severe side-effects were observed. CONCLUSIONS: GMA, which depletes activated neutrophils and monocytes/macrophages, appears to be effective for inflammatory skin ulcers which do not respond to conventional medications.

Total ankle arthroplasty for deformity of the foot in patients with rheumatoid arthritis using the TNK ankle system: clinical results of 21 cases.

We report the results of total ankle arthroplasty (TAA) of 21 ankle joints performed on 19 patients with rheumatoid arthritis (RA) using the Japanese TNK ankle system. The clinical evaluation for an average follow-up period of 33.8 months was based on the ankle analysis system. The total score, pain score, range of motion, and walking ability significantly improved postoperatively compared with the preoperative period. These parameters also showed significantly different values between the preoperative and the follow-up periods. However, the range of motion significantly improved postoperatively. In the evaluation of TAA using the TNK ankle system, a radiolucent line of about 1 mm was detected, but there was no dislocation or sinking of the tibial and talar prostheses. There were no severe complications except for two cases with a delayed wound healing and one with a deep infection. These results suggest that if the talocrural joint only was destroyed and the neighboring joints (subtalar or talonavicular) had fibrous fusion, or the patient had relatively fewer activities in daily life or was an elderly person, TAA using the TNK ankle system was effective for the treatment of painful and disabling ankle joints in patients with RA in the middle of the follow-up period.

An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis.

Rheumatoid arthritis is a common inflammatory disease with complex genetic components. We investigated the genetic contribution of the cytokine gene cluster in chromosome 5q31 to susceptibility to rheumatoid arthritis in the Japanese population by case-control linkage disequilibrium (LD) mapping using single nucleotide polymorphisms (SNPs). Here we report that there is significant association between rheumatoid arthritis and the organic cation transporter gene SLC22A4 (P = 0.000034). We show that expression of SLC22A4 is specific to hematological and immunological tissues and that SLC22A4 is also highly expressed in the inflammatory joints of mice with collagen-induced arthritis. A SNP affects the transcriptional efficiency of SLC22A4 in vitro, owing to an allelic difference in affinity to Runt-related transcription factor 1 (RUNX1), a transcriptional regulator in the hematopoietic system. A SNP in RUNX1 is also strongly associated with rheumatoid arthritis (P = 0.00035). Our data indicate that the regulation of SLC22A4 expression by RUNX1 is associated with susceptibility to rheumatoid arthritis, which may represent an example of an epistatic effect of two genes on this disorder.

Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis.

Individuals with rheumatoid arthritis frequently have autoantibodies to citrullinated peptides, suggesting the involvement of the peptidylarginine deiminases citrullinating enzymes (encoded by PADI genes) in rheumatoid arthritis. Previous linkage studies have shown that a susceptibility locus for rheumatoid arthritis includes four PADI genes but did not establish which PADI gene confers susceptibility to rheumatoid arthritis. We used a case-control linkage disequilibrium study to show that PADI type 4 is a susceptibility locus for rheumatoid arthritis (P = 0.000008). PADI4 was expressed in hematological and rheumatoid arthritis synovial tissues. We also identified a haplotype of PADI4 associated with susceptibility to rheumatoid arthritis that affected stability of transcripts and was associated with levels of antibody to citrullinated peptide in sera from individuals with rheumatoid arthritis. Our results imply that the PADI4 haplotype associated with susceptibility to rheumatoid arthritis increases production of citrullinated peptides acting as autoantigens, resulting in heightened risk of developing the disease.

Bone resorption and inflammatory inhibition efficacy of intermittent cyclical etidronate therapy in rheumatoid arthritis.

OBJECTIVE: Osteoclast activation or cartilage and bone destruction are developed in patients with rheumatoid arthritis (RA). The efficacy of etidronate with respect to osteoporosis, inhibition of bone resorption and destruction, and antiinflammation in RA was examined for 72 weeks. METHODS: Sixty-three patients with RA (56 women, 7 men) were divided into a group that received intermittent cyclical etidronate therapy (ICET) (31 patients) and a non-ICET group (32 patients). Over a 72 week followup period, the urinary deoxypyridinoline (DPD), serum bone alkaline phosphatase (BAP), bone mineral density (BMD), Larsen damage score, Lansbury activity index, and concentrations of serum C-reactive protein (CRP) and serum interleukin 6 (IL-6) of the 2 groups were compared. RESULTS: In the non-ICET group, a significant decrease in BMD and a significant increase in the Larsen damage score were observed. In the ICET group, the level of DPD started to decrease 12 weeks after etidronate administration and progression of the Larsen damage score was significantly inhibited. IL-6 concentration was significantly decreased 72 weeks after etidronate administration. Concentrations of BAP and CRP and the Lansbury activity index were not significantly different between the ICET and the non-ICET groups. A significant correlation between the IL-6 and DPD concentrations was observed. CONCLUSION: Etidronate was effective at inhibiting bone resorption and destruction in study patients with RA, while not increasing BAP concentrations; and a correlation was observed between the concentration of DPD and IL-6, indicating the antiinflammatory effect of etidronate.