Influences of advanced age in rheumatoid arthritis: A multicentre ultrasonography cohort study.

OBJECTIVES: We aimed to evaluate the effects of age on clinical characteristics and outcomes in biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD)-naïve patients with rheumatoid arthritis (RA). METHODS: We analysed the cases of 234 Japanese b/tsDMARD-naïve RA patients who underwent b/tsDMARD treatment in a multicentre ultrasound prospective observational cohort. We compared the clinical characteristics at baseline and outcomes at 12 months between those aged ≥60 years and those <60 years. RESULTS: Compared to the <60-year-old group (n = 78), the ≥60-year-old group (n = 156) had higher inflammatory marker values and ultrasound combined scores, especially wrist joints, at baseline. Age at baseline positively correlated significantly with the ultrasound scores at baseline; however, age was not a significant variable by the multiple regression analysis. The patients treated with different MOAs in the ≥60-year-old group had comparable outcomes and multiple regression analysis revealed that mechanism of action (MOA) was not a significant contributor to the Clinical Disease Activity Index at 12 months. CONCLUSIONS: RA patients with advanced age demonstrated distinctive clinical characteristics. The MOAs were not associated with clinical outcomes and ultrasound outcomes in RA patients with advanced age.

The impact of glucocorticoid use on the outcomes of rheumatoid arthritis in a multicenter ultrasound cohort study.

OBJECTIVE: Glucocorticoids are effective in treating rheumatoid arthritis (RA) when used appropriately considering the balance of the risks and benefits, especially at low doses. We aimed to evaluate the response of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients having already been treated with glucocorticoids. METHODS: We reviewed RA patients treated with b/tsDMARDs in a prospective multicenter ultrasound cohort study. We compared the differences in the clinical characteristics at baseline and outcomes at 12 months between the two groups having been treated with and without glucocorticoids at baseline. The differences in the clinical characteristics and the treatments were balanced by the inverse probability weighting (IPW) with the propensity score. RESULTS: Of 307 patients with RA, 160 patients were treated with glucocorticoids at baseline. The median dose of glucocorticoids was equivalent to 5.0 mg/day of prednisolone. Significant differences were in age and concomitant methotrexate use, composite measures for the disease activity, and the ultrasound grayscale score at baseline. Patients treated with glucocorticoids had less frequent remissions defined by composite measures and ultrasound findings than those treated without glucocorticoids. These significant differences in the achievement of remissions remained robust even after adjusting differences in the clinical characteristics and the treatments between the two groups by IPW. CONCLUSION: RA patients treated with glucocorticoids had a higher disease activity at baseline and a poorer response to treatments with b/tsDMARDs than those without glucocorticoids. The states of patients requiring glucocorticoids might be associated with the poor response to the b/tsDMARDs.

Efficacy of Diagnosing Carpal Tunnel Syndrome Using the Median Nerve Stenosis Rate Measured on Ultrasonographic Sagittal Imagery: Clinical Case-Control Study.

BACKGROUND: The purpose of the present study was to evaluate the usefulness of the median nerve stenosis rate (MNSR) measured on sagittal sonographic images of the median nerve in the diagnosis of carpal tunnel syndrome (CTS). METHODS: The study population consisted of 45 hands from 37 patients with idiopathic CTS (CTS group), and 60 hands from 35 asymptomatic healthy subjects (control group). Carpal tunnel syndrome was diagnosed by clinical findings and positive electrophysiological study results. All patients and control subjects underwent ultrasonographic examination. At the carpal tunnel level, the transducer was placed longitudinally to the median nerve, and an image of the longitudinal median nerve was obtained. The minimum median nerve diameter (MND) was measured at the middle part of the capitate level, while the maximum MND was measured at the distal radioulnar joint level. The MNSR was calculated as (1 - minimum MND/maximum MND) × 100 (%). The cross-sectional area of the median nerve was also measured at the level of the pisiform. RESULTS: On longitudinal sonographic images, the MNSR was significantly larger in the CTS group than the control group. When the cut-off value of the MNSR was 26.73%, the sensitivity and specificity were 91.1% and 80%, respectively. The area under the receiver operating characteristic curve was larger for the MNSR than for the cross-sectional area. CONCLUSION: The results suggest that the MNSR proposed in the present study may be useful as an auxiliary method for CTS diagnosis on ultrasonographic examination.

Contamination of sea surface water offshore the Tokai region and Tokyo Bay in Japan by small microplastics.

A nested double neuston net was prepared and used to collect samples from the surface of coastal waters around Japan to obtain information about the properties of both small microplastics (SMPs; <350 µm) and large microplastics (LMPs; >350 µm). The SMP concentrations ranged from 1000 to 5900 pieces m-3 in the open ocean and averaged approximately 3000 pieces m-3 in the inner part of Tokyo Bay. The SMP concentrations were around 20-60 times greater than the LMP concentrations. By analyzing the seawater, we obtained a microplastic size distribution that spanned 50-5000 µm. The LMPs mainly comprised packaging-related plastics, such as polyethylene (PE) and polypropylene, while the SMPs were dominated by paint-related plastics. SMPs derived from packaging materials (e.g., PE) may have gradually sank down from the sea surface when they were smaller than 600 µm.

Effect of abatacept treatment on serum osteoclast-related biomarkers in patients with rheumatoid arthritis (RA): A multicenter RA ultrasound prospective cohort in Japan.

ABSTRACT: We evaluated the effect of abatacept treatment on osteoclast-related biomarkers and explored whether the biomarkers are associated with the therapeutic response in rheumatoid arthritis (RA) patients treated with abatacept.We enrolled 44 RA patients treated with abatacept from a multicenter prospective ultrasound cohort study of patients who received biologic or targeted synthetic disease-modifying antirheumatic drug therapy. We evaluated the disease activity score (DAS) 28-CRP (C-reactive protein), musculoskeletal ultrasound scores including the total grayscale score (GS)/power Doppler (PD) score and the serum concentrations of isoform 5b of tartrate-resistant acid phosphate (TRACP-5b) and soluble receptor activator of nuclear factor-κB ligand (sRANKL) at baseline and at 3 and 6 months of treatment. "PD responder" was defined as a patient whose Δtotal PD score over 6 months was greater than the median change of that.Abatacept significantly improved DAS28-CRP as well as the total GS/PD score over 6 months. Serum TRACP-5b was significantly elevated and serum sRANKL was significantly decreased at 6 months (P < .0001 and P < .01, respectively). At 6 months, serum sRANKL was significantly decreased in the patients who achieved DAS28-CRP remission and the PD responders but not in those who did not. However, serum TRACP-5b rose regardless of the therapeutic response.Among RA patients treated with abatacept, serum sRANKL decreased in the patients with a good therapeutic response, but serum TRACP-5b elevated paradoxically regardless of the therapeutic response.

Association between serum bone biomarker levels and therapeutic response to abatacept in patients with rheumatoid arthritis (RA): a multicenter, prospective, and observational RA ultrasound cohort study in Japan.

BACKGROUND: To evaluate the effect of treatment on serum bone biomarkers and explore whether serum bone biomarkers are associated with therapeutic response in rheumatoid arthritis (RA) patients treated with abatacept. METHODS: We enrolled 59 RA patients treated with abatacept from a multicenter, exploratory, short-term, prospective and observational ultrasound cohort study of patients who received biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) therapy. We evaluated the patients' clinical disease activity and musculoskeletal ultrasound (MSUS) scores. The serum concentrations of five bone biomarkers were evaluated (dickkopf-1 [Dkk-1], sclerostin [SOST], osteocalcin [OC], osteopontin [OPN], and osteoprotegerin [OPG]) by multiplex bead assays at baseline, 3, and 6 months: the change over 6 months was defined as the Δ value. 'Power Doppler (PD) responder' was defined as a patient whose Δtotal PD score over 6 months was greater than the median change. RESULTS: Abatacept significantly improved the clinical disease activity and MSUS score over 6 months. Serum OPG was significantly elevated at 6 months after the abatacept introduction (p = 0.016). The ΔSOST and ΔOPG were significantly greater in the PD responders versus the non-PD responders (p = 0.0041 and 0.0073, respectively). The serum Dkk-1 at baseline was significantly lower in the PD responders (n = 30) vs. the non-PD responders (n = 29) (p = 0.026). A multivariate logistic regression analysis showed that the serum Dkk-1 at baseline (odds ratio 0.50, 95% confidence interval [CI] 0.23-0.91, p = 0.043) was an independent predictor of PD responder status. CONCLUSION: Serum levels of bone biomarkers may be useful for predicting RA patients' therapeutic responses to abatacept. TRIAL REGISTRATION: Name of the registry: Assessment of therapeutic responsiveness by imaging of the joints in patients with rheumatoid arthritis; A observational cohort study Trial registration number: UMIN000012524 Date of registration: 12/9/2013 URL of trial registry record: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000014657.

Utility of a simplified ultrasonography scoring system among patients with rheumatoid arthritis: A multicenter cohort study.

ABSTRACT: We aimed to evaluate the utility of a simplified ultrasonography (US) scoring system, which is desired in daily clinical practice, among patients with rheumatoid arthritis (RA) receiving biological/targeted synthetic disease-modifying antirheumatic drugs (DMARDs).A total of 289 Japanese patients with RA who were started on tumor necrosis factor inhibitors, abatacept, tocilizumab, or Janus kinase inhibitors between June 2013 and April 2019 at one of the 15 participating rheumatology centers were reviewed. We performed US assessment of articular synovia over 22 joints among bilateral wrist and finger joints, and the 22-joint (22j)-GS and 22-joint (22j)-PD scores were evaluated as an indicator of US activity using the sum of the GS and PD scores, respectively.The top 6 most affected joints included the bilateral wrist and second/third metacarpophalangeal joints. Therefore, 6-joint (6j)-GS and -PD scores were defined as the sum of the GS and PD scores from the 6 synovial sites over the aforementioned 6 joints, respectively. Although the 22j- or 6j-US scores were significantly correlated with DAS28-ESR or -CRP scores, the correlations were weak. Conversely, 6j-US scores were significantly and strongly correlated with 22j-US scores not only at baseline but also after therapy initiation.Using a multicenter cohort data, our results indicated that a simplified US scoring system could be adequately tolerated during any disease course among patients with RA receiving biological/targeted synthetic DMARDs.

Non-TNF inhibitor switchers versus TNF inhibitor cyclers from multicentre rheumatoid arthritis ultrasonography prospective cohort in Japan.

To compare therapeutic efficacy of tumour necrosis factor inhibitor (TNFi) cyclers and non-TNFi switchers in patients with rheumatoid arthritis (RA) having inadequate response to previous TNFis (TNF-IR patients) using composite measures including imaging assessment with power Doppler ultrasonography (PDUS). Patients with RA who had inadequate response to one or more previous TNFi agents with moderate or higher disease activity were enrolled. The outcomes of 56 TNF-IR patients were analysed. Patients were divided into 19 TNFi cyclers and 37 non-TNFi switchers (16 abatacept [ABT] and 21 tocilizumab [TCZ] switchers). Retention ratio at 6 months was significantly higher in non-TNFi switchers than in TNFi cyclers (p < .05). Although there was no significant difference, non-TNFi switchers tended to have a larger decrease than TNFi cyclers in efficacy indicators based on clinical disease activity index and PDUS. Multivariate logistic regression analysis identified a following independent factor associated with both EULAR good response and retention of a biologic agent: non-TNFi switch (p < .05 for both). Non-TNFi switchers were shown to have significantly higher percentage of EULAR good response and higher retention than TNFi cyclers. A non-TNFi biologic agent may hence be a preferential next-line treatment for TNF-IR patients.

Acetabular reinforcement ring with additional hook improves stability in three-dimensional finite element analyses of dysplastic hip arthroplasty.

BACKGROUND: The stability of acetabulum reconstructions using reinforcement rings and hooks is important for successful replacement surgery. The objective of this study was to biomechanically determine the effects of the hook on stress and the related micromotions of the acetabular reinforcement ring during the immediate postoperative period. METHODS: Acetabular reinforcement ring models were developed using a nonlinear, three-dimensional, finite element method. Using a pre-prepared template, we constructed without-hook and bone graft models of varying volumes and material properties. RESULTS: The stress on the inferior margin of the acetabulum was higher in the with-hook model than in the without-hook model, especially with increased bone graft volumes, and the stiffness of the bone graft material was decreased. Relative micromotions in the without-hook model were higher than in the with-hook models. The highest relative micromotion was observed in the model with increased bone graft volume and lower stiffness of bone graft material. CONCLUSIONS: In biomechanical analyses, the hook effectively dispersed stress and improved the initial fixation strength of the acetabular reinforcement ring.

Finite element analysis of the tibial bone graft in cementless total knee arthroplasty.

BACKGROUND: Achieving stability of the tibial implant is essential following cementless total knee arthroplasty with bone grafting. We investigated the effects of bone grafting on the relative micromotion of the tibial implant and stress between the tibial implant and adjacent bone in the immediate postoperative period. METHODS: Tibial implant models were developed using a nonlinear, three-dimensional, finite element method. On the basis of a preprepared template, several bone graft models of varying sizes and material properties were prepared. RESULTS: Micromotion was larger in the bone graft models than in the intact model. Maximum micromotion and excessive stress in the area adjacent to the bone graft were observed for the soft and large graft models. With hard bone grafting, increased load transfer and decreased micromotion were observed. CONCLUSIONS: Avoidance of large soft bone grafts and use of hard bone grafting effectively reduced micromotion and undue stress in the adjacent area.

Ultrasonographic Efficacy of Biologic and Targeted Synthetic Disease-Modifying Antirheumatic Drug Therapy in Rheumatoid Arthritis From a Multicenter Rheumatoid Arthritis Ultrasound Prospective Cohort in Japan.

OBJECTIVE: To explore the variables associated with initial favorable power Doppler (PD) ultrasound (US) response induced by biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients with rheumatoid arthritis (RA). METHODS: We have been prospectively investigating the course of active RA patients using US after the introduction of b/tsDMARDs in the Kyushu region of Japan since June 2013. A total of 150 patients have completed the first 6 months of observation at present and have been evaluated. US was assessed in 22 joints of bilateral hands using gray-scale and PD images on a scale from 0-3. The sum of these scores was used as the indicator of US disease activity. We defined PD remission as attaining a total PD score of 0 at 6 months and investigated the associated variables by multivariate logistic regression analysis. RESULTS: The total PD and gray-scale scores and the clinical composite measures significantly improved at 6 months, whereas these reductions were less in bDMARD switchers as compared with bDMARD-naive patients. Multivariate logistic regression analysis showed that short disease duration, the absence of any previous use of bDMARDs, and low total PD scores at baseline were independent predictors of PD remission at 6 months. CONCLUSION: This present prospective US cohort has for the first time shown the variables that are associated with initial PD response to b/tsDMARDs.

Aortic Aneurysm as a Complication of Myeloperoxidase-antineutrophil Cytoplasmic Antibody-associated Vasculitis.

Myeloperoxidase-antineutrophil cytoplasmic antibody-associated vasculitis (MPO-AAV) does not usually involve large vessels, such as the aorta. However, we experienced three cases having an aortic aneurysm as a complication of MPO-AAV with renal insufficiency. In one patient it involved the onset of descending aortic dissection during treatment for MPO-AAV; another two patients had an abdominal aortic aneurysm at the time of our diagnosis of MPO-AAV. Although we found no pathological evidence in our patients, MPO-AAV might result in large vessel inflammation. Therefore, we suggest that patients with MPO-AAV should be examined by computed tomography scan to check for the presence of an aortic aneurysm.

Experimental verification of reconstructed absorbers embedded in scattering media by optical power ratio distribution.

Experimental investigation to show the effectiveness of the extraction method of absorber information in a scattering medium by taking the output power ratio distribution is presented. In the experiment, two metallic wires sandwiched by three homogeneous scattering media are used as absorbers in transmission geometry. The output power ratio distributions can extract the influence of the absorbers to enhance the optical signal. The peak position of the output power ratio distributions agree with the results suggested by numerical simulation. From the reconstructed results of tomography in the scattering media, we have confirmed that the tomographic image of two wires can distinguish them successfully from 41×21 output power ratio distributions by using continuous-wave light.

Prevalence of chronic kidney disease and administration of RA-related drugs in patients with RA: The NinJa 2012 study in Japan.

OBJECTIVES: To estimate the prevalence of chronic kidney disease in patients with rheumatoid arthritis (RA) and the administration of disease-modifying anti-rheumatic-drugs (DMARDs), using data from the National Database of Rheumatic Disease by iR-net in Japan (NinJa) 2012 study. METHODS: From a total of 11,940 RA patients, 7135 who underwent an estimated glomerular filtration rate (eGFR) test were studied. Renal dysfunction staging was assessed using Japanese eGFR equations and classified according to the Kidney Disease Improving Global Outcomes 2012 clinical practice guideline. RESULTS: The prevalence of GFR stages was as follows: stage G1, 25.4%; stage G2, 55.9%; stage G3, 17.5%; stage G4, 0.8%; and stage G5, 0.2%. Overall, 92.7% of patients received at least one DMARD. Sulfasalazine, tacrolimus, and biologics (except inflixmab) were administered in all GFR stages. Methotrexate was not prescribed in patients with stage G5, but methotrexate 3.5 mg/week (mean) was prescribed in four patients (6.8%) with stage G4. Non-steroidal anti-inflammatory drugs and glucocorticoids were prescribed in 40.5% and 43.7% of patients, respectively. CONCLUSION: The prevalence of kidney disease in this large sample of RA patients was higher than that in the general population, and the results suggest that RA patients with renal dysfunction require careful drug selection.

[Association of blood pressure control effects on renal impairment with urinary protein: a study on the validity of the Japanese Society of Hypertension Guidelines for Management of Hypertension 2014].

BACKGROUND AND OBJECTIVE: Progression of chronic kidney disease (CKD) leads to the onset of cardiovascular dis- eases and an increase in the number of patients requiring dialysis initiation. In prder to promote the early detection and treatment of CKD, we assessed the effects of blood pressure control on renal impairment based on common test items and verified the usefulness of the target blood pressure for patients with CKD described in the Japanese Society of Hypertension Guidelines for the Management of Hypertension in 2014 (JSH 2014). SUBJECTS AND METHODS: Among patients who had been regularly visiting the outpatient clinic of Kasukabe Kisen Hospital for 24 months or more, 67 with a serum creatinine level of 1.2 mg/dL or higher were included in this study. Clinical blood pressure measurements obtained at the start of follow-up and at 6, 12, 18, and 24 months were averaged to serve as the 2-year mean blood pressure, and the progression rates of renal impairment were com- pared between patients achieving and those not achieving the target blood pressure of the JSH 2014. RESULTS: Among the diabetic patients with CKD, significant differences in renal impairment progression rates were observed between those achieving and those not achieving the target blood pressure. Among the non-diabetic patients with CKD, those achieving the target blood pressure tended to show slower progression of renal impair- ment, but their progression rates were not significantly different from those of the patients not achieving the target blood pressure. CONCLUSION: Blood pressure control is essential for patients with CKD. In patients with diabetes mellitus, the pro- gression rates of renal impairment can be substantially reduced by maintaining blood pressure below the target blood pressure described in the JSH 2014.

Pathological Renal Findings of Chronic Renal Failure in a Patient with the E66Q Mutation in the α-galactosidase A Gene.

A 66-year-old Japanese man was diagnosed with interstitial nephritis on a renal biopsy at 45 years of age and began to receive hemodialysis at 65 years of age. He was suspected of having Fabry disease as a result of a screening study for Fabry disease performed in hemodialysis patients. He had an E66Q mutation in the α-galactosidase A gene. We conducted an electron microscopic examination of a renal biopsy specimen obtained when the patient was diagnosed with chronic renal failure at 45 years of age in order to elucidate the pathogenicity of the E66Q mutation. Interestingly, an electron microscopic examination of the renal biopsy specimen indicated no characteristic findings of Fabry disease.

Segmental copy number loss in the region of Semaphorin 4D gene in patients with acetabular dysplasia.

Acetabular dysplasia (AD) appears to be a multi-factorial disease, which may involve both genetic and environmental factors and whose pathogenesis remains obscure. The present study aims to identify a genetic variation that might confer risk of AD. We performed whole-genome screening of a copy number variation (CNV) using a deCODE-Illumina CNV beadchip with 20 female AD patients and 131 control subjects. Subsequently, Agilent's region-targeted high-density oligonucleotide tiling microarray was used to analyze 64 female AD patients and 32 female control subjects. By sequential analyses, we found a copy number loss in 18 of 64 AD patients, but none in the 32 controls. The loss occurred within a 472 kb region on 9q22.2, which harbors the gene for Semaphorin 4D (Sema4D; 18/64 vs. 0/32, p = 4.81 × 10(-4) , OR = 25.86). We suggest that a copy number loss of the Sema4D gene region may play a role in the etiology of AD.

Relationship between oligomer and functional serum mannose-binding lectin in chronic renal failure.

INTRODUCTION: Mannose-binding lectin (MBL) plays an important role in first-line host defence against pathogens via the lectin pathway. The binding affinity for ligands is greatly increased by oligomerization, although the basic triplet does not bind solid phase mannan and cannot activate complement. Besides, MBL is a positive acute-phase protein. In this study, we examined the relationship between oligomer and functional serum MBL in chronic renal failure patients who were either uraemic [Pre-haemodialysis (pre-HD) patients], or who were receiving maintenance haemodialysis treatment (HD patients). MATERIALS AND METHODS: This study included a total of 20 Pre-HD patients, 130 HD patients and 28 healthy subjects. The oligomer and functional serum MBL levels were measured using enzyme-linked immunosorbent assays established previously. RESULTS: The median serum functional MBL levels were significantly reduced in both Pre-HD and HD patients compared with healthy subjects (P<0·05 for both). Furthermore, the median functional MBL level in Pre-HD patients was significantly lower than that in HD patients (P<0·05). The median serum oligomer MBL levels in both Pre-HD and HD patients were significantly higher compared with healthy subjects (P<0·05 for both). Furthermore, the median oligomer MBL level in HD patients was significantly (P<0·05) higher than that in Pre-HD patients. The ratios of median serum functional MBL levels to oligomer MBL levels were significantly reduced in both Pre-HD and HD patients compared with healthy subjects (P<0·05 for both). CONCLUSIONS: We found significant reductions in the ratios of serum functional MBL levels to oligomer MBL levels in HD and Pre-HD patients compared with healthy subjects.

Plasma adrenomedullin and proadrenomedullin N-terminal 20 peptide in patients diagnosed as having early rheumatoid arthritis.

The aim of this study was to investigate plasma adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) level in patients diagnosed with early rheumatoid arthritis (RA). Furthermore, several inflammatory cytokines were measured in those patients to clarify the roles of AM and PAMP. Forty patients diagnosed with early RA (women 46 +/- 8.5 years old) and 10 healthy controls (women 57 +/- 5 years old) were studied. Plasma levels of AM, PAMP, matrix metalloprotease 3 (MMP-3), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and C-reactive protein (CRP) were measured using an immunoradiometric assay and enzyme-linked immunosorbent asay (ELISA) methods. The plasma levels of AM (17.5 +/- 8.4 fmol/ml) and PAMP (2.01 +/- 0.57 fmol/ml) in patients exceeded those in healthy controls (AM 8.6 +/- 1.7, PAMP 1.17 +/- 0.34 fmol/ml). Moreover, plasma AM and PAMP levels demonstrated a significantly positive correlation with plasma MMP-3 and IL-6 levels. Nevertheless, CRP and TNF-alpha levels in these patients showed no significant correlation with plasma AM and PAMP levels. These data support the possible role for AM and PAMP in the pathophysiology of early RA.

Therapeutic efficacy of intra-articular adrenomedullin injection in antigen-induced arthritis in rabbits.

INTRODUCTION: Adrenomedullin is a potent vasodilatory and hypotensive peptide as well as an endogenous immunomodulatory factor with predominantly anti-inflammatory effects. The purpose of the present study was to evaluate the therapeutic effects of adrenomedullin in rabbits with antigen-induced arthritis, an experimental model of rheumatoid arthritis. METHODS: Following the induction of arthritis in both knee joints by ovalbumin injection into the joint spaces of pre-immunized rabbits, increasing daily doses of adrenomedullin were injected into the knee joint spaces or saline was injected into the contralateral knee joint spaces as the control. For time-course experiments, adrenomedullin and saline were injected into the knee joint spaces daily for 7 days and 20 days. The degree of joint swelling and the histological change in the knee joints injected with adrenomedullin were compared with the control knee joints. Histological evaluation of the infrapatellar fat pads and synovial tissue was performed. TNFalpha, IL-6, vascular endothelial growth factor and transforming growth factor-beta mRNA levels in the synovial tissue were measured using real-time quantitative PCR. RESULTS: Daily injections of adrenomedullin into the knee joint spaces of rabbits with antigen-induced arthritis decreased joint swelling. Histological examination revealed that adrenomedullin reduced edematous changes and the infiltration of inflammatory cells in the synovial tissues. Analysis of mRNA levels showed that adrenomedullin significantly reduced TNFalpha mRNA expression by 21% to 49% in a dose-dependent manner, and dose-dependently increased IL-6 mRNA expression by 45% to 121%. CONCLUSIONS: These results suggest that daily injections of adrenomedullin into the knee joint spaces of rabbits with antigen-induced arthritis ameliorated the inflammatory response in arthritic joints. Adrenomedullin may thus be useful as a treatment for rheumatoid arthritis; however, the effect of adrenomedullin on IL-6 production in the synovial tissue may be an undesirable adverse effect in rheumatoid arthritis therapy.