Th17/IL-17A axis is critical for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc): SSc patients with high levels of serum IL-17A exhibit reduced lung functions and increased prevalence of PAH.

BACKGROUND: It is thought that systemic sclerosis (SSc) might be a T helper 17 (Th17) cell-driven autoimmune disease. Noticeably, pulmonary arterial hypertension (PAH) is a leading cause of death in patients with SSc. Here, we investigated the association between serum Th17-related cytokines and prevalence of PAH in SSc patients. METHODS: This study included 72 SSc patients and 51 healthy controls (HC). We determined clinical manifestations, immunophenotypes including Th subsets in peripheral blood lymphocytes, and the serum levels of interleukin (IL)-17A, IL-17A/F, IL-17B. IL-17C, IL-17D. IL-1ß, IL-6, IL-21, IL-22, and IL-23. RESULTS: The frequency of Th17 cells was significantly increased in SSc patients compared to HC and was positively correlated with the modified Rodnan skin scores. Furthermore, the serum levels of IL-17A, IL-17D, IL-1ß, and IL-6 were significantly increased in SSc patients compared to HC. SSc patients with detected IL-17A showed high levels of IL-17A/F, IL-1ß, IL-6, and IL-22, and high frequency of Th17 cells. Interestingly, these patients exhibited the reduced lung functions and increased prevalence of PAH significantly compared to patients with undetected IL-17A. Similarly, SSc patients with detected IL-17A and high IL-6 (≥1.2 pg/mL) exhibited the decreased lung functions and increased prevalence of PAH compared to patients with undetected IL-17A and low IL-6. CONCLUSION: We found that SSc patients with high levels of serum IL-17A or both IL-17A and IL-6 show reduced lung functions and high prevalence of PAH. Consequently, it is highly probable that Th17/IL-17A axis is critical for the prevalence of PAH in SSc patients.

Dropped head in systemic sclerosis: a case based review.

Dropped head syndrome is a rare disease entity characterized by severe weakness of the cervical para-spinal muscles, resulting in a chin-on-chest deformity. Systemic sclerosis is one of the causes of dropped head syndrome, but its characteristics and prognosis remain unclear due to the extreme rarity of this condition. We present a case of dropped head which occurred in systemic sclerosis. He presented with severe dropped head and relatively mild weakness of the proximal limb muscles. Serum level of creatine kinase was elevated, myopathic change was observed in electromyography, and gadolinium enhancement was found in magnetic resonance imaging of his posterior neck muscles. Anti-topoisomerase I antibody was positive, while other autoantibodies such as anti-PM/Scl and anti-Ku antibodies were negative. Since his dropped head acutely progressed, high dose of glucocorticoid therapy was initiated, which successfully improved dropped head, serum level of creatine kinase, and gadolinium enhancement in magnetic resonance imaging. Our present case and literature review suggest that dropped head occurring in systemic sclerosis can be treatable with immunosuppressive therapy. It is important to recognize this rare but treatable involvement of systemic sclerosis because early diagnosis and treatment initiation are crucial to prevent the irreversible organ damage and the significant decrease of daily activities.

Rheumatoid arthritis with nontuberculous mycobacterial pulmonary disease: a retrospective, single-centre cohort study.

OBJECTIVES: Nontuberculous mycobacterial pulmonary disease (NTM-PD) is a rare but important comorbidity of rheumatoid arthritis (RA). Our objective was to investigate the association between NTM-PD and RA, especially regarding the immunosuppressive treatment of RA such as biological disease-modifying antirheumatic drugs (bDMARDs). METHODS: We conducted a retrospective, single-centre cohort study. All RA patients regularly followed up at our rheumatology division in December 2012 were included in the study, and followed for 5 years. RESULTS: At baseline, 26 of 1639 RA patients had NTM-PD. During the observation period, 14 were newly diagnosed with NTM-PD. For new diagnosis of NTM-PD, bDMARD use at baseline was not a significant risk factor. Among the 40 patients with NTM-PD, 16 were treated with a total of 27 bDMARDs after NTM-PD diagnosis. They did not present with a greater exacerbation of NTM-PD than those not treated with bDMARDs (25 vs. 17%, p = .52). A total of 55 patients died, but nobody died of NTM-PD. NTM-PD was not associated with worse mortality in multivariate analysis (hazard ratio, 2.0; 95% CI, 0.6-6.4; p = .26). CONCLUSIONS: Biological DMARD was not associated with worse prognosis of NTM-PD. Careful use of bDMARDs could be tolerated in RA patients with NTM-PD.

Clinical and immunological effects of hydroxychloroquine in patients with active rheumatoid arthritis despite antirheumatic treatment.

OBJECTIVE: To investigate the efficacy and safety of hydroxychloroquine (HCQ) in patients with rheumatoid arthritis (RA). METHODS: Patients with active RA, despite conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), were recruited. HCQ was administered for 24 weeks, in addition to prior treatment. The primary endpoint was the proportion of American College of Rheumatology (ACR) 20 achievement at week 24, compared to that of a propensity score matched historical control group. RESULTS: Sixty patients were enrolled and administered HCQ. We also identified 276 patients as candidates for the historical control group. Propensity score matching yielded 46 patients in each group. The proportion of ACR20 achievements at week 24 was significantly higher in the HCQ group than that in the control group (54.4% vs. 28.3%, P = 0.007). The proportion of ACR50 and ACR70 achievement at week 24 were also higher in the HCQ group than those in the control group (ACR50, 30.4% vs. 4.3%, P = 0.006; ACR70, 17.4% vs. 0%, P = 0.005). Neither hydroxychloroquine retinopathy nor any new safety signal was observed during the study. CONCLUSION: The addition of HCQ to csDMARDs was effective, with no new safety signal in patients with RA.

COVID-19 shares clinical features with anti-melanoma differentiation-associated protein 5 positive dermatomyositis and adult Still's disease.

OBJECTIVES: To investigate the similarities and differences between Coronavirus disease 2019 (COVID-19) and autoimmune and autoinflammatory rheumatic diseases characterised by hyperferritinaemia, such as antimelanoma differentiation-associated protein 5 (MDA5) autoantibody-positive dermatomyositis and adult Still's disease. METHODS: We reviewed consecutive, newly diagnosed, untreated patients with COVID-19, anti-MDA5 dermatomyositis, or adult Still's disease. We compared their clinical, laboratory, and radiological characteristics, including the prevalence of macrophage activation syndrome and lung involvement in each disease. RESULTS: The numbers of patients with COVID-19, anti-MDA5 dermatomyositis, and adult-onset Still's disease with hyperferritinaemia (serum ferritin ≥500ng/dL) who were included for main analysis were 22, 14, and 59, respectively. COVID-19 and adult Still's disease both featured hyperinflammatory status, such as high fever and elevated serum C-reactive protein, whereas COVID-19 and anti-MDA5 dermatomyositis both presented with severe interstitial lung disease and hypoxaemia. While two-thirds of the patients in each group met the criteria for macrophage-activated syndrome that is used in systemic juvenile idiopathic arthritis, the HScore, an indicator of haemophagocytic lymphohistiocytosis, was low in anti-MDA5 dermatomyositis and COVID-19 even in severe or critical cases. The findings of chest computed tomography were similar between COVID-19 and anti-MDA5 dermatomyositis. CONCLUSIONS: COVID-19 shared clinical features with rheumatic diseases characterised by hyperferritinaemia, including anti-MDA5 dermatomyositis and adult Still's disease. These findings should be investigated further in order to shed light on the pathogenesis of not only COVID-19 but also the aforementioned rheumatic diseases.

A nationwide survey on the incidence and characteristics of traumatic spinal cord injury in Japan in 2018.

STUDY DESIGN: Retrospective epidemiological study. OBJECTIVES: Since the causes and incidences of traumatic spinal cord injury (TSCI) in each country change over time, up-to-date epidemiological studies are required for countermeasures against TSCI. However, no nationwide survey in Japan has been conducted for about 30 years. The purpose of this study was therefore to investigate the recent incidence and characteristics of TSCI in Japan. SETTING: Japan METHODS: Survey sheets were sent to all hospitals (emergency and acute care hospitals) that treated TSCI persons in Japan in 2018 and case notes were retrospectively reviewed. Frankel grade E cases were excluded from analysis. RESULTS: The response rate was 74.4% (2804 of 3771 hospitals). The estimated annual incidence of TSCI excluding Frankel E was 49 per million, with a median age of 70.0 years and individuals in their 70s as the largest age group. Male-to-female ratio was 3:1. Cervical cord injuries occurred in 88.1%. Frankel D was the most frequent grade (46.3%), followed by Frankel C (33.0%). The most frequent cause was fall on level surface (38.6%), followed by traffic accident (20.1%). The proportion of fall on level surface increased with age. TSCI due to sports was the most frequent cause in teenagers (43.2%). CONCLUSIONS: This nationwide survey in Japan showed that estimated incidence of TSCI, rate of cervical cord injury, and incomplete injury by falls appear to be increasing with the aging of the population.

New diagnostic support tool for patients with leg symptoms caused by lumbar spinal stenosis and lumbar intervertebral disc herniation: A self-administered, self-reported history questionnaire.

BACKGROUND: There are no diagnostic support tools composed of a simple, single-sheet, self-administered, self-reported history questionnaire (SSHQ) for patients with leg symptoms caused by either lumbar spinal stenosis (LSS) or lumbar disc herniation (LDH), at the same time, can discriminate the two diseases. METHODS: We conducted retrospective and prospective derivation studies and a prospective validation study. Based on data from 137 patients with LSS and 206 with LDH, we identified key prediction factors to establish the diagnosis of LSS and LDH, which became the basis of a temporary SSHQ. Next, we performed a prospective derivation study in which 296 patients with LSS or LDH completed preoperatively this temporary SSHQ. After univariate and multivariate analyses of each question, questions on both diseases in addition to age factor were selected, providing the final version of the SSHQ. A validation study was subsequently performed with 342 consecutive patients with leg symptoms. The sensitivity, specificity and likelihood ratio of this SSHQ were calculated to determine the cut-off points for LSS and LDH. RESULTS: A SSHQ with 15 questions was developed from retrospective and prospective derivation studies. The score of each question was weighted based on the multivariate analysis and then, it was approximated to integer value. According to assessment of the discriminatory performance of the clinical prediction rule of the SSHQ, the cut-off point for LSS was ≥13 and that for LDH was ≥11. The sensitivity, specificity, and positive and negative likelihood ratios of this SSHQ at those cut-off points were, respectively, 92.7%, 84.7%, 6.07, and 0.09 for LSS, and 91.0%, 85.2%, 6.15, and 0.11 for LDH. CONCLUSIONS: This is the first report of a diagnostic support tool for patients with LSS- or LDH-induced leg symptoms combined in a single SSHQ that could help establish diagnosis of the two diseases in the daily clinical practice.

Successful treatment with tofacitinib for relapse of rapidly progressive interstitial lung disease in anti-melanoma differentiation-associated gene 5 antibody-positive clinically amyopathic dermatomyositis.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody is associated with clinically amyopathic dermatomyositis (CADM) with rapidly progressive interstitial lung disease (RP-ILD). Recently, several studies have reported that tofacitinib (TOF), a Janus kinase inhibitor, might be effective for cases of new or refractory RP-ILD in anti-MDA5 antibody-positive CADM; however, it is unknown whether TOF can also be effective for relapsed cases. We herein report a relapsed case of RP-ILD in anti-MDA5 antibody-positive CADM, which was successfully treated by combination therapy with TOF (5 mg twice daily). Our case suggests that TOF may also be a potential treatment option for relapsed cases of this disease.

Acute encephalitis in primary Sjögren's syndrome: A case report and literature review.

Acute encephalitis is an extremely rare condition in primary Sjogren's syndrome (pSS), and its characteristics and prognosis remain unclear. Here, we report the case of pSS presented with acute encephalitis. She was admitted to our hospital for acute disturbance of consciousness. Acute encephalitis was diagnosed based on the results of the cerebrospinal fluid test (the increase of leucocyte counts, proteins, and interleukin-6 levels), magnetic resonance imaging, and single-photon emission computed tomography with 99mTc. The infectious aetiologies and underlying malignancies were excluded. Serum anti-Sjogren's syndrome-related antigen A autoantibody was positive with extremely high titre. The biopsy specimen of her labial salivary gland revealed a focal lymphocytic sialadenitis with a score of grade 4 in the Greenspan grade. She also developed diffuse alveolar haemorrhage during the clinical course. She was diagnosed with pSS complicated with acute encephalitis followed by diffuse alveolar haemorrhage and successfully treated with pulse steroids, high dose of prednisolone and intravenous cyclophosphamide. Our present case and literature review suggest that acute encephalitis associated with pSS can be treatable with the immunosuppressive therapy, and thus early recognition and treatment initiation are important for this life-threatening condition. Thus, pSS should be included in the differential diagnosis of unexplained encephalitis. Notably, our case characteristically showed diffuse alveolar haemorrhage, adding new insights into the pathogenesis of acute encephalitis associated with pSS that capillaritis might be the underlying cause of this condition.

Dermatomyositis Which Was Double Positive for Anti-MDA5 and Anti-ARS Antibodies That Was Successfully Treated by Intensive Immunosuppressive Therapy.

Myositis-specific autoantibody is associated with the clinical phenotype and prognosis of dermatomyositis. Anti-melanoma differentiation-associated gene 5 (MDA5) and anti-aminoacyl-tRNA synthetase (ARS) antibodies are generally mutually exclusive. We herein present an extremely rare case of dermatomyositis which showed double positivity for anti-MDA5 and anti-ARS antibodies. There have been very few reported cases of double positive anti-MDA5, anti-ARS antibodies. In such cases, the clinical characteristics of each autoantibody can coexist. Thus, we should pay attention to the rapidly progressing features of anti-MDA5 as well as the chronic relapsing features of anti-ARS for the better management of this rare condition.

Early combination of pulmonary vasodilators prevents chronic kidney disease progression in connective tissue disease-associated pulmonary hypertension.

AIM: Pulmonary hypertension (PH) and chronic kidney disease (CKD) are interdependent for their development and exacerbation. We evaluated the effect of PH on CKD progression in patients with connective tissue disease (CTD)-associated PH. METHODS: We reviewed consecutive patients with CTD who were diagnosed with PH with right heart catheter (RHC) examinations in our hospital. Patients were divided into 2 groups according to the use of vasodilators: monotherapy or combination therapy. We further divided the patients with combination therapy into early and non-early combination groups. Early combination was defined as the addition of the second vasodilator within 1 month after starting the first drug. The clinical course of hemodynamics and CKD progression were compared. RESULTS: Thirty-eight patients were included in the analysis: 10 were treated with monotherapy and 28 with combination therapy (14 with early and 14 with non-early). At baseline, patients who received combination therapy had a significantly higher mean pulmonary arterial pressure with RHC and a higher right ventricular systolic pressure (RVSP) with echocardiography (P = .04) and showed a greater improvement in RVSP after treatment than those who underwent monotherapy. The incidence of CKD progression was significantly lower in patients who received combination therapy than in those who received monotherapy (P = .05). Among patients who received combination therapy, the early combination group had a lower incidence of CKD progression than the non-early combination group (P = .03). CONCLUSIONS: Early combination therapy is associated with a lower incidence of CKD progression in patients with CTD-associated PH.

Aryl hydrocarbon receptor signals attenuate lung fibrosis in the bleomycin-induced mouse model for pulmonary fibrosis through increase of regulatory T cells.

BACKGROUND: Interstitial lung disease (ILD) is a serious complication of connective tissue diseases (CTDs). Although immune dysregulation triggered by genetic and environmental factors is thought to provoke inflammation and subsequent fibrosis, precise mechanisms of these processes remain unclear. Recent reports suggest that activation of aryl hydrocarbon receptor (AhR) signals by various ligands such as tryptophan derivatives can induce hyper-immune responses and are involved in autoimmunity. We investigated the effects of AhR signals on the process of lung fibrosis and changes in immunological features using a bleomycin (BLM)-induced lung fibrosis mouse model. METHODS: BLM was administered intratracheally to C57BL/6JJcl mice and either 5,11-dihydroindolo[3,2-b]carbazole-6-carboxaldehyde (FICZ), a natural AhR ligand, or vehicle was subsequently injected intraperitoneally on day 0, 1, and 2 from BLM administration. Mice were sacrificed at week 3, and lung fibrosis was quantified by the histological changes using the Ashcroft score and deposition of soluble collagen levels in the lung using Sircol assay. The population of immune cells infiltrated into the lungs was analyzed using flow cytometry. RESULTS: Both the Ashcroft score and soluble collagen level in FICZ-treated mice were significantly lower than those in the vehicle group. Moreover, the survival rate of FICZ-treated mice was significantly higher than that of control mice during the 3 weeks after treatment. Interestingly, flow cytometric analysis revealed that the number of CD4+Foxp3+ regulatory T cells (Tregs) was significantly increased and CD4+IFNγ+ and γδ+IL-17A+ T cells were decreased in the lungs of FICZ-treated mice, while the total number of T, B, and NK cells were unaffected by FICZ treatment. CONCLUSIONS: Our findings suggest that stimulation of AhR signals attenuated lung fibrosis by increasing Tregs and suppressing inflammatory T cell subsets in a BLM-induced fibrosis model. AhR signaling pathways may therefore be useful therapeutic targets for connective tissue disease-associated ILD.

A diagnostic support tool for lumbar spinal stenosis: a self-administered, self-reported history questionnaire.

BACKGROUND: There is no validated gold-standard diagnostic support tool for LSS, and therefore an accurate diagnosis depends on clinical assessment. Assessment of the diagnostic value of the history of the patient requires an evaluation of the differences and overlap of symptoms of the radicular and cauda equina types; however, no tool is available for evaluation of the LSS category. We attempted to develop a self-administered, self-reported history questionnaire as a diagnostic support tool for LSS using a clinical epidemiological approach. The aim of the present study was to use this tool to assess the diagnostic value of the history of the patient for categorization of LSS. METHODS: The initial derivation study included 137 patients with LSS and 97 with lumbar disc herniation who successfully recovered following surgical treatment. The LSS patients were categorized into radicular and cauda equina types based on history, physical examinations, and MRI. Predictive factors for overlapping symptoms between the two types and for cauda equina symptoms in LSS were derived by univariate analysis. A self-administered, self-reported history questionnaire (SSHQ) was developed based on these findings. A prospective derivation study was then performed in a series of 115 patients with LSS who completed the SSHQ before surgery. All these patients recovered following surgical treatment. The sensitivity of the SSHQ was calculated and clinical prediction rules for LSS were developed. A validation study was subsequently performed on 250 outpatients who complained of lower back pain with or without leg symptoms. The sensitivity and specificity of the SSHQ were calculated, and the test-retest reliability over two weeks was investigated in 217 patients whose symptoms remained unchanged. RESULTS: The key predictive factors for overlapping symptoms between the two categories of LSS were age > 50, lower-extremity pain or numbness, increased pain when walking, increased pain when standing, and relief of symptoms on bending forward (odds ratio > or = 2, p < 0.05). The key predictive factors for cauda equina type symptoms were numbness around the buttocks, walking almost causes urination, a burning sensation around the buttocks, numbness in the soles of both feet, numbness in both legs, and numbness without pain (odds ratio > or = 2, p < 0.05). The sensitivity and specificity of the SSHQ were 84% and 78%, respectively, in the validation data set. The area under the receiver operating characteristic curve was 0.797 in the derivation set and 0.782 in the validation data set. In the test-retest analysis, the intraclass correlation coefficient for the first and second tests was 85%. CONCLUSION: A new self-administered, self-reported history questionnaire was developed successfully as a diagnostic support tool for LSS.

Intriguing Findings of the Muscle on Magnetic Resonance Imaging in Polyarteritis Nodosa.

Polyarteritis nodosa (PAN) confined to the muscle is rare and hard to diagnose. Recently, the utility of magnetic resonance imaging (MRI) for detecting muscle involvement of PAN has been introduced. We herein report the case of biopsy-proven, refractory PAN confined to the lower limb muscles with enhanced MRI demonstrating discretely granular hyperintensities, which was contrary to previous reports. Our results, with those of previous reports, suggest that the MRI findings of muscles in PAN reflect the vessel size involved and disease severity.

Absence of biglycan accelerates the degenerative process in mouse intervertebral disc.

STUDY DESIGN: A study of the histologic changes of the intervertebral discs (IVDs) in biglycan (Bgn)-deficient mice. OBJECTIVE: In this study, we investigate whether the absence of Bgn accelerates the degenerative process in mouse intervertebral disc (IVD). SUMMARY OF BACKGROUND DATA: Proteoglycans and collagen fibrils are major components in the extracellular matrix (ECM) composition of IVD. The ECM of IVD contains several members of the small leucine repeat proteoglycans (SLRPs) family. Bgn is one member of SLRPs family, and showed a unique expression with age and degeneration in the human IVD. To date, there have been no in vivo studies to see whether SLRPs have a role in maintaining the structural integrity of IVD. To explore the functions of Bgn in the IVD, we examined discs in Bgn-deficient mice. METHODS: A total of 30 spine specimens were harvested from wild-type (WT) and Bgn-deficient mice. Five specimens for each genotype at 4-, 6-, and 9-month old were examined in the experiments. Histologic analysis of the IVD was performed. Histologic gradings were performed separately on nucleus pulposus, anulus fibrosus, and endplate according to the classification system proposed by Boos et al. RESULTS: We found that Bgn-deficient mice developed an early onset of disc degeneration compared with WT mice. The degenerative scores of Bgn-deficient mice were significantly higher than those of WT mice at 4- and 9-month-old. High scores for nucleus pulposus and anulus fibrosus in Bgn-deficient mice significantly affected the difference in total degenerative scores at 9 months of age. CONCLUSION: Bgn deficiency significantly accelerated disc degeneration.

The long-term follow-up of surgical treatment for cervical myelopathy with severe nape and upper arm pain caused by the anomalous vertebral artery: case report.

STUDY DESIGN: A case of cervical myelopathy with a severe nape and upper arm pain caused by anomalous bilateral vertebral arteries is reported. OBJECTIVE: To report over six and a half years results of a microsurgical decompression for high cervical myelopathy with a severe pain of nape and upper arm resulting from spinal cord compression by the anomalous vertebral arteries. SUMMARY OF BACKGROUND DATA: Although symptomatic cases of anomalies of vertebral artery (VA), such as fenestration or elongation, leading to severe cervical pain, cervical myelopathy, or accessory nerve palsy have been reported, no long-term results of microsurgical decompression for those cases have been reported. METHODS: The clinical features of the case and over 6(1/2) years results of microsurgical decompression by retracting the arteries with silicon tapes and a dural patch are reported. An etiology and the treatment of the cases are discussed with a review of the previous documented cases. RESULTS: The cord compression was relieved surgically, and the patient's symptoms have improved after surgery throughout the follow-up period. CONCLUSION: Anomalous vertebral arteries should be included in the differential diagnosis of the upper cervical lesion of unknown origin. The microsurgical decompression with presented technique has relieved the symptoms for over 6(1/2) years.

Gene expression analysis of osteoblastic cells contacted by orthopedic implant particles.

Particles generated from orthopedic implants through years of wear play an essential role in the aseptic loosening of a prosthesis. We have investigated the biocompatibility of these orthopedic particles on different osteoblast-like cells representative of different stages of osteoblast maturation. We found the particles induced a caspase-dependent apoptosis of osteoblasts, with less mature osteoblasts being the most susceptible. An analysis of gene expression was performed on the less mature osteoblasts, which were in contact with the particles. We found that the particles had a profound impact on genes that code for inflammatory cytokines and genes involved in controlling the nuclear architecture. Results from this study suggest that the peri-implant osteolysis after a total joint replacement can be due in part to a decrease of bone formation and not solely to an overstimulation of bone resorption as is generally proposed. Development of new drugs that promote normal bone formation and osteoblast survival would possibly control peri-implant osteolysis, resulting in a better prognosis for patients with orthopedic implants.

Hyaluronate inhibits the interleukin-1beta-induced expression of matrix metalloproteinase (MMP)-1 and MMP-3 in human synovial cells.

Intra-articular administration of hyaluronate (HA) is an effective treatment for arthritis. HA injections can decrease not only joint pain but also synovial effusion, although little is known concerning the mechanism of HA action. The aim of this study was to investigate the role of HA on the expression and production of matrix metalloproteinase (MMP) in synovial cells activated by interleukin (IL)-1beta in order to achieve a better understanding of exogenous HA function in the extracellular matrix degradation in arthritic joints. Human synovial cells were incubated with HA (0.1-1000 microg/ml) and/or IL-1beta (1 ng/ml). The expression of MMP-1 and MMP-3 mRNAs was analyzed by quantitative real-time polymerase chain reaction. The protein levels of MMP-1 and MMP-3 in cultured media were measured by immunoblotting. Expression of MMP-1 and MMP-3 mRNAs was induced by IL-1beta. The IL-1beta-mediated induction of MMP-1 mRNA expression was attenuated by 10 microg/ml HA (p=0.026) and that of MMP-3 mRNA was strongly down-regulated in the presence of 10 or 1000 microg/ml HA (p<0.001). The increased protein levels of MMP-1 and MMP-3 were also reduced by 1000 microg/ml HA. These data suggest that HA inhibits the expression and production of MMP-1 and MMP-3 in IL-1beta-stimulated human synovial cells. We therefore prepose that intra-articular HA may rescue inflamed joints from bone and cartilage destruction by reducing the production of MMP-1 and MMP-3.