Theodora Simopoulou

Lipid metabolism and osteoarthritis: lessons from atherosclerosis.

Osteoarthritis (OA) is an age-related degenerative disease comprising the main reason of handicap in the Western world. Interestingly, to date, there are neither available biomarkers for early diagnosis of the disease nor any effective therapy other than symptomatic treatment and joint replacement surgery. OA has long been associated with obesity, mainly due to mechanical overload exerted on the joints. Recent studies however, point to the direction that OA is a metabolic disease, as it also involves non-weight bearing joints. In fact, altered lipid metabolism may be the underlying cause. First, adipokines have been shown to be key regulators of OA pathogenesis. Second, epidemiological studies have shown serum cholesterol to be a risk factor for OA development. Third, lipid deposition in the joint is observed at the early stages of OA before the occurrence of histological changes. Fourth, proteomic analyses have shown an important connection between OA and lipid metabolism. Finally, recent gene expression studies reveal a deregulation of cholesterol influx and efflux and in the expression of lipid metabolism-related genes. Interestingly, lipids and lipid metabolism are known to be implicated in the development and progression of another age-related degenerative disease, atherosclerosis (ATH). Thus, although it is tempting to speculate that the osteoarthritic chondrocyte has been transformed to foam cell, it has not been proven yet. However, this may be an intriguing theory linking ATH and OA, which may open new avenues to novel therapeutic interventions for OA taking advantage of previous knowledge from ATH.

Impaired expression of genes regulating cholesterol efflux in human osteoarthritic chondrocytes.

Altered lipid metabolism has been implicated as a critical player in osteoarthritis (OA). Our study aimed to investigate the expression of genes regulating cholesterol efflux in human chondrocytes and to study the effect of an LXR agonist on cholesterol efflux and lipid accumulation in osteoarthritic chondrocytes. ATP‐binding‐cassette transporter A1 (ABCA1), apolipoprotein A1 (ApoA1), and liver X receptors (LXRα and LXRβ) mRNA expression levels were evaluated using real‐time polymerase chain reaction (PCR) and ApoA1 protein levels by Western blot analysis in normal and osteoarthritic articular cartilage samples. Cholesterol efflux was evaluated in osteoarthritic chondrocytes radiolabeled with [1,2(n)‐3H] cholesterol after LXR treatment, while intracellular lipid accumulation was studied after Oil‐red‐O staining. Cholesterol efflux gene expressions were significantly lower in osteoarthritic cartilage compared to normal. Treatment of osteoarthritic chondrocytes with the LXR agonist TO‐901317 significantly increased ApoA1 and ABCA1 expression levels, as well as cholesterol efflux. Additionally, osteoarthritic chondrocytes presented intracellular lipids deposits, while no deposits were found after treatment with TO‐901317. Our findings suggest that impaired expression of genes regulating cholesterol efflux may be a critical player in osteoarthritis, while the ability of the LXR agonist to facilitate cholesterol efflux suggests that it may be a target for therapeutic intervention in osteoarthritis.

Acute renal failure after antibiotic-impregnated bone cement treatment of an infected total knee arthroplasty

Antibiotic-impregnated cement is used frequently in revision procedures of infected total hip and knee arthroplasties. Local antibiotic treatment is as effective as the use of systemic antibiotics. The purpose of such treatment is to provide high tissue concentrations of antibiotics and minimize systemic toxicity, especially nephrotoxicity. Though antibiotic-impregnated cement is considered safe in terms of nephrotoxicity, two cases that have implicated aminoglycoside-impregnated cement in acute renal failure (ARF) after surgery for an infected total knee arthroplasty (TKA) have been reported [Curtis et al. 2005, Van Raaij et al. 2002]. Two more cases of postoperative ARF after use of combined tobramycin- plus vancomycin-impregnated cement, this time in total hip arthroplasty, have been recently reported [Patrick et al. 2006]. We report a case of ARF in a 61-year-old patient with a history of diabetes mellitus and hypertension after treatment of a febrile infection of a TKA with combined gentamicin- plus vancomycin-impregnated cement. The ARF could not sufficiently be attributed to other causes and though serum concentrations of antibiotics obtained from the 8th postoperative day and thereafter were far below the trough levels associated with nephrotoxicity, gentamicin and vancomycin seem to have contributed significantly to ARF in our case.

Protective effect of atorvastatin in cultured osteoarthritic chondrocytes.

The aim of our study was to evaluate the in vitro effect of an HMG‐CoA reductase inhibitor, atorvastatin, on the expression of significant anabolic and catabolic genes in human osteoarthritic chondrocytes and to explore the metabolic pathways involved in this process. Human articular osteoarthritic chondrocytes were cultured in the presence and absence of atorvastatin (10 and 50 µmol/L) for 24 h. Metalloproteinase 13 (MMP‐13), collagen type II (COL2A1), and aggrecan (AGC) mRNA expression levels were evaluated by real‐time PCR, and protein expression levels by Western blot analysis. IL‐1β levels in culture medium was analyzed with ELISA. The effect of the treatment with the mevalonate isoprenoid derivatives farnesol and geranylgeraniol, or the cholesterol precursor squalene, was evaluated in the atorvastatin osteoarthritic chondrocyte cultures. Incubation of osteoarthritic chondrocyte cultures with atorvastatin produced a significant dose‐dependent reduction in IL‐1β production. Atorvastatin supplementation in cultures produced a decrease in MMP‐13 mRNA and protein expression levels, which was reversed by the addition of farnesol. Regarding AGC and COL2A1 mRNA expression, a significant increase was observed only in chondrocytes cultures treated with 50 µmol/L atorvastatin. Our findings suggest that atorvastatin may have potential chondroprotective effects mostly by reducing cartilage degradation.

Breg Cells Are Numerically Decreased and Functionally Impaired in Patients With Systemic Sclerosis.

Breg cells, a regulatory cell subset that produces interleukin‐10 (IL‐10), play a significant role in suppressing autoimmune responses and preventing autoimmunity. This study was undertaken to examine the number and function of Breg cells in patients with systemic sclerosis (SSc), a disease with many autoantibodies.

A multicenter, open-label, comparative study of B-cell depletion therapy with Rituximab for systemic sclerosis-associated interstitial lung disease

OBJECTIVES Rituximab (RTX) may favorably affect lung function and skin fibrosis in patients with systemic sclerosis (SSc). We aimed to assess long-term efficacy and safety of RTX in SSc compared to standard treatment. METHODS A total of 51 patients with SSc-associated interstitial lung disease were recruited and treated with RTX (n = 33) or conventional treatment (n = 18). Median follow-up was 4 years (range: 1-7). Conventional treatment consisted of azathioprine (n = 2), methotrexate (n = 6), and mycophenolate mofetil (n = 10). RESULTS Patients in the RTX group showed an increase in FVC at 2 years (mean ± SD of FVC: 80.60 ± 21.21 vs 86.90 ± 20.56 at baseline vs 2 years, respectively, p = 0.041 compared to baseline). In sharp contrast, patients in the control group had no change in FVC during the first 2 years of follow-up. At the 7 year time point the remaining patients in the RTX group (n = 5) had higher FVC compared to baseline (mean ± SD of FVC: 91.60 ± 14.81, p = 0.158 compared to baseline) in contrast to patients in the control group (n = 9) where FVC deteriorated (p < 0.01, compared to baseline). Direct comparison between the 2 groups showed a significant benefit for the RTX group in FVC (p = 0.013). Improvement of skin thickening was found in both the RTX and the standard treatment group; however, direct comparison between groups strongly favored RTX at all-time points. Adverse events were comparable between groups. CONCLUSIONS Our data indicate that RTX has a beneficial effect on lung function and skin fibrosis in patients with SSc. Randomized controlled studies are highly needed.

Early systemic sclerosis—opportunities for treatment

Systemic sclerosis (SSc) is characterized by microvasculopathy (Raynaud’s phenomenon and fibrointimal proliferation), presence of autoantibodies and collagen deposition in skin (scleroderma) and internal organs. Microvasculopathy, detected by nailfold capillaroscopy, and disease-specific autoantibodies (anti-topoisomerase I, anti-centromere, anti-RNA polymerase III antibodies) usually appear earlier, even years before scleroderma. At that stage of the disease, immune activation with T cells and B cells promote fibrosis. Diagnosis of SSc has been relied on scleroderma, and by this time, internal organs may have developed fibrosis, a lethal feature with no available treatment. The new EULAR/ACR 2013 criteria for the classification of SSc will help identify SSc patients before fibrosis of internal organs. The early diagnosis of SSc, before the development of fibrosis in internal organs, will allow the introduction of immunosuppressive medications in these patients in a controlled setting (randomized trials). It is anticipated that this approach will change the hitherto grim prognosis of SSc for the better.

Acute Renal Failure: A Rare Presentation of Hypothyroidism

Thyroid hormones affect the function of almost every body organ, and thyroid dysfunction produces a wide range of metabolic disturbances. Severe hypothyroidism is associated with significant effects on the kidney. The pathophysiology is thought to be multifactorial, while the exact mechanism remains unclear. Hypothyroidism as a cause of renal impairment is usually overlooked, leading to unnecessary diagnostic procedures. We describe two patients with acute renal failure due to severe hypothyroidism in whom thyroid hormone substitution therapy led to a significant improvement in renal function.

Psoas abscess in a dialysis patient with dialysis-related amyloidosis

Psoas abscess is an infrequent clinical entity which poses diagnostic and therapeutic challenges. Few cases have been reported in chronic hemodialysis patients. We describe a case of psoas abscess in a dialysis patient with dialysis-related amyloidosis, successfully treated with percutaneous drainage and parenteral antibiotics.

Tuberculous pyomyositis: a re-emerging entity of many faces.

Tuberculosis (TB) has become a global concern due to its increasing incidence, particularly in immunocompromised patients, closely following the migratory patterns of populations. TB pyomyositis is a rare extrapulmonary manifestation of TB. Its clinical presentation varies and requires a high degree of suspicion for early diagnosis. We present three patients diagnosed with TB pyomyositis: a 46-year-old man with dermatomyositis (DM) and hepatitis B who presented with fever, muscle weakness, and an abscess at the right proximal arm; a 71-year-old immunocompetent male, with a past medical history of tuberculous lymphadenopathy in childhood, who presented with a 2-month history of fever and pain at the right thigh, and a 44-year-old woman with systemic lupus erythematosus (SLE) on prednisone and methotrexate who presented with skin eruption at her thighs mimicking lupus panniculitis. In all three patients, Mycobacterium tuberculosis was identified as the causative agent. The lack of specific signs, the false negative tuberculin skin test in some cases, and the unfamiliarity of many clinicians with this entity can cause diagnostic delays. Prompt diagnosis requires a high index of suspicion especially in immunocompromised patients with fever.