Pharmacogenomic Advances in the Prediction and Prevention of Cutaneous Idiosyncratic Drug Reactions.

Cutaneous idiosyncratic drug reactions (CIDRs) are usually unpredictable, ranging from mild maculopapular exanthema (MPE) to severe cutaneous adverse drug reactions (SCARs) such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Increasing evidence suggests that HLA alleles are strongly associated with drug-induced-CIDRs. The pathomechanisms for CIDRs include genetic polymorphisms affecting complex immune-specific HLA/drug antigen/T-cell receptor interactions and drug metabolism. Pharmacogenomic tests to prevent CIDRs have been widely implemented in clinical practice in recent years.

Prevalence and severity by age and other clinical correlates of haemophilic arthropathy of the elbow, knee and ankle among Taiwanese patients with haemophilia.

INTRODUCTION & AIMS: Haemophilic arthropathy (HA) is a major complication in patients with haemophilia (PWH), but the study of age-specific prevalence and severity of HA is very limited in Asian countries. MATERIALS & METHODS: This study retrospectively reviewed 146 severe- and moderate-type Taiwanese PWH aged 4-73 years, with roentgenograms of elbows, knees and ankles and calculated Pettersson scores. RESULTS: The prevalence of HA, mean number of HAs per patient and mean Pettersson scores of all the joints were 42.8%, 1.3 and 1.9 points in PWH aged 4-10 years; 64.3%, 1.4 and 4.1 points in PWH aged 11-19 years; 97.1%, 2.9 and 15.6 points in PWH aged 20-29 years; 93.1%, 4.4 and 33.1 points in PWH aged 30-39 years; 100%, 5.1 and 46.1 points in PWH aged 40-49 years and 100%, 5 and 49.6 points in PWH aged ≥50 years, respectively. There was a high prevalence of HA for PWH aged ≥20 years. Among PWH aged <20 years, prevalence of HA was low and mild ankle arthropathy was the most common. Besides, in the four age groups aged <40 years, the prevalence of ankle arthropathy was the highest, followed by elbow arthropathy and then knee arthropathy. CONCLUSIONS: Although severe arthropathy of the six major joints was rare in PWH aged <30 years, it increased rapidly in PWH after 30 years. Analysis of clinical correlates suggested that age, severity of haemophilia, absence of prophylaxis and presence of HCV infection correlated positively with Pettersson scores.

Experimental osteoarthritis induced by surgical realignment of the patella in BALB/c mice.

The patellofemoral joint is an important source of symptoms in osteoarthritis of the knee. We have used a newly designed surgical model of patellar strengthening to induce osteoarthritis in BALB/c mice and to establish markers by investigating the relationship between osteoarthritis and synovial levels of matrix metalloproteinases (MMPs). Osteoarthritis was induced by using this microsurgical technique under direct vision without involving the cavity of the knee. Degeneration of cartilage was assessed by the Mankin score and synovial tissue was used to determine the mRNA expression levels of MMPs. Irrigation fluid from the knee was used to measure the concentrations of MMP-3 and MMP-9. Analysis of cartilage degeneration was correlated with the levels of expression of MMP. After operation the patellofemoral joint showed evidence of mild osteoarthritis at eight weeks and further degenerative changes by 12 weeks. The level of synovial MMP-9 mRNA correlated with the Mankin score at eight weeks, but not at 12 weeks. The levels of MMP-2, MMP-3 and MMP-14 mRNA correlated with the Mankin score at 12 weeks. An increase in MMP-3 was observed from four weeks up to 16 weeks. MMP-9 was notably increased at eight weeks, but the concentration at 16 weeks had decreased to the level observed at four weeks. Our observations suggest that MMP-2, MMP-3 and MMP-14 could be used as markers of the progression of osteoarthritic change.

Stress fracture of the proximal tibia after total knee arthroplasty: a case report.

Stress fracture of the proximal tibia after total knee arthroplasty (TKA) is very rare. We found only 16 cases in a review of the literature. We report the case of a 76-year-old obese woman who sustained a stress fracture of the right proximal tibia without trauma 18 months after TKA. Pain developed in the proximal medial aspect of the tibia during walking. Physical examination showed tenderness of the proximal medial aspect of the tibia and varus deformity of 15 degrees during stress test of the knee. Roentgenography 4 weeks after symptom onset showed an obvious stress fracture line. Treatment with bed rest and above-the-knee plaster cast immobilization for 8 weeks was successful. The causes of this rare complication may include increased level of activity after TKA, generalized osteoporosis, and varus deformity of the knee.

Therapy and prevention of arthritis by recombinant adeno-associated virus vector with delivery of interleukin-1 receptor antagonist.

OBJECTIVE: To evaluate the recombinant adeno-associated virus vector encoding interleukin-1 receptor antagonist (rAAV-IL-1Ra) complementary DNA for its potential in the treatment and prevention of lipopolysaccharide (LPS)-induced arthritis. METHODS: The therapeutic effect of rAAV-IL-1Ra on arthritis was studied by injecting knees of Sprague-Dawley rats with LPS and rAAV-IL-1Ra and then evaluating the severity of arthritis by leukocyte counts in synovial fluid, histologic changes of synovium, and uptake of 67Ga citrate in joint tissue. To study the therapeutic effect on recurrent arthritis, we induced recurrent arthritis by a second injection of LPS 80 days after primary LPS and rAAV-IL-1Ra injections and then evaluated the severity of recurrent arthritis. To study the prevention of arthritis, rAAV-IL-1Ra was injected into normal joints. After 100 days, LPS was used to induce arthritis, and the severity of arthritis was evaluated. RESULTS: The production of the rAAV-IL-1Ra transgene was up-regulated by LPS-induced joint inflammation and proved to be efficacious in the therapeutic and preventative protocols. Not only primary but also recurrent arthritis could be suppressed by a single injection of rAAV-IL-1Ra. We found that the transgene expression of IL-1Ra could be reactivated by a second challenge with LPS delayed for 80 days after rAAV administration. The therapeutic level of IL-1Ra protein reached a mean +/- SD of 5.8+/-0.5 ng/ml in synovial fluid. In addition, the rAAV transgene persisted within normal joints for at least 100 days and could still be induced to express, after LPS insult, a high level of IL-1Ra (mean +/- SD 5.2+/-0.8 ng/ml) that prevented the occurrence of arthritis. CONCLUSION: This gene therapy, by combining highly efficient and stable rAAV gene delivery, disease-regulated gene expression, and the antiinflammatory effect of IL-1Ra, provides a valuable approach for long-term protection against, and prevention of, arthritis.

Disease-inducible transgene expression from a recombinant adeno-associated virus vector in a rat arthritis model.

Rheumatoid arthritis (RA) is a systemic autoimmune disease affecting 1% of the world's population, with significant morbidity and mortality. In this study, we investigated a recombinant adeno-associated virus (rAAV) vector for its potential application in RA gene therapy. rAAV encoding Escherichia coli beta-galactosidase was injected into rat joints which had already been induced into acute arthritis after local lipopolysaccharide (LPS) administration, and the efficiency of in vivo transduction was evaluated. We observed a striking correlation between vector transgene expression and disease severity in arthritic joints. The inflammatory reaction peaked at 3 to 7 days after LPS treatment, and, at the same time, 95% of the synoviocytes had high-level transgene expression. Gene expression diminished to the basal level (5%) when the inflammation subsided at 30 days after LPS treatment. More importantly, the diminished transgene expression could be efficiently reactivated by a repeated insult. The transgene expression in normal joints transduced with rAAV remained low for a long period of time (30 days) but could still be induced to high levels (95%) at 3 to 7 days after LPS treatment. This is the first demonstration of disease state-regulated transgene expression. These findings strongly support the feasibility of therapeutic as well as preventative gene transfer approaches for RA with rAAV vectors containing therapeutic genes, which are expected to respond primarily to the disease state of the target tissue.