Yu-Tsan Lin

Therapeutic effects of hyaluronic acid on osteoarthritis of the knee. A meta-analysis of randomized controlled trials.

BACKGROUND The magnitude of the therapeutic effects of intra-articular injection of hyaluronic acid on osteoarthritis of the knee is still in question. The aim of this meta-analysis was to elucidate the therapeutic efficacy and safety of intra-articular injection of hyaluronic acid for osteoarthritis of the knee. METHODS We conducted a meta-analysis of twenty blinded randomized controlled trials that compared the therapeutic effect of intra-articular injection of hyaluronic acid with that of intra-articular injection of a placebo to treat osteoarthritis of the knee. The outcome end points were classified into three categories: pain with activities, pain without activities, and function. The outcome measures of the efficacy of hyaluronic acid were the mean differences in the efficacy scores between the hyaluronic acid and placebo groups. The outcome measure of the safety of hyaluronic acid was the relative risk of adverse events. RESULTS Intra-articular injection of hyaluronic acid can decrease symptoms of osteoarthritis of the knee. We found significant improvements in pain and functional outcomes with few adverse events. However, there was significant between-study heterogeneity in the estimates of the efficacy of hyaluronic acid. Subgroup analysis and meta-regression analysis showed that lower methodological quality such as a single-blind or single-center design resulted in higher estimates of hyaluronic acid efficacy, that introduction of acetaminophen as an escape analgesic in the trial resulted in lower estimates of hyaluronic acid efficacy, and that patients older than sixty-five years of age and those with the most advanced radiographic stage of osteoarthritis (complete loss of the joint space) were less likely to benefit from intra-articular injection of hyaluronic acid. CONCLUSIONS This meta-analysis confirmed the therapeutic efficacy and safety of intra-articular injection of hyaluronic acid for the treatment of osteoarthritis of the knee. Additional well-designed randomized controlled trials with high methodological quality are needed to resolve the continued uncertainty about the therapeutic effects of different types of hyaluronic acid products on osteoarthritis of the knee in various clinical situations and patient populations. LEVEL OF EVIDENCE Therapeutic study, Level II-3b (systematic review; nonhomogeneous Level-I studies). See Instructions to Authors for a complete description of levels of evidence.

Inverse correlation between CD4+ regulatory T-cell population and autoantibody levels in paediatric patients with systemic lupus erythematosus.

CD4+ CD25+ regulatory T cells (Tregs) are critical in maintaining self‐tolerance and preventing organ‐specific autoimmunity. Their role in paediatric systemic lupus erythematosus (SLE), an autoimmune disease characterized by inappropriate regulation of hyperactivated B and T cells, has not been clearly defined. Using flow cytometry to determine cell populations and real‐time polymerase chain reaction to assay mRNA expression for FOXP3, CTLA‐4, and GITR, we characterized CD4+ CD25+ T cells in paediatric SLE patients and healthy subjects. The frequency of CD4+ CD25+ Tregs was significantly decreased in patients with active SLE compared with patients with inactive SLE and with controls (7·27% ± 2·50%, 9·59% ± 2·80% and 9·78% ± 2·11%, respectively; P = 0·027 and P < 0·001, respectively), and was inversely correlated with disease activity, as assessed with the Systemic Lupus Erythematosus Disease Activity Index 2000 scores (r = −0·59, P = 0·001) and serum anti‐double‐stranded DNA levels (r = −0·65, P < 0·001). Our preliminary investigations found elevated surface expression of GITR in CD4+ CD25+ T cells, elevated mRNA expression of CTLA‐4 in CD4+ T cells and higher amounts of mRNA expression for FOXP3 in CD4+ cells in patients with active SLE compared with patients with inactive disease and controls. We demonstrated reduced CD4+ CD25+ Treg levels were inversely correlated with disease activity, indicating a defective Treg population in paediatric SLE patients. The differences in the expression of FOXP3, CTLA‐4 and GITR imply the possible role of CD4+ Tregs in the pathogenesis of SLE.

The levels of CD4+CD25+ regulatory T cells in paediatric patients with allergic rhinitis and bronchial asthma

Our purpose was to determine whether numbers of CD4+CD25+ T [T regulatory (Treg)] cells and mRNA expression of functional molecules of Treg are related to airway allergy and disease severity in 51 paediatric patients with allergic rhinitis or bronchial asthma and 47 healthy controls. Surface markers were evaluated with flow cytometry, and mRNA was determined with real‐time polymerase chain reaction. Children with allergic disease had fewer CD4+CD25+ T cells (8·49% ± 2·41% versus 9·58% ± 2·43%, P < 0·05) and CD4+CD25hi T cells (1·32% ± 0·68% versus 1·70% ± 0·68%, P < 0·01) than control subjects. Numbers of CD4+CD25+ and CD4+CD25hi T lymphocytes were higher in children with persistent allergic rhinitis and/or moderate–severe bronchial asthma than in those with respective milder disease. The number of Treg cells was correlated positively with total immunoglobulin E level. The mRNA expression of forkhead box P3 (FoxP3) was increased in moderate–severe versus mild asthma (2·93 ± 0·38 versus 1·60 ± 0·31, P < 0·01). Patients with moderate–severe bronchial asthma also had increased mRNA expression of interleukin (IL)‐10 compared with patients with mild asthma (15·24 ± 4·07 versus 3·77 ± 2·18, P < 0·01). The suppressive function of Treg cells from patients with more severe asthma was competent in vitro. On average, decreased numbers of Treg cells in children with allergic airway disease might represent a defect of the Treg population. With increased expression of FoxP3 and IL‐10 in Treg from patients with relatively severe allergic disease, adaptive and functional Treg might be generated in response to aggravated atopy and disease severity.

Gastrointestinal manifestations in Henoch-Schönlein purpura: a review of 261 patients.

Aim: Henoch‐Schönlein purpura is an IgA‐mediated autoimmune vasculitis of children. It often presents with symptoms including purpuric rash, abdominal pain, renal involvement or arthritis. Abdominal pain is a frequent symptom in children with HSP and raises the suspicion of intussusception or perforation. We sought to evaluate abdominal pain via stool occult blood and image studies. Methods: A retrospective study of 261 patients diagnosed with Henoch‐Schönlein purpura from December 1991 to December 2001 was conducted. Image studies, including abdominal echo, abdominal CT and panendoscopy, were performed for patients who suffered from abdominal pain. Results: Of the 261 patients, 151 (58%) had abdominal pain, and 46 (17.6%) suffered either overt gastrointestinal bleeding or had positive stool occult blood. Seven patients had gross bloody stools. One acute intussusception and one bowel perforation were noted. One patient suffered from hypovolemic shock due to massive gastrointestinal bleeding. When stool occult blood was 3+ or 4+, the incidence of a positive image finding was high.

The pathogenesis of oligoarticular/polyarticular vs systemic juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) has had a long and difficult problem with classification. It is clearly a heterogeneous and multi-factorial autoimmune disease but all too often the distinctions among subtypes were unclear. In fact, there is now increasing evidence of a distinct pathogenesis of oligo/polyarticular JIA compared to systemic JIA. Oligo/polyarticular JIA is an antigen-driven lymphocyte-mediated autoimmune disease with abnormality in the adaptive immune system. Cartilage-derived auto-antigens activate autoreactive T cells including Th1 and Th17 cells with production of pro-inflammatory cytokines IFN-γ and IL-17. On the other hand, the inhibition of regulatory T (Treg) cells including natural Foxp3(+) Treg and self-heat shock protein-induced Treg cells with decreased anti-inflammatory cytokine IL-10 results in the loss of immune tolerance. Imbalance between autoreactive Th1/Th17 and Treg cells leads to the failure of T cell tolerance to self-antigens, which contributes to the synovial inflammation of oligo/polyarticular JIA. By contrast, systemic JIA is an autoinflammatory disease with abnormality in the innate immune system. A loss of control of the alternative secretory pathway leading to aberrant activation of phagocytes including monocytes, macrophages and neutrophils seems to be involved in the release of pro-inflammatory cytokines IL-1, IL-6, IL-18 and pro-inflammatory S100-proteins, which contribute to the multisystem inflammation of systemic JIA. Markedly distinct pathogenesis of oligo/polyarticular JIA and systemic JIA implies that they might need different treatment strategies.

Renal manifestations in Henoch–Schönlein purpura: a 10-year clinical study

Henoch–Schönlein purpura (HSP) is an IgA-mediated systemic small vessel vasculitis of childhood. It is characterized by the symptoms including nonthrombocytopenic purpura, abdominal pain, hematuria/proteinuria, and arthargia/arthritis. We conducted a retrospective study of 261 patients diagnosed with HSP from December 1991 to December 2001. Of the 261 patients, fifty-three (20.3%) developed renal manifestations after onset of the disease. Two patients developed nephrotic syndrome. Four patients had group A beta-hemolytic streptococcal pharyngitis and subsequent depressed serum C3 concentration typical of post streptococcal glomerulonephritis. During the study period, the renal survival rate after disease onset was 100%. The prognosis of renal involvement was better than reports from other series. In this study we also found factors associated with HSP nephritis; these included older age at onset, GI bleeding, and central nervous system involvement. The long-term morbidity of HSP is predominantly attributed to renal involvement. It is thus recommended that patients with HSP nephritis are followed for longer periods of time.

Staphylococcus colonization in atopic dermatitis treated with fluticasone or tacrolimus with or without antibiotics

BACKGROUND The skin of patients with atopic dermatitis (AD) exhibits a striking susceptibility to colonization and infection by Staphylococcus aureus. Treatment with topical anti-inflammatory drugs alone can reduce S. aureus colonization. OBJECTIVES To compare the clinical severity of AD and the S. aureus colonization rate between AD patients treated with topical glucocorticoids and those treated with tacrolimus and to evaluate the effects of complementary topical antistaphylococcal antibiotic therapy and the development of fusidic acid-resistant S. aureus. METHODS Sixty AD patients were enrolled in a prospective, parallel, randomized study of an 8-week treatment with topical 0.05% fluticasone propionate or 0.03% tacrolimus, with or without complementary fusidic acid. Disease severity scoring of AD based on SCORing of Atopic Dermatitis (SCORAD), colonization rate and density of S. aureus on the skin, and antibiotic susceptibility of S. aureus isolates were evaluated. RESULTS The reduction in SCORAD scores correlated with the reduction of S. aureus numbers. Treatment with topical tacrolimus resulted in a comparable reduction in SCORAD scores to fluticasone but a slower eradication of S. aureus. Complementary fusidic acid had no additional benefit compared with fluticasone or tacrolimus alone. Two patients developed fusidic acid-resistant S. aureus after 8 weeks of fusidic acid treatment. CONCLUSION Tacrolimus is an appropriate alternative treatment for chronic AD. Topical anti-inflammatory therapy alone to improve the allergic skin inflammation of AD can reduce S. aureus colonization of the skin. Topical antibiotics should be reserved for short-term use in obvious secondary bacterial infection.

Increased transforming growth factor-beta (TGF-β)-secreting T cells and IgA anti-cardiolipin antibody levels during acute stage of childhood Henoch–Schönlein purpura

Henoch–Schönlein purpura (HSP) is a small vessel vasculitis characterized by increased serum IgA and IgA‐dominant immune complex deposition in lesions. The involvement of IgA implies a probable role for TGF‐β, a major factor in IgA production, in the pathogenesis of HSP. Among IgA antibodies, serum IgA anti‐cardiolipin antibodies (aCL) have been found in many diseases, including vasculitis. In addition to the clinical presentations and laboratory parameters, we further investigated the roles of IgA aCL and TGF‐β in childhood HSP. Twenty‐six Chinese children with the diagnosis of HSP were enrolled. Blood samples from these patients were collected at both acute and convalescent stages. Intracellular staining of lymphocytes was performed to enumerate type 1 (interferon‐gamma‐secreting), type 2 (IL‐4‐secreting), and type 3 (TGF‐β‐secreting) helper T cells. Serum levels of TGF‐β were detected by ELISA. Serum IgA aCL of 21 of 26 patients at the acute stage, 11 of them at the convalescent stage, were measured by ELISA. The data showed that IgA aCL serum levels were significantly elevated in patients compared with healthy controls (P < 0·001), and those patients at the convalescent stage (P < 0·001). In addition, TGF‐β‐secreting T cells were significantly elevated during the acute stage, and decreased at the convalescent stage. Although more studies are needed, the high prevalence of IgA aCL and increased TGF‐β‐secreting T cells in children with acute HSP revealed some points which should permit a better understanding of the pathogenesis of HSP.

Clinical manifestations and outcomes of Henoch-Schönlein purpura: comparison between adults and children.

BACKGROUND Henoch-Schönlein purpura (HSP) primarily affects children, but age at onset is thought to be important in determining disease severity and outcome. This study compared the clinical and laboratory data from children and adults with HSP. METHODS This retrospective 5-year study enrolled 65 children and 22 adult HSP patients attending a medical center. RESULTS Gross hematuria and lower-extremity edema were significantly more frequent in adults (p < 0.05). All the children developed renal involvement within 2 weeks, while 67% of the adult patients developed hematuria by the fifth week of disease onset. Elevated white blood cell count and increased erythrocyte sedimentation rate were significantly more common in children (p < 0.05). Adults had a higher frequency of renal involvement (p < 0.05), though this was also present in 14 children (21.54%), 12 with isolated hematuria and proteinuria and two with nephrotic syndrome. All the children maintained normal renal function. Twelve adults had renal involvement (52.6%), six with progression to renal insufficiency. Patients with abdominal pain at disease onset had a significantly higher probability of developing nephrotic syndrome (p < 0.05). Logistic regression revealed that age >20 years, male, bloody stools, clinical course with relapse of purpuric rash, and persistent rash for >1 month were poor prognostic indicators for HSP nephritis (p < 0.05). CONCLUSIONS HSP nephritis in adults had a higher risk of progression to renal insufficiency. More aggressive treatment and extended follow-up with repeated urinalysis for at least 6 weeks were often necessary, especially in older patients.

The level of IgA antibodies to human umbilical vein endothelial cells can be enhanced by TNF-α treatment in children with Henoch–Schönlein purpura

Anti‐endothelial cell antibodies (AECA) have been found to play an important role in many vascular disorders. In order to determine the presence of AECA in children with Henoch–Schönlein purpura (HSP), and to elucidate the pathogenic and clinical value of their measurement in this disease, AECA were detected by immunofluorescence staining and a human umbilical vein endothelial cell (HUVEC)‐based enzyme‐linked immunosorbent assay (ELISA) in 20 children with HSP, 10 children with juvenile rheumatoid arthritis (JRA) without vasculitis and 10 normal healthy children. Antibodies against another endothelial cells, human dermal microvascular endothelial cells (HMVEC‐d) were also detected by cell‐based ELISA. In some experiments, we compared the binding activity of antibodies to HUVEC with and without tumour necrosis factor‐α (TNF‐α) or interleukin‐1 (IL‐1) pretreatment. Patients with acute onset of HSP had higher serum levels of IgA antibodies, both against HUVEC and against HMVEC‐d, than healthy controls (P = 0·001, P = 0·008, respectively). Forty‐five per cent of patients had positive IgA AECA to HUVEC, and 35% had positive IgA AECA to HMVEC‐d. The titres of IgA antibodies to HUVEC paralleled the disease activity. After TNF‐α treatment, the values of IgA AECA to HUVEC in HSP patients were significantly increased (P = 0·02). For IgG and IgM AECA, there was no difference between HSP patients and controls (P = 0·51, P = 0·91). Ten JRA children without vasculitis had no detectable IgG, IgM or IgA AECA activity. The results of this study showed that children with HSP had IgA AECA, which were enhanced by TNF‐α treatment. Although the role of these antibodies is not clear, IgA AECA provide another immunological clue for the understanding of HSP.