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Chronic synovitis is a serious complication of haemophilia that should be understood to avoid or minimize its consequences (articular damage and joint degeneration). Haematological prophylaxis and treatment are paramount during the life of people with haemophilia. However, as about 80% of bleedings in haemophilia affect the musculo-skeletal system, the role of orthopaedic surgeons, rehabilitation physicians and physiotherapists is very important in the context of the multidisciplinary team. Synovitis can firstly be prevented and/or controlled with medical treatment and then be treated by synoviorthesis or surgical synovectomy. In this article, the author reviews some current basic principles on the prevention and treatment of haemophilic synovitis to avoid further development of joint destruction (haemophilic arthropathy).

A study of major joint outcomes, specifically range of motion and synovitis, was conducted with data from a subset of adolescents enrolled in the prospective Hemophilia Growth and Development Study (HGDS). Clinical observations were carried out over a 7-year period from 1989 to 1996. A secondary aim was to gain insight into factors that might influence decisions regarding maintaining or discontinuing prophylaxis during early adulthood. Twenty-nine participants (median age 17.4 at entry) were included. Median follow-up was 7 years (range: 4.8-7.7). Range of motion (ROM) and synovitis in six major joints (knees, elbows and ankles), were evaluated by physical examination every 6-12 months. At the baseline observation, 73.6% of joints showed no ROM abnormalities or synovitis, and all joints were normal in 11 patients. Of the 11 participants, 54.5% developed abnormalities and 28.1% of normal joints at baseline became abnormal during the follow-up. Ankles were the most severely affected and had persistent progression during late adolescence and adulthood. Elbows and knees did not show progression after the first few years of the follow-up. The progression of haemophilic arthropathy in adolescents and young adults varies from individual to individual and also in the site of affected joints. In view of this, the decision regarding discontinuation of prophylaxis in patients with haemophilia should be individualized.

Objective: To determine the outcome after 52 weeks of early intervention with intraarticular corticosteroid injections followed by sulfasalazine versus conservative therapy in patients with recent-onset oligoarthritis in a randomized controlled trial., Methods: Patients with

Objective: Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease involving the breakdown of cartilage and juxta-articular bone, which is often accompanied by decreased bone mineral density (BMD) and increased risk of fracture. Anti-inflammatory omega-3 fatty acids may prevent arthritis and bone loss in MRL/lpr mice model of arthritis and in humans., Methods: In this study, the effect of long term feeding of 10% dietary n-3 (fish oil (FO)) and n-6 (corn oil (CO)) fatty acids begun at 6 weeks of age on bone mineral density (BMD) in different bone regions in an MRL/lpr female mouse model of RA was measured at 6, 9, and 12 months of age by dual energy x-ray absorptiometry (DEXA). After sacrificing the mice at 12 months of age, antioxidant enzyme activities were measured in spleen, mRNA for receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG) was measured by RT-PCR in lymph nodes, and synovitis was measured in leg joints., Results: At 6, 9 and 12 months of age, BMD was significantly higher (p < 0.05) in distal femur, proximal tibia, and lumbar spine of FO fed mice than those of CO fed mice. Spleen catalase (CAT) and superoxide dismutase (SOD) activities were also significantly higher (p < 0.01) in FO fed mice than in CO fed mice. Histology of knee joints revealed mild synovitis in CO fed mice, which was not present in FO fed mice. RT-PCR analysis of lymph nodes revealed decreased RANKL mRNA (p < 0.001) expression and enhanced OPG mRNA expression (p < 0.01) in FO fed mice compared to CO fed mice., Conclusions: These results suggest beneficial effects of long-term FO feeding in maintaining higher BMD and lower synovitis in this mouse model. These beneficial effects may be due, in part, to increased activity of antioxidant enzymes, decreased expression of RANKL, and increased expression of OPG in FO fed mice thereby altering the RANKL/OPG ratio. These significant beneficial effects on BMD suggest that FO may serve as an effective dietary supplement to prevent BMD loss in patients with RA.

Purpose: To evaluate the results for patients treated arthroscopically for anterolateral soft tissue impingement syndrome, to determine the factors affecting the outcome, and to report on a synovial shelf., Type of Study: Retrospective clinical review., Methods: Forty-one patients underwent operative arthroscopy for anterolateral impingement of the ankle between 1990 and 2001; the mean follow-up was 83.7 months (range, 21 to 152 months). There were 25 men and 16 women with an average age of 33.2 years (range, 15 to 63 years). All patients reported a history of inversion injury to the ankle. The most frequent preoperative complaints were tenderness localized to the anterolateral aspect of the ankle, swelling, crepitation, and pain at weight-bearing. All patients had failed to respond to at least 3 months of conservative treatment. The results were assessed according to Meislin's criteria and the American Orthopaedics Foot and Ankle Society (AOFAS) scoring table. For statistical analysis, the Mann-Whitney U test was used where appropriate and the significance was set at P < .005., Results: According to Meislin's criteria, there were excellent results in 21 patients, good in 16, fair in 2, and poor in 2. The mean AOFAS score was 89.6 points (range, 60-100) at follow-up. Four different soft tissue pathologies causing impingement were described. It has been statistically shown that cartilage damage located at the anterolateral region of the ankle and not advanced to the subchondral bone, and repeated inversion injuries had negative effects on clinical results at long-term follow-up., Conclusions: The arthroscopic diagnosis and treatment of anterolateral soft tissue impingement is a safe and effective method. Any combination of associated intra-articular pathologies, such as a chondral lesion or a new inversion injury of the ankle, after the arthroscopic procedure resulted in a poor outcome., Level of Evidence: Level IV, Therapeutic Study.

Objective: To examine the therapeutic efficacy of N-acetylglucosamine (GlcNAc) in rabbits with experimental osteoarthritis (OA)., Methods: Experimental OA was induced in rabbits by anterior cruciate ligament transection (ACLT). In the first study, rabbits (six in each group) received intramuscular injections of GlcNAc or normal saline three times a week starting 1 week postoperatively. In the second study, rabbits (eight in each group) were injected intra-articularly with GlcNAc (either once or twice a week) or normal saline. In the third study, rabbits (seven in each group) were injected intra-articularly twice a week with either GlcNAc, hyaluronan, or normal saline. Animals were killed 8 weeks after ACLT for macroscopic and histological assessment of the knee joints., Results: Intramuscular administration of GlcNAc in rabbits with experimental knee OA did not show chondroprotective effects but showed mild anti-inflammatory activity. In contrast, intra-articular administration of GlcNAc twice a week reduced cartilage degradation. Additionally, intra-articular GlcNAc also suppressed synovitis. Once a week intra-articular injections of GlcNAc did not demonstrate therapeutic efficacy. The chondroprotective efficacy of GlcNAc was better than that of viscosupplementation treatment with hyaluronan., Conclusion: Intra-articular GlcNAc has chondroprotective and anti-inflammatory activity in experimental OA.

Bleeding into the joints is the most common manifestation of severe haemophiliacs. Although it may resolve spontaneously or with treatment, some patients find that one particular joint has recurrent bleeding; this is termed a target joint. Recurrent bleeding prevents the joint from regaining its range of motion, muscle strength and normal appearance. These changes become permanent, leading eventually to osteoarthritis. A target joint requires urgent and comprehensive treatment, especially in young patients, if permanent damage is to be prevented. Treatment with factor concentrate prophylaxis and physiotherapy can help to prevent new bleeds and allow the synovitis to resolve, but for persistent synovitis, synovectomy is recommended. The target ankle joint is a special challenge as it often develops in very young children when the articular cartilage is susceptible and compliance with conservative treatment is difficult.

The aim of the current study was to investigate the effect of inhibition of nitric oxide (NO) production after injury on inflammatory cell accumulation and fibrosis around digital flexor tendon and synovium. A standard crush injury was applied to the flexor tendons of the middle digit of the hindpaw and the overlying muscle and synovium of female Wistar rats. Thirty animals received an intraperitoneal injection of either isotonic saline or N(G)-nitro-l-arginine methyl ester (L-NAME; 5 mg/kg) immediately following the crush injury, and five animals were then sacrificed at various intervals and the paws processed for histology. Another group of five animals was sacrificed after 3 days for nitrite determinations. The results showed that nitrite production and hence NO synthase activity is doubled at the acute phase of tendon wound healing, and we can prevent this by administering a single dose of L-NAME immediately after injury. The incidence and severity of fibrocellular adhesions between tendon and synovium was much more marked in animals treated with L-NAME. Treatment with L-NAME elicited a chronic inflammatory response characterised by a persistent and extraordinarily severe accumulation of large numbers of inflammatory cells in the subcutaneous tissues, in muscle and in tendon. These findings indicate that in the case of injured tendon and synovium, NO could act to protect the healing tissue from an uncontrolled inflammatory response.

We evaluated the therapeutic effect of secretory phospholipase A2 (sPLA2)-inhibitory peptide at a cellular level on joint erosion, cartilage destruction, and synovitis in the human tumor necrosis factor (TNF) transgenic mouse model of arthritis. Tg197 mice (N = 18) or wild-type (N = 10) mice at 4 weeks of age were given intraperitoneal doses (7.5 mg/kg) of a selective sPLA2 inhibitory peptide, P-NT.II, or a scrambled P-NT.II (negative control), three times a week for 4 weeks. Untreated Tg197 mice (N = 10) were included as controls. Pathogenesis was monitored weekly for 4 weeks by use of an arthritis score and histologic examinations. Histopathologic analysis revealed a significant reduction after P-NT.II treatment in synovitis, bone erosion, and cartilage destruction in particular. Conspicuous ultrastructural alterations seen in articular chondrocytes (vacuolated cytoplasm and loss of nuclei) and synoviocytes (disintegrating nuclei and vacuoles, synovial adhesions) of untreated or scrambled-P-NT.II-treated Tg197 mice were absent in the P-NT.II-treated Tg197 group. Histologic scoring and ultrastructural evidence suggest that the chondrocyte appears to be the target cell mainly protected by the peptide during arthritis progression in the TNF transgenic mouse model. This is the first time ultrastructural evaluation of this model has been presented. High levels of circulating sPLA2 detected in untreated Tg197 mice at age 8 weeks of age were reduced to basal levels by the peptide treatment. Attenuation of lipopolysaccharide- and TNF-induced release of prostaglandin E2 from cultured macrophage cells by P-NT.II suggests that the peptide may influence the prostaglandin-mediated inflammatory response in rheumatoid arthritis by limiting the bioavailability of arachidonic acid through sPLA2 inhibition.

Twenty-four healthy, mixed-breed hound-type dogs were evenly and randomly assigned to a placebo control group, one of four dosages of deracoxib (0.3, 1, 3, or 10 mg/kg), or carprofen (2.2 mg/kg). Oral dosing of placebo, carprofen, or deracoxib was done 30 minutes before intraarticular injection of urate crystal suspension for induction of synovitis. Ground reaction forces, subjective clinical lameness scores, pain, joint effusion, and quantitative pain threshold responses were measured in a blinded fashion before induction of synovitis and 2, 4, 6, 8, 12, and 24 hours after injection. The medium and high dosages of deracoxib were effective in preventing lameness and pain associated with synovitis. Carprofen was also somewhat effective in attenuating the severity of urate-induced synovitis but to a lesser degree than the medium dose of deracoxib. Preemptive deracoxib treatment at dosages as low as 1 mg/kg reduced lameness and pain of synovitis associated with intraarticular administration of urate crystals.

There are currently unprecedented opportunities to treat rheumatoid arthritis using well-designed, highly effective, targeted therapies. This will result in a substantial improvement in the outcome of this disorder for most affected individuals, if they can afford these therapies. Yet our lack of understanding of the basic mechanisms that initiate and sustain this disease remains a major obstacle in the search for a definitive cure. It is possible, if not likely, that our best approach will be to identify individuals at risk and devise reliable, safe methods of preventing the disease before it occurs. The means to do this are currently unknown but should serve as a major focus of research.

Objective: Joint protection aims to reduce pain and local inflammation, preserve the integrity of joint structures and improve function. There is evidence that it can improve pain and function in the short term, but the long-term effects are uncertain. This study evaluated the effects of joint protection in early rheumatoid arthritis (RA)., Methods: A randomized, controlled, assessor-blinded trial of duration 1 yr was conducted. Two interventions (both 8 h) were compared: standard arthritis education, including 2.5 h of joint protection education based on typical UK practice; and a joint protection arthritis education programme, using educational-behavioural teaching methods. Assessments were made at entry and 6 and 12 months., Results: Sixty-five people with RA attended the joint protection programme and 62 the standard programme. The groups were matched for age (51 and 49 yr), disease duration (21 and 17.5 months) and use of non-steroidal anti-inflammatory drugs and disease-modifying anti-rheumatic drugs. In comparison with the standard group, the joint protection group significantly improved with respect to adherence to the joint protection programme (P=0.001), hand pain (P=0.02), general pain (P=0.05), early morning stiffness (P=0.01), self-reported number of disease flare-ups (P=0.004), visits to the doctor for arthritis (P<0.01), and the AIMS2 (Arthritis Impact Measurement Scales) activities of daily living scale (P=0.04). A trend to improved swollen joint counts was identified (P=0.07). Within-group analyses also showed improvements in arthritis self-efficacy and perceived control. Hand deformity scores continued to increase in both groups., Conclusion: We found significant improvements in adherence, pain, disease status and functional ability amongst those attending the joint protection programme. Benefits became more apparent with time, suggesting that joint protection can help slow the progression of the effects of RA over and above the effects of drug therapy.

Objective: Anti-tumor necrosis factor a (anti-TNFalpha) therapy has shown efficacy in the treatment of rheumatoid arthritis (RA). Since interleukin-1 (IL-1), TNFalpha, and IL-17 have many additive and/or synergistic effects in vitro, we tested whether their combined inhibition by soluble receptors would lead to an enhanced effect on ex vivo models of synovial inflammation and bone destruction., Methods: RA synovium and bone explants were cultured for 7 days in the presence of 1 microg/ml soluble TNFalpha receptor (STNFR; as in current therapy), type II soluble IL-1 receptor (sIL-1RII), or sIL-17R either alone or in combination. Their effects on the production of IL-6 and the release of C-telopeptide of type I collagen (CTX), a marker of type I collagen destruction, were measured by enzyme-linked immunosorbent assay., Results: In synovium, each soluble receptor alone decreased IL-6 production and CTX release by approximately 35% and approximately 55%, respectively. The combination of all 3 receptors was more effective, inhibiting IL-6 production and collagen degradation by up to 70%. Neither sIL-17R, sIL-1RII, or sTNFR alone had no effect (or an effect of <20% inhibition) on IL-6 production in 18%, 33%, and 22%, respectively, of the samples. In bone, sIL-17R, sIL-1RII, and sTNFR decreased IL-6 production by 23%, 50%, and 37%, respectively, while the combination decreased IL-6 production by 75%. A 50% inhibition of CTX release was obtained with sIL-1RII for 63% of the samples versus 38% of the samples with either sTNFR or sIL-17R. However, the combination of all 3 receptors was not more potent than sIL-1RII alone., Conclusion: The inhibitory effect of sTNFR on IL-6 production and collagen degradation in RA synovium and bone was increased in combination with sIL-17R and sIL-1RII. These results support the concept of combination therapy, which may increase the percentage of responding patients as well as the degree of individual patient response.

Unlabelled: Inflammation and hyperalgesia during surgical procedures are caused by the local release of multiple inflammatory mediators. We used a rat knee joint model of acute inflammation (synovial plasma extravasation) to determine whether preemptive intraarticular irrigation of the antiinflammatory drugs ketoprofen, amitriptyline, or oxymetazoline, alone or in combination, can reduce inflammatory soup-induced plasma extravasation. These three drugs were selected because of their abilities to collectively inhibit the inflammatory effects of biogenic amines, eicosanoid production, and the release of neuropeptides from C-fiber terminals. Synovial perfusion of each one of the three drugs 10 min before, and then in combination with, the inflammatory soup (bradykinin, 5-hydroxytryptamine, and mustard oil) did not reduce plasma extravasation. Similarly, two-drug combinations did not significantly reduce inflammatory soup-induced plasma extravasation. The combination of all three drugs (amitriptyline, ketoprofen, and oxymetazoline) produced a dramatic inhibition of plasma extravasation and was more effective than any of the two-drug combinations. A comparison between the preemptive (10 min before inflammatory soup perfusion) and postinflammatory administration (10 min after inflammatory soup perfusion) showed that the postinflammatory administration of the three-drug solution lost all ability to inhibit inflammatory soup-induced plasma extravasation. We conclude that acute synovial inflammation, which is induced and maintained by multiple mediators, can be substantially inhibited only by the preemptive administration of a drug combination that targets multiple inflammatory mediators., Implications: Preemptive, intraarticular irrigation of a combination of multiple antiinflammatory drugs is a novel and potentially effective method for reducing the synovial inflammatory response, such as that during arthroscopy. In this study, a three-drug combination infusion was statistically superior to one- or two-drug infusions in a rat model.

The effects of chondroitin sulfate-C (CAS 25322-46-7, Chondroitin ZS Tab) on type II collagen (CII)-induced arthritis (CIA) in mice were evaluated. DBA/1J mice were immunized with bovine CII emulsified in Freund's complete adjuvant, followed by a booster injection 21 days later. Chondroitin sulfate-C at doses of 100, 300 and 1000 mg/kg was administered orally once daily beginning 14 days before initial immunization. An arthritis index and hind paw edema were examined from day 0 to day 49, when the mice were killed by ether anesthesia for histopathological examination. The delayed-type hypersensitivity (DTH) reaction, serum anti-CII antibody titer, and histopathologic characteristics of both synovitis and destruction of articular cartilage were analyzed. Both the arthritis index and the serum anti-CII antibody titer were reduced by treatment with chondroitin sulfate-C in a dose-dependent manner. Chondroitin sulfate-C (1000 mg/kg) significantly inhibited hind paw edema, synovitis and destruction of the articular cartilage, but not DTH reaction.

Objective: Annexin I is an endogenous antiinflammatory mediator, expressed in rheumatoid arthritis (RA) synovium, the contribution of which to autoregulation of the synovial inflammatory response has not been examined in models of RA. We investigated the antiinflammatory role of annexin I in rat adjuvant arthritis., Methods: Rats with adjuvant-induced arthritis (AIA) were treated with a specific anti-annexin I monoclonal antibody (mAb), isotype control IgG, and/or dexamethasone. Clinical outcomes and synovial synthesis of tumor necrosis factor alpha (TNFalpha), prostaglandin E2 (PGE2), and nitric oxide were examined, and annexin I expression was assessed by flow cytometry and reverse transcription-polymerase chain reaction., Results: Anti-annexin I mAb reversed the effects of dexamethasone on the clinical features of AIA and exacerbated AIA in the absence of exogenous glucocorticoid. Clinical exacerbation of AIA by anti-annexin I mAb was accompanied by significantly increased synovial TNFalpha and PGE2, suggesting that annexin I tonically inhibits the production of these mediators. Anti-annexin I mAb treatment was associated with significantly reduced leukocyte intracellular annexin I, despite increased annexin I messenger RNA expression, consistent with a depletion effect of extracellular mAb via the cell surface., Conclusion: Annexin I is a key endogenous inhibitory mediator of arthritis via mechanisms that include inhibition of cytokine and effector molecule production. Moreover, a synthesis-independent depletion of intracellular annexin I by extracellular antibody supports the hypothesis that externalization of annexin I is involved in its mode of action.

Background: Oils enriched in gammalinolenic acid, an unsaturated fatty acid, reduce joint pain and swelling in patients with rheumatoid arthritis. The cytokines interleukin-1 beta and tumor necrosis factor-alpha appear to contribute directly to joint tissue damage in patients with rheumatoid arthritis. Agents designed to interfere with the actions of interleukin-1 beta and tumor necrosis factor-alpha are being used to treat rheumatoid arthritis., Methods: We examined the influence of gammalinolenic acid added to cells in vitro and administered orally in vivo on interleukin-1 beta and tumor necrosis factor-alpha secretion from activated human peripheral blood monocytes. Secretion of both cytokines was reduced by gammalinolenic acid. Administration of safflower oil as a polyunsaturated fatty acid control devoid of gammalinolenic acid did not change secretion of either cytokine., Conclusion: Suppression of IL-beta and TNF-alpha secretion by activated cells may be one mechanism whereby gammalinolenic acid suppresses synovitis in patients with rheumatoid arthritis.

Intraarticular bleeding and muscle bleeding occur spontaneously or as a result of trauma in hemophilia A or B. The most common sites for hemarthrosis are the knees joints, elbows and ankles joints. Resorption of intraarticular blood induces reactive hemophilic synovitis Hyperplasia of the synovium can be followed by recurrent bleedings. These early reactions can change to a chronic synovitis and cause cartilage damage, finally resulting in a complete destruction of the joint. Since 1981 158 adults and 61 children with a hemophilia A or B were treated at the Center for hemophilic disorders Frankfurt in an interdisciplinary approach. Consequent prophylactic treatment with factor substitution can prevent the incidence of severe hemarthrosis. Minor joint bleedings are treated by adequate factor substitution, temporarily non-weight bearing of the extremity, application of ice-packs and physical therapy. More severe joint hemorrhages should be aspirated in order to reduce the acute synovitis. This is followed by a consequent physical therapy (joint and soft tissue techniques) and anti-inflammatory drugs. The goal is a sufficient muscular balance of the joint, the improvement of the coordination, and the proprioception. The chronic synovitis is less painful and poorly responses to conservative interventions. Local ice application, systemic and local anti-inflammatory treatment support the physical therapy. Soft heel shock absorber, elastic and semi-rigid bandages prevent recurrent bleeding episodes by shock absorption and decrease of synovial impingement. Synovectomy is indicated in cases of chronic persistent synovitis. Radiosynoviorthesis (RSO), which is an alternative in certain cases, has been performed with great success in 12 cases in our hospital. In advanced arthropathy joint mobilization should be the emphasis of the physical therapy. Bandages, crutches and ortopaedic shoe devices improve the walking capacity.

A 7- to 9-month protocol of prophylactic transfusion was used to treat 33 joints in 19 children with severe hemophilia (< 1 U/dL Factors VIII or IX) and hypertrophic synovitis. The overall rate of hemarthrosis was reduced, but only 36% (12 of 33 joints) achieved a good result (defined as 0-0.5 bleeding episodes per month and decreased synovial hypertrophy 1 year after completing treatment). Age and severity of arthropathy at initiation of treatment did not affect the result. The degree of synovial hypertrophy and involvement of the knee joint showed an adverse trend, but these factors did not achieve statistical significance. The number of episodes of breakthrough bleeding during the first 6 weeks of therapy was significantly associated with a poor result. Based on the results of this study, a trial of transfusion therapy is recommended for recurrent hemarthroses and synovitis in patients with hemophilia, but the duration of thrice weekly treatment has been increased and the duration of prophylaxis has been reduced in selected cases.

The knee joint is the most frequently affected articulation in patients suffering from hemophilia. Before the availability of active coagulation factors, orthotic use was aimed at corrective functions. Orthotics in the modern era play a protective and preventative role, and they are used in the treatment of hemarthroses and in joints affected by chronic synovitis. Because levels of availability of clotting factors and orthotic material vary extensively world-wide, an overview is provided whereby each group of therapists can adapt themselves to the principles.

A prospective study from 1974 to 1996 was done to determine optimal treatment for chronic hemophilic synovitis of the knee and synovitis of the elbow. Sixty-five patients with synovitis affecting 65 knee joints and 40 patients who had synovitis of the elbow (44 elbows), despite a 3-month trial of prophylactic substitution therapy, were treated by synovectomy. Radiation synovectomies (Au-198 synoviorthesis) were done on 38 knees, open surgical synovectomy on 18, and nine had an arthroscopic procedure. Radioactive gold synoviorthesis was performed on 29 elbows, and 15 had a resection of the radial head and partial open synovectomy. Synovectomy (by any method) significantly reduced bleeding episodes, but did not halt the radiographic deterioration of the joints. It is thought that radiation synovectomy is the best choice for patients with persistent synovitis of the knee and synovitis of the elbow unresponsive to a 3-month trial of prophylactic factor replacement. If two to three consecutive synoviortheses with 3 to 6 months intervals had been ineffective, or when the radiographic score is more than two points, an open synovectomy is indicated.

The most common clinical manifestation of hemophilia is intraarticular bleeding (hemarthrosis). Although any joint can be involved, the articulations most frequently affected are the knees, elbows, and ankles. Hemorrhages may occur spontaneously, or as a result of trauma. Because hemophilia is a genetically determined coagulation disorder, the bleeding incidences may start early in a child's life. After several hemarthroses, hemophilic synovitis will develop and, because of the profusion and fragility of vessels within the tissue, will lead to a vicious cycle of bleeding-synovitis-bleeding. If the synovitis is not controlled, cartilage damage will occur. hemophilic arthropathy then will become apparent clinically and radiographically, causing functional impairment of the affected joint. Prophylaxis and early diagnosis of acute hemarthrosis are essential to prevent the development of hemophilic synovitis. Hemarthroses must be treated aggressively if hemophilic synovitis is to be prevented. Continuous prophylaxis from age 2 to 18 years has been claimed to reduce the incidence of chronic hemophilic synovitis and joint damage, which remain the main causes of disability in the life of the patient who has hemophilia.

Acute hemarthroses are probably the most frequent type of bleeding in the patient with hemophilia. Delayed and/or inadequate treatment can trigger a series of pathologic changes within the joint leading to a painful and disabling arthropathy. Despite the advent of prophylactic treatment with factor concentrates, the majority of patients in the world have no access to even on demand factor replacement. Care for all patients involves a team approach led by the hematologist but including input from orthopaedic surgeons and physiotherapists. Optimal treatment involves a combination of factor replacement, rest, ice, and supervised rehabilitation. In certain cases, joint aspiration may be considered. In developing countries, where factor concentrates are in short supply, such bleeding episodes usually are treated by physical means alone or with the addition of cryoprecipitate or fresh frozen plasma. After successful resolution of such episodes by whatever means, the events leading to the bleeding episode and its subsequent management should be considered within the setting of the treating unit. Such debriefings should aim to provide counsel regarding any appropriate lifestyle modifications and, where necessary, treatment should be arranged to minimize the risk of additional episodes.

The IFN regulatory factor-1 (IRF-1) DNA binding protein regulates expression of genes that are involved with the induction of immune and inflammatory responses. The present study used mice with a targeted disruption of the IFN regulatory factor-1 gene (IRF-1-/-) to examine the role of this transcription factor in synovial inflammation and nitric oxide production. Intraarticular injection of IL-1 or LPS was associated with a significantly reduced intensity of synovial lining hyperplasia and leukocyte infiltration in the IRF-1-/- mice as compared with wild-type mice of the same parental lineage C57BL/6. Nitric oxide (NO) is involved with the pathogenesis of arthritis, and IRF-1 regulates expression of inducible NO synthase (iNOS) in mononuclear phagocytes. Articular chondrocytes from IRF-1-/- mice produced similar levels of NO in response to IL-1 or LPS. Furthermore, the synergistic induction of NO by IFN-gamma and IL-1 or LPS was almost identical in chondrocytes from wild-type and IRF-1-/- mice. This was in contrast to the expected decrease in NO production by peritoneal macrophages from IRF-1-/- mice, suggesting that IRF-1 is not required for iNOS expression in chondrocytes. These results indicate that IRF-1 has a tissue-specific role in the induction of iNOS. Inhibition of this transcription factor may represent a novel approach in controlling inflammatory diseases such as arthritis.

Hemophilia is a hereditary lifelong bleeding disorder affecting males. The nature of the condition predisposes the person to bleed intraarticularly and intermuscularly. Without intervention with replacement factor therapy and physiotherapy, the consequences can lead to chronic synovitis and severe joint hemarthropathy. Physiotherapeutic interventions are available that may help to prevent and treat the sequelae of recurrent hemarthrosis. No particular method of treatment has been shown to eradicate hemorrhages; however, there are protocols that can help. The use of physiotherapy techniques including electrotherapy, joint care, and exercise are extremely important, especially in developing countries where blood products are scarce.

The ankle is the second most affected joint in hemophilia. Recurrent bleeding leads to chronic synovitis. Prevention of chronic synovitis should start with prophylactic replacement therapy or on demand treatment of recurrent hemarthrosis. Attention must be given to the function of the ankle joint. When instability is present, an extensive range of exercises is important. An orthotic or shoe adaption may be useful during the rehabilitation process. Viscoheels worn in shoes seem to reduce the bleeding frequency and pain.

The aim of our study was to assess local anti-inflammatory effects of high dose immunoglobulin G (IgG) in rheumatoid arthritis (RA). Eleven patients with definite RA, having flare-up of knee joint synovitis, were included in the study. Six received an intra-articular injection of 1 g of IgG in 10 ml saline and five received an intra-articular injection of 10 ml physiological saline alone. The effect of the treatment was evaluated clinically and by magnetic resonance imaging using gadolinium contrast enhancement. In one of the six patients that received intra-articular IgG and one of the five patients that received physiologic saline a modest decrease of synovial hypertrophy was noted. None of the patients experienced clinical signs of increased joint inflammation as a consequence of the treatment procedures. The results of this pilot, double-blind, placebo-controlled study do not support local administration of IgG as an anti-inflammatory treatment in patients with RA.

The effect of temporary inflammatory suppression on synovial membrane enhancement, as determined by dynamic and static gadolinium-DTPA enhanced magnetic resonance imaging (MRI), was studied. MRI of 18 arthritic knees was performed before and 1, 7, 30 and 180 days after intra-articular methylprednisolone injection until clinical relapse. MRI of another six knees was performed twice within 2-4 days in order to assess interobserver and inter-MRI variation. The rate of early enhancement of the entire synovial membrane of a pre-selected central sagittal slice (REEsyn,tot), determined by dynamic T1-weighted FLASH MRI, decreased in all knees within the first post-treatment week and remained low during remission, although gradually increasing. In cases of clinical relapse, REEsyn,tot increased to pre-treatment levels. The interobserver plus inter-MRI variation was maximally 27%. The predictive values of a REEsyn,tot below/above 1.0%/s were 0.94 and 0.91, respectively, with respect to the absence/presence of clinical synovitis. Evaluation of small synovial areas revealed marked regional heterogeneity. Static spin echo MRI was not informative. The study indicates that the rate of early synovial enhancement reflects synovial inflammatory activity. Subclinical changes may be revealed. Evaluation of large synovial areas increases reproducibility and reduces the effect of regional heterogeneity. Dynamic MRI may prove a clinically useful measure of synovial inflammation.

Objective: To study the effect of chimeric anti-CD4 monoclonal antibody (MAb) therapy on synovial inflammation, in order to interpret the clinical experience with anti-CD4 treatment., Methods: The immunohistologic features of synovial biopsy specimens before and 4 weeks after anti-CD4 MAb (cM-T412) therapy were studied in patients with rheumatoid arthritis. The patients received intravenous doses of either placebo (n = 1) or 10 mg (n = 4), 25 mg (n = 2), or 50 mg (n = 1) of cM-T412 daily for 5 consecutive days., Results: Although the patients did not experience clinical improvement, significant decreases in the number of circulating CD4+ cells, the degree of synovial inflammatory infiltration, and the mean scores for expression of adhesion molecules were found in the 7 patients 4 weeks after receiving cM-T412. The scores for infiltration with CD4+ and other inflammatory cells were particularly reduced following treatment with either 25 mg or 50 mg cM-T412. Cytokines, such as interleukin-1 beta and tumor necrosis factor alpha, could still be detected in the synovial tissue after treatment., Conclusion: The decline in the numbers of inflammatory cells and adhesion molecules in synovial tissue after CD4+ cell depletion supports the view that CD4+ T cells orchestrate local cellular infiltration. The lack of clinical effect of anti-CD4 therapy might be explained by an insufficient decrease in the number of synovial CD4+ cells and by the persistence of cytokines. Determination of whether more adequate dosing would lead to a clinical improvement must await further study.

Activated components of the complement system are potent mediators of inflammation that may play an important role in numerous disease states. For example, they have been implicated in the pathogenesis of inflammatory joint diseases including rheumatoid arthritis (RA). To target complement activation in immune-mediated joint inflammation, we have utilized monoclonal antibodies (mAbs) that inhibit the complement cascade at C5, blocking the generation of the major chemotactic and proinflammatory factors C5a and C5b-9. In this study, we demonstrate the efficacy of a mAb specific for murine C5 in the treatment of collagen-induced arthritis, an animal model for RA. We show that systemic administration of the anti-C5 mAb effectively inhibits terminal complement activation in vivo and prevents the onset of arthritis in immunized animals. Most important, anti-C5 mAb treatment is also highly effective in ameliorating established disease. These results demonstrate a critical role for activated terminal complement components not only in the induction but also in the progression of collagen-induced arthritis and suggest that C5 may be an attractive therapeutic target in RA.

Purpose: Studies of the efficacy of hydroxychloroquine in rheumatoid arthritis have had methodological flaws and have failed to produce definitive results. The benefits and toxicity of hydroxychloroquine sulfate in 120 patients with rheumatoid arthritis of less than 2 years duration are assessed., Patients and Methods: A 36-week randomized double-blind, placebo-controlled trial was conducted at two university centers and four community rheumatology private practices. Patients had to have had their disease for less than 2 years and to have never received a second-line drug. Patients were randomly assigned to receive hydroxychloroquine or an equivalent number of placebo tablets in a dose of up to 7 mg/kg per day (maximum 400 mg/day). The initial dose was half the maximum dose and, if after 2 weeks of treatment there had been no side effects, the full dose was prescribed. There were four a priori primary outcomes: (1) a joint index composed of the tender joint count, the swollen joint count, the grip strength, and the duration of morning stiffness; (2) a pain index composed of the pain dimension of the Arthritis Impact Measurement Scales (AIMS) and the visual analog pain scale of the Health Assessment Questionnaire (HAQ); (3) a physical function index composed of the HAQ, the physical disability dimension of the AIMS, and the McMaster-Toronto Arthritis Patient Performance Disability Questionnaire; (4) the psychological function subscale of the AIMS. Secondary outcomes included adverse events, patient and physician global assessments, hematocrit, erythrocyte sedimentation rate (ESR) and corticosteroid usage. An intent-to-treat analysis assessed improvement at 36 weeks by Student's t-test and average improvement over the course of the study by analysis of variance for repeated measures., Results: Of 148 eligible patients, 120 were randomized. The characteristics of those randomized to hydroxychloroquine compared to placebo were similar at the study onset. At 36 weeks and over the course of the study there was statistically significant improvement in the joint index (P = 0.004, P = 0.034, respectively), the pain index (P = 0.007, P = 0.001, respectively), and the physical function index (P = 0.020, P = 0.011, respectively) in the group receiving hydroxychloroquine compared to the placebo group. There was no improvement in psychological function for hydroxychloroquine compared to placebo (P = 0.837 at 36 weeks, P = 0.89 over the course of the study). Among the secondary outcomes there was significant improvement only in the patient's (P = 0.01) and the outcome assessor's (P = 0.03) assessment of change and a trend towards a fewer number of intra-articular corticosteroid injections (P = 0.05) in the hydroxychloroquine-treated group. There were no important differences in the side effects between hydroxychloroquine or placebo., Conclusion: Over 36 weeks, hydroxychloroquine had a significant benefit on synovitis, pain, and physical disability of recent-onset rheumatoid arthritis, but did not benefit psychological function.

Chronic haemophilic arthropathy of the knee is a debilitating condition that also carries the risk of rapid degeneration of the articular cartilage of the affected joint. The swelling is a combination of haemarthroses, irritative synovial effusions, synovial thickening and actual epiphyseal overgrowth that is the result of chronic hyperemia. In the knee joint the enlarged appearance is accentuated by quadriceps wasting. Replacement of deficient factor remains the cornerstone of management, followed by splinting in the position of function, synoviorthesis and surgical synovectomy (open or arthroscopic). End stage arthropathy of the knee is the most frequent cause of severe pain and disability in haemophiliacs. Our surgical experience may be divided into five categories: synovectomy, ostectomy, hamstring tenotomy, debridement and prosthetic arthroplasty. Over the last 20 years advanced arthropathy of the knee has been approached with a broad spectrum of procedures with varying success and durability. Early treatment and prevention of chronic synovitis and progressive arthropathy is the key. Where end stage arthropathy does occur and is severely disabling, durable, functional reconstruction with minimal risk must be our goal.

Transforming growth factor beta (TGF-beta) induces leukocyte recruitment and activation, events central to an inflammatory response. In this study, we demonstrate that antagonism of TGF-beta with a neutralizing antibody not only blocks inflammatory cell accumulation, but also tissue pathology in an experimental model of chronic erosive polyarthritis. Intraarticular injection of monoclonal antibody 1D11.16, which inhibits both TGF-beta 1 and TGF-beta 2 bioactivity, into animals receiving an arthropathic dose of bacterial cell walls significantly inhibits arthritis. Inhibition was observed with a single injection of 50 micrograms antibody, and a 1-mg injection blocked acute inflammation > 75% compared with the contralateral joints injected with an irrelevant isotype control antibody (MOPC21) as quantitated by an articular index (AI = 0.93 +/- 0.23 for 1D11.16, and AI = 4.0 +/- 0 on day 4; p < 0.001). Moreover, suppression of the acute arthritis achieved with a single injection of antibody was sustained into the chronic, destructive phase of the disease (on day 18, AI = 0.93 +/- 0.07 vs. AI = 2.6 +/- 0.5; p < 0.01). The decreased inflammatory index associated with anti-TGF-beta treatment was consistent with histopathologic and radiologic evidence of a therapeutic response. These data implicate TGF-beta as a profound agonist not only in the early events responsible for synovial inflammation, but also in the chronicity of streptococcal cell wall fragment-induced inflammation culminating in destructive pathology. Interrupting the cycle of leukocyte recruitment and activation with TGF-beta antagonists may provide a mechanism for resolution of chronic destructive lesions.

Intradermal immunization of female Lewis rats with 100 micrograms of a nine-amino acid synthetic peptide corresponding to the arthritic T cell-reactive epitope of mycobacterial heat shock protein, three weeks prior to induction of adjuvant arthritis, produced inhibition of day 16 ankle swelling and histologic score. Intraarticular injection of 10 micrograms of bovine articular cartilage proteoglycan monomer emulsified in heavy mineral oil into normal Lewis rat stifle joints produced several hallmarks of chronic synovitis at day 16. Pre-treatment with nonapeptide did not inhibit proteoglycan-induced synovitis. These results indicate that tolerance to the critical epitope of heat shock protein does not abrogate the ability of proteoglycan to induce synovitis in rats.

Intra-articular injection of interleukin-1 (IL-1) into the knee joints of rabbits produces a synovitis associated with the loss of proteoglycan from the matrix of articular cartilage. This experimental finding supports the hypothesis that IL-1 is a possible mediator of the pathology of inflammatory joint diseases and suggests that antagonism of IL-1 could offer a therapeutic approach to these diseases. It has recently been reported that culture of human monocytes on adherent IgG stimulates these cells to synthesize a specific inhibitor of IL-1 bioactivity (IL-1ra) that acts as a receptor antagonist with lymphocytes and mesenchymal cells. We have now shown that intravenous injection of IL-1ra into rabbits given an intra-articular injection of recombinant IL-1 beta not only inhibits the entry of leukocytes into the synovial lining and joint cavity but blocks the ability of IL-1 to cause loss of proteoglycan from articular cartilage. This ability of IL-1ra to inhibit IL-1-induced arthritis in the rabbit reveals that this protein has appropriate pharmacokinetic and pharmacodynamic properties and further strengthens the belief that it may be a useful therapeutic agent.

We investigated the effect of cyclosporin A, an inhibitor of T helper/inducer lymphocyte activation, on the development of streptococcal cell wall-induced arthritis and hepatic granulomas in female LEW/N rats. Continuous daily treatment with cyclosporin A, begun either 24 hours before or 7-12 days after streptococcal cell wall administration and continued for 6 weeks, resulted in significant inhibition of the chronic proliferative, erosive synovitis and total inhibition of hepatic granuloma formation. When cyclosporin A was stopped at 6 weeks, its effects continued for at least another 5 weeks, demonstrating long-term benefit without continued administration of the drug. In contrast, therapy given only during the acute phases of the experimental disease (days 1-12) did not inhibit the development of chronic disease. Cyclosporin A had no apparent effects on streptococcal cell wall antigen distribution or persistence in tissues. These data provide additional evidence of an important role for the T helper/inducer lymphocyte in the experimental model and suggest that cyclosporin A may be a useful probe in defining molecular and cellular processes involved in chronic proliferative and erosive synovitis.

There is considerable clinical and both in vivo and in vitro experimental evidence that toxic oxygen radicals contribute to the development of tissue injury associated with the inflammatory response. There is also strong evidence that cell injury caused by activation of phagocytic cells is iron dependent. Several of the clinical studies and in vivo and in vitro experimental models supporting these conclusions and suggesting mechanisms through which iron may participate in inflammation are discussed.

The author applied a continuous cooling (for 72 hours) in 40 patients after operations on the knee joint. A favourable effect has been noted. The author concludes that the local hypothermia lessens the inflammatory process activity in the joint.

Haemophilia is a congenital, life-long disorder that may cause major disabilities. The goal of comprehensive care is to prevent problems when possible, to treat early in order to minimize morbidity, and to restore function to disabled patients. The co-ordinated efforts of many experts are needed for success.

The suppression of the immediate postmeniscectomy synovial reaction by a potent prostaglandin inhibitor (flurbiprofen 400 mg daily) resulted in significantly less knee pain and swelling in 50 patients compared to 50 age-matched controls taking a simple analgesic (paracetamol 4 g daily) (P less than 0.001), thus enhancing recovery by three to four weeks. In the patients undergoing partial meniscectomy knee function was restored by 27 days, a figure comparable with endoscopic methods.

Twenty-seven patients with hemophilia treated with intra-articular injection of radioactive gold were followed up clinically and radiologically for 3 to 9 years after treatment. To assess the radiological changes, a new classification was designed, with a score describing the severity of the changes in a more accurate manner than the methods previously used. The treatment decreased the bleeding frequency and stopped the progress of the arthropathy if applied at an early stage when the arthropathy was still reversible. If the treatment was begun at a later stage, the arthropathy seemed to progress independently of the effect on the bleeding frequency. No negative effect of the radioactive gold was observed on the joint or the growing zone.

To prevent postoperative synovitis in 382 patients operated upon for injuries and diseases of the knee joint (traumas of menisci, ruptures of crucial and collateral ligaments, Hoffa's disease etc.) 60 mg of prednisolone was administered into the joint cavity at the end of the operation. The intra-articular injection of prednisolone was shown to considerably reduce incidence of synovitis.

Wy-41,770 [(5H-dibenzo[a,d]cyclohepten-5-ylidene)acetic acid], a novel acrylic acid, was compared to indomethacin and aspirin in standard antiinflammatory, analgesic and antipyretic animal models. The acute antiinflammatory, analgesic and antipyretic activity of Wy-41,770 (oral ED50S 50-170 mg/kg) was similar to aspirin; however, it was considerably more potent orally in adjuvant arthritis in the rat (ED50, 16 mg/kg) and urate-induced synovitis in the dog (ED50, 4.5 mg/kg). Wy-41,770 was a weak inhibitor of prostaglandin biosynthesis and did not inhibit either 5- or 15-lipoxygenase. Furthermore, the cellular migration characteristic of carrageenan pleurisy was not affected by Wy-41,770. Unlike a majority of NSAIDs, it produced no gastric irritation in rats after either acute or chronic oral administration over the range 400-800 mg/kg. The major mechanism of action of Wy-41,770 has yet to be identified but does not seem to involve interference of arachidonic acid metabolism.

A new nonionic dimer (Iotrol; Schering AG) and diatrizoate meglumine-diatrizoate sodium (Renografin-60; Squibb) were compared as arthrographic agents by injecting these substances into the knees of rabbits. Three experienced arthrographers judged the image quality produced by Iotrol to be superior to that of Renografin-60. Following animal sacrifice, histologic examination of the synovium revealed a significant difference in the inflammatory response evoked by the contrast agents: Iotrol caused less inflammation. In a second group of rabbits, methylprednisolone was subcutaneously injected 24 hours before the arthrographic studies. The methylprednisolone significantly reduced the inflammation in the Renografin-60 subgroup when compared with the nonmedicated counterparts. No significant effect was noted in a like comparison with Iotrol. In addition, the administration of methylprednisolone led to a deterioration of the radiographic images. Based upon our data, we believe Iotrol is superior to Renografin-60 as an arthrographic agent.

Tiamulin was compared, under a variety of experimental conditions, with 4 water-soluble antibiotic preparations available commercially for the control and treatment of mycoplasmal infections in poultry. In chickens, tiamulin was more effective than the reference antibiotics in preventing and eradicating airsacculitis caused by Mycoplasma gallisepticum and preventing airsacculitis and synovitis caused by M. synoviae. In turkeys, tiamulin and tylosin were equally active in preventing airsacculitis caused by M. gallisepticum. Tiamulin was highly effective in preventing airsacculitis also when administered as a single subcutaneous dose.

Use of the flexible-hinge, double-stemmed implant has eliminated many of the complications that followed correction of an arthritic first metatarsophalangeal joint caused by hallux valgus. There were no reports in the literature of acute gout after this type of correction. The authors present such a case in a patient with a history of gout, and they suggest that, when a synovectomy is performed in a patient with gouty arthritis, the joint should be freed of synovial tissue in which a uric acid crystal-induced synovitis could occur.