Prevention and treatment of exercise related leg pain in young soldiers; a review of the literature and current practice in the Dutch Armed Forces.

Overuse injuries of the leg are a common problem for young soldiers. This article reviews the literature concerning the prevention and treatment of exercise related leg pain in military settings and presents the latest developments in proposed mechanisms and treatments. Current practice and treatment protocols from the Dutch Armed Forces are reviewed, with an emphasis on the most prevalent conditions of medial tibial stress syndrome and chronic exertional compartment syndrome. The conclusion is that exercise related leg pain in the military is an occupational problem that deserves further study.

High cerebrospinal fluid levels of interleukin-10 attained by AAV in dogs.

Intrathecal (IT) gene transfer using adeno-associated virus (AAV) may be clinically promising as a treatment for chronic pain if it can produce sufficiently high levels of a transgene product in the cerebrospinal fluid (CSF). Although this strategy was developed in rodents, no studies investigating CSF levels of an analgesic or antiallodynic protein delivered by IT AAV have been performed in large animals. Interleukin-10 (IL-10) is an antiallodynic cytokine for which target therapeutic levels have been established in rats. The present study tested IT AAV8 encoding either human IL-10 (hIL-10) or enhanced green fluorescent protein (EGFP) in a dog model of IT drug delivery. AAV8/hIL-10 at a dose of 3.5 × 10(12) genome copies induced high hIL-10 levels in the CSF, exceeding the target concentration previously found to be antiallodynic in rodents by >1000-fold. AAV8/EGFP targeted the primary sensory and motor neurons and the meninges. hIL-10, a xenogeneic protein in dogs, induced anti-hIL-10 antibodies detectable in the CSF and serum of dogs. The high hIL-10 levels demonstrate the efficacy of AAV for delivery of secreted transgenes into the IT space of large animals, suggesting a strong case for further development toward clinical testing.

Gender differences in the incidence and prevalence of patellofemoral pain syndrome.

The purpose of this investigation was to determine the association between gender and the prevalence and incidence of patellofemoral pain syndrome (PFPS). One thousand five hundred and twenty-five participants from the United States Naval Academy (USNA) were followed for up to 2.5 years for the development of PFPS. Physicians and certified athletic trainers documented the cases of PFPS. PFPS was defined as retropatellar pain during at least two of the following activities: ascending/descending stairs, hopping/jogging, prolonged sitting, kneeling, and squatting, negative findings on examination of knee ligament, menisci, bursa, and synovial plica, and pain on palpation of either the patellar facets or femoral condyles. Poisson and logistic regressions were performed to determine the association between gender and the incidence and prevalence of PFPS, respectively. The incidence rate for PFPS was 22/1000 person-years. Females were 2.23 times (95% CI: 1.19, 4.20) more likely to develop PFPS compared with males. While not statistically significant, the prevalence of PFPS at study enrollment tended to be higher in females (15%) than in males (12%) (P=0.09). Females at the USNA are significantly more likely to develop PFPS than males. Additionally, at the time of admission to the academy, the prevalence of PFPS was not significantly different between genders.

AAV for pain: steps towards clinical translation.

Recombinant adeno-associated virus (rAAV) vectors consisting of self-complementary genomes and packaged in certain capsids can target primary sensory neurons efficiently and can control neuropathic pain long term by expressing opioid or non-opioid analgesic genes. This review examines the therapeutic potential of the approach in five sections: Pain control in oncology (including a discussion of cancer centers as translational pain research environment); vector biology; safety considerations and immunological lessons learned from rAAV clinical trials of other disorders; development of intrathecal rAAV therapy in rodent models of pain; and preclinical steps towards clinical translation of rAAV for pain. In the field of analgesic drug development, clinical validation of new approaches identified in rodents is currently a critical limiting step. Small-molecule therapeutics suitable as conventional drugs to probe novel targets in clinical trials are often unavailable. In this context, gene therapy could fill an important gap in the drug development process facilitating first-into-human trials of untested targeted treatments, each instantiated as a therapeutic gene.

Infliximab inhibits progression of radiographic damage in patients with active psoriatic arthritis through one year of treatment: Results from the induction and maintenance psoriatic arthritis clinical trial 2.

OBJECTIVE: To evaluate the effect of infliximab on progression of structural damage over 1 year in patients with active psoriatic arthritis (PsA) enrolled in the Induction and Maintenance Psoriatic Arthritis Clinical Trial 2. METHODS: In this double-blind, placebo-controlled study, 200 patients with active PsA were randomly assigned (1:1 ratio) to receive infusions of infliximab (5 mg/kg) or placebo at weeks 0, 2, and 6, and every 8 weeks thereafter through week 54. At week 24, patients initially assigned to receive placebo crossed over to receive infliximab (5 mg/kg). Based on predefined criteria, patients randomized to receive placebo could enter early escape by receiving infliximab (5 mg/kg) starting at week 16, and patients randomized to receive infliximab could have the dose increased to 10 mg/kg starting at week 38. Patients were analyzed according to the treatment they were randomized to receive. Radiographs of hands and feet were obtained at baseline and at weeks 24 and 54. Two readers blinded to treatment assignment and radiograph sequence independently evaluated erosions and joint space narrowing using the Sharp/van der Heijde scoring method modified for PsA. RESULTS: At week 24, patients randomized to receive infliximab 5 mg/kg had significantly less radiographic progression compared with patients randomized to receive placebo, with mean +/- SD changes from baseline in the total Sharp/van der Heijde score of -0.70 +/- 2.53 and 0.82 +/- 2.62, respectively (P < 0.001). At week 54, mean +/- SD changes from baseline in the total Sharp/van der Heijde score were -0.94 +/- 3.40 in patients randomized to receive infliximab and 0.53 +/- 2.60 in those receiving placebo/infliximab (P = 0.001). CONCLUSION: Infliximab significantly inhibits radiographic progression in patients with PsA as early as 6 months after starting treatment, and the beneficial effect continues through 1 year of infliximab therapy.

Infliximab maintains a high degree of clinical response in patients with active psoriatic arthritis through 1 year of treatment: results from the IMPACT 2 trial.

OBJECTIVE: To evaluate the efficacy and safety of infliximab through 1 year in patients with psoriatic arthritis (PsA) enrolled in the IMPACT 2 trial. METHODS: In this double blind, placebo controlled, phase III study, 200 patients with active PsA were randomised to receive infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, and every 8 weeks thereafter through 1 year. Patients with persistent disease activity could enter early escape at week 16, and all remaining placebo patients crossed over to infliximab at week 24. Patients randomised to infliximab who had no response or who lost response could escalate their dose to 10 mg/kg starting at week 38. Clinical efficacy was assessed based on the proportion of patients achieving ACR 20 and PASI 75 responses. Major clinical response (that is, maintenance of ACR 70 response for 24 continuous weeks) was assessed for the first time in PsA. RESULTS: Through 1 year of treatment, 58.9% and 61.4% of patients in the randomised infliximab and placebo/infliximab groups, respectively, achieved ACR 20; corresponding figures for PASI 75 were 50.0% and 60.3%. At week 54, major clinical response was achieved by 12.1% of patients in the infliximab group. The safety profile of infliximab through week 54 was consistent with that seen through week 24. Two malignancies occurred: basal cell skin cancer (placebo) and stage I Hodgkin's lymphoma (infliximab). CONCLUSION: Infliximab maintains a high degree of clinical efficacy and continues to be well tolerated in patients with PsA through 1 year of treatment.

The Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT): results of radiographic analyses after 1 year.

OBJECTIVE: Infliximab is effective in improving signs and symptoms of joint/skin involvement, functional status, and quality of life in patients with psoriatic arthritis (PsA). Using IMPACT trial data, we assessed the effect of infliximab (IFX) on structural damage in PsA. METHODS: Patients with active PsA were randomly assigned to receive placebo (PBO/IFX) or infliximab 5 mg/kg (IFX/IFX) at weeks 0, 2, 6, and 14, with the primary endpoint at week 16. The PBO group received infliximab loading doses at weeks 16, 18, and 22. Thereafter, all patients received infliximab 5 mg/kg every 8 weeks through week 50. Hand/feet radiographs were obtained at weeks 0 and 50. Total radiographic scores were determined using the PsA modified van der Heijde-Sharp (vdH-S) score. Projected annual rate of progression was calculated by dividing x ray score by disease duration (years). RESULTS: As reported previously, 65% of infliximab treated patients versus 10% of PBO treated patients achieved an ACR20 response at week 16 (p<0.001). At week 50, 69% of patients achieved an ACR20 response. Radiographs (baseline and week 50) were available for 72/104 patients. At baseline, estimated mean annual rate of progression was 5.8 modified vdH-S points/year. Mean (median) changes from baseline to week 50 in the total modified vdH-S score were -1.95 (-0.50) for PBO/IFX and -1.52 (-0.50) for IFX/IFX patients (p = NS). At week 50, 85% and 84% of patients in the PBO/IFX and IFX/IFX groups had no worsening in the total modified vdH-S score. CONCLUSION: Infliximab inhibits radiographic progression in patients with PsA through week 50.

Infliximab improves health related quality of life and physical function in patients with psoriatic arthritis.

OBJECTIVES: To evaluate the effect of infliximab on health related quality of life (HRQoL) and physical function in patients with active psoriatic arthritis (PsA) in the IMPACT 2 trial. METHODS: 200 patients with PsA unresponsive to conventional treatment were randomised to intravenous infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, 14, and 22; patients with inadequate response entered early escape at week 16. HRQoL was assessed using the Short Form-36 (SF-36) at weeks 0, 14, and 24. Functional disability was assessed using the Health Assessment Questionnaire (HAQ) at every visit through week 24. Associations between changes in quality of life (SF-36) and articular (American College of Rheumatology (ACR)) and dermatological (Psoriasis Area and Severity Index (PASI)) responses were examined. RESULTS: Mean percentage improvement from baseline in HAQ was 48.6% in the infliximab group compared with worsening of 18.4% in the placebo group at week 14 (p < 0.001). Furthermore, 58.6% and 19.4% of infliximab and placebo treated patients, respectively, achieved a clinically meaningful improvement in HAQ (that is, > or = 0.3 unit decrease) at week 14 (p < 0.001). Increases in physical and mental component summary (PCS and MCS) scores and all eight scales of the SF-36 in the infliximab group were greater than those in the placebo group at week 14 (p < or = 0.001). These benefits were sustained through week 24. Patients achieving ACR20 and PASI75 responses had the greatest improvements in PCS and MCS scores. CONCLUSIONS: In patients with PsA, infliximab 5 mg/kg significantly improved HRQoL and physical function compared with placebo through 24 weeks.

Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial.

OBJECTIVES: To evaluate further in a phase III, double blind trial the efficacy of infliximab in patients with active psoriatic arthritis (PsA), as observed in the smaller IMPACT trial. METHODS: 200 patients with active PsA unresponsive to previous treatment were randomised to infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, 14, and 22. Patients with inadequate response entered early escape at week 16. The primary measure of clinical response was ACR20. Other measures included Psoriatic Arthritis Response Criteria (PsARC), Psoriasis Area and Severity Index (PASI), and dactylitis and enthesopathy assessments. RESULTS: At week 14, 58% of patients receiving infliximab and 11% of those receiving placebo achieved an ACR20 response and 77% of infliximab patients and 27% of placebo patients achieved PsARC (both p<0.001). Among the 85% of patients with at least 3% body surface area psoriasis involvement at baseline, 53/83 (64%) patients receiving infliximab had at least 75% improvement in PASI compared with 2/87 (2%) patients receiving placebo at week 14 (p<0.001). These therapeutic effects were maintained through the last evaluation (week 24). Fewer infliximab patients than placebo patients had dactylitis at week 14 (18% v 30%; p = 0.025) and week 24 (12% v 34%; p<0.001). Fewer infliximab patients (22%) than placebo patients (34%) had active enthesopathy at week 14 (p = 0.016); corresponding figures at week 24 were 20% and 37% (p = 0.002). Infliximab was generally well tolerated, with a similar incidence of adverse events in each group. CONCLUSIONS: Infliximab 5 mg/kg through 24 weeks significantly improved active PsA, including dactylitis and enthesopathy, and associated psoriasis.

Treatment of chronic gout. Can we determine when urate stores are depleted enough to prevent attacks of gout?

OBJECTIVE: To determine if lowering of serum uric acid (SUA) concentrations below 6 mg/dl or longer duration of lowered SUA will result in depletion of urate crystals from the knee joints and prevent further attacks of gout. METHODS: A prospective study was initiated 10 years ago at Philadelphia VA Medical Center to attempt to maintain SUA levels of patients with crystal proven gout at < 6.0 mg/dl. We recalled all 57 patients who were available during 1999. Patients were divided into 2 groups: Group A, with SUA still > 6 mg/dl, and Group B, with SUA < or = 6 mg/dl. A knee joint aspirate was requested from all asymptomatic Group B patients and many in Group A. Aspirates were examined by polarized light microscopy for identification of crystals. RESULTS: There were no differences between the groups in age, sex, duration of gout, or serum creatinine. Group A (n = 38) had a mean of 6 attacks of gout for the recent year, those with tophi having the most frequent attacks. Among the 16 patients in this group who agreed to knee aspiration, monosodium urate (MSU) crystals were found in 14, although they were asymptomatic at the time. Nineteen patients (Group B) were able to maintain serum urate levels < or = 6 mg/dl for > 12 months. Nearly half of them had no attack of gout for 2 or more years, with a mean of 1 attack in the last year for the whole group. Three patients in whom tophi were found did not have major flares of gout within the past year. Knee joint aspiration was done on 16 asymptomatic patients. Seven (44%) still had MSU crystals present in their knees. Patients in this group who were taking prophylactic colchicine did not differ with respect to the character of synovial fluid from those who had discontinued it for up to several years, although the frequency of attacks was less in those who continued colchicine. CONCLUSION: A majority of patients were able to deplete urate crystal stores in their knee joint fluids when their SUA levels were kept to < or = 6 mg/dl for several years. The mechanisms for persistence in some patients, and whether such crystals have clinical implications, are not known. Patients with chronic gout need serum urate concentrations to be kept low to prevent further attacks.

Acute gouty arthritis involving a prosthetic knee joint.

A painful and swollen prosthetic joint, accompanied by fever, is considered to be an intra-articular infection until proven otherwise. Acute gout is one of the rare causes of arthritis in a prosthetic joint, and it may be misdiagnosed as an infection, especially when a high leukocyte count is present in the joint fluid. We report a case of crystal-proven, gouty arthritis with a low synovial fluid leukocyte count presenting with pain and swelling in a prosthetic knee and responding to treatment with colchicine and corticosteroids. Physicians taking care of patients with prosthetic joints should be aware that acute gout can occur in an artificial joint and that aspirated prosthetic joint fluid should be routinely screened for crystals independently from the WBC counts obtained.

Tumor gene therapy made easy: allogeneic major histocompatibility complex in the C6 rat glioma model.

The C6 glioma in the immune-competent rat is a frequently used model in brain tumor gene therapy research. It displays the histologic hallmarks of the human glioblastoma and has been employed to demonstrate new mechanisms of anti-tumor immunity and therapeutic strategies. We noted that C6 tumors regressed spontaneously in three of five animals and that protective anti-tumor immunity ensued without therapeutic intervention. A review of the literature revealed that different rat strains are used as "syngeneic" host for the C6 cell glioma, namely, BDIX, BDX, Sprague-Dawley, and Wistar. Allelotyping of the RT1.A (rat MHC I homolog) by a serologic technique and of the RT1.B (rat MHC II homolog) by a newly developed molecular technique showed that C6 cells express the haplotype RT1u and are allogeneic in the preceding rat strains. Expression of the gene encoding the transactivator CIITA in C6 gliomas using an EBV-based transduction system led to induction of MHC I and II and thereby mimicked therapeutic responses that could not operate in syngeneic models. These data suggest that the C6 glioma model in the immune-competent rat should no longer be used to study gene therapy strategies, that the available data obtained in this model need to be critically reinterpreted, and that findings obtained in the C6 glioma model may not be sufficient to support a clinical trial in glioblastoma patients.

Acute gouty arthritis is seasonal.

OBJECTIVE: Information regarding effect of weather conditions on gout is sparse. We conducted a study in the USA to examine whether gout is seasonal. METHODS: We reviewed synovial fluid (SF) analyses from our laboratory during 1990-1995 and identified 359 patients who had acute gouty attacks. All fluids of patients with acute gout had intracellular monosodium urate crystals and SF leukocyte counts > 2000/mm3 or more than 10 leukocytes per high power field (HPF). Retrospective chart review of all patients was performed to confirm a clinical picture of acute gout. A control group included 76 patients with acute pseudogout whose SF were analyzed during the same period and who had intracellular calcium pyrophosphate crystals and inflammatory leukocyte counts as in patients with gout. RESULTS: Acute gout was most common during the spring; n = 115 (32%). Ninety (25%) patients had acute gout attacks in the fall; 81 (23%) had acute attacks during the summer; 73 (20%) had acute attacks in the winter. One-way analysis of variance (ANOVA) was used to compare the overall frequency of acute gout during the months and seasons. Using ANOVA, there was no overall statistically significant difference in the incidence of gout per season (p = 0.07), although it approached statistical significance. Acute gouty attacks were more common in the spring compared with winter (p = 0.002) and summer (p = 0.015). There was a trend but no statistically significant difference compared with fall. Winter was the season in which the fewest acute gouty cases were seen, although it was not statistically significant. No seasonal difference was seen in the pseudogout group. There was no correlation between either mean monthly temperature or humidity and the incidence of acute gouty attacks. CONCLUSION: Acute gout attacks are significantly more common in the spring. No seasonal variation was seen in patients with acute pseudogout attacks.

Morphometric studies on synovium in advanced osteoarthritis: is there an association between apatite-like material and collagen deposits?

OBJECTIVE: To look for the frequency and the influence of apatite-like deposits in the synovial membrane of advanced osteoarthritic joints. METHODS: Synovium of 16 joints undergoing total arthroplasty for advanced primary osteoarthritis was embedded in paraffin. Adjacent sections were stained with alizarin red S, Mowat's pentachrome, Hematoxylin-eosin and Gomori to show apatite-like deposits, collagen, cartilage fragments, vessels, cells and iron respectively. Histomorphometry was carried out for the apatite-like and collagen deposits by the point counting method; the density of vessels and cells was also quantified. RESULTS: 14 out of the 16 specimens contained apatite-like material, mostly on the synovial surface or just beneath. There was no correlation between the apatite-like deposits and any other measured histological parameter (fibrosis, villus length, synovial lining cell width, density of synovial vessels or cells). Interestingly, the p value for a correlation between the amounts of apatite and collagen deposits was close to significance (r = 0.53; p = 0.055) when the relative volume of the apatite-like material was less than 1.2% (n = 13). CONCLUSIONS: Apatite-like deposits are frequently observed in the synovium of late stage osteoarthritis. Although not statistically significant, these results suggest a possible association between apatite-like and collagen deposits when the amount of apatite deposits is low. Further quantitative studies are recommended to investigate this observation.

Reactive arthritis: is it a useful concept?

Reactive arthritis (ReA) is one of the most common arthritides affecting young adults. In most cases it follows urogenital or enteric bacterial infection, but its pathogenesis is not fully understood. It is generally considered a sterile arthritis which appears to involve immune response to bacterial organisms and genetic host susceptibility associated with the presence of HLA-B27 antigen. New findings suggest that in some ReA cases, viable bacteria are present inside the joints, and these organisms may cause the disease and trigger the inflammatory response. ReA manifests clinically as a rheumatoid factor negative oligoarthritis associated with enthesopathy and certain mucosal and skin lesions. Laboratory findings in ReA are non-specific. Although concepts of its pathogenesis are still evolving, so-called ReA remains an important condition to be distinguished from rheumatoid arthritis. Prognosis is generally better. Treatments with known effects in some cases include non-steroidal anti-inflammatory drugs, intra-articular corticosteroids, oral tetracyclines and sulphasalazine. The occasional chronic and severe ReA may be very difficult to treat.

Chlamydia trachomatis Can Persist in Joint Tissue After Antibiotic Treatment in Chronic Reiter's Syndrome / Reactive Arthritis.

Considerable evidence suggests that viable Chlamydia trachomatis are present in joint tissues of patients with Reiter's syndrome/reactive arthritis (RS/ReA), but the use of antibiotics to treat such patients remains controversial. We investigated the continued presence of chlamydia in synovial tissues of patients with RS/ReA; these patients had been treated with antibiotics for relatively extended periods, had shown clinical improvement, but had persistent active disease. Knee synovial tissue was obtained from two patients with RS/ReA and two controls with osteoarthritis (OA). Each sample was screened for chlamydia by culture, direct fluorescent antibody assay (DFA), in situ hybridization (ISH), and polymerase chain reaction (PCR).Synovial tissues from antibiotic-treated RS/ReA patients were negative for chlamydia when analyzed by culture and DFA, but positive when analyzed by ISH for chlamydial RNA and by PCR for chlamydial DNA. Samples from OA patients were negative by all screening methods. Thus, antibiotic treatment does not appear to easily eradicate chlamydia from the joints of RS/ReA patients. Rather, the organism can persist in synovial tissue in a form not detectable by routine laboratory screening methods. Further studies are needed to determine whether antibiotic regimens other than those used here can eradicate synovial chlamydia and to determine how this relates to disease activity. Optimal therapy for patients with RS/ ReA is therefore not yet clear.