Diagnostic delay of pyogenic vertebral osteomyelitis and its associated factors.

OBJECTIVES: Pyogenic vertebral osteomyelitis (PVO) is a rare disease with possible severe complications (e.g. sepsis and spinal cord injury). In the 1990s, diagnostic delay (DD) was often extensive as PVO has a non-specific clinical spectrum, mostly afebrile with back pain, and access to magnetic resonance imaging (MRI) was not straightforward. Our aim was to perform a new study focusing on the clinical spectrum and DD of PVO and its associated factors. METHOD: This study examined a prospective cohort of 88 patients having PVO with microbiological identification between 15 November 2006 and 15 November 2010. RESULTS: The 88 patients included in the study (female:male ratio 1:8) had a mean age of 64.1 years. The mean (sd) DD was 45.5 (50.4) days (range 2-280), and 46 patients (52.2%) were febrile at diagnosis. The main microorganism involved was Staphylococcus (n = 45; 51.1%). In univariate and multivariate analyses, age > 75 years, antecedent back pain, involvement of bacteria, topography of PVO, and anti-inflammatory drug intake did not affect the DD, unlike a C-reactive protein (CRP) value > 63 mg/L or a positive blood culture (DD lowered from 73 to 17 days and from 90 to 30 days, respectively). Conversely, X-ray investigation was associated with a longer DD (from 14 to 34.7 days). Severity at diagnosis was not significantly different depending on the intake of anti-inflammatory drugs. CONCLUSIONS: Despite easier access to MRI, the DD for PVO remains long. One shortening factor is a high CRP value, which could be a useful diagnostic tool in case of back pain. Anti-inflammatory drugs seem to have no impact on DD and severity at diagnosis.

Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium.

Biopharmaceuticals (BPs) represent a rapidly growing class of approved and investigational drug therapies that is contributing significantly to advancing treatment in multiple disease areas, including inflammatory and autoimmune diseases, genetic deficiencies and cancer. Unfortunately, unwanted immunogenic responses to BPs, in particular those affecting clinical safety or efficacy, remain among the most common negative effects associated with this important class of drugs. To manage and reduce risk of unwanted immunogenicity, diverse communities of clinicians, pharmaceutical industry and academic scientists are involved in: interpretation and management of clinical and biological outcomes of BP immunogenicity, improvement of methods for describing, predicting and mitigating immunogenicity risk and elucidation of underlying causes. Collaboration and alignment of efforts across these communities is made difficult due to lack of agreement on concepts, practices and standardized terms and definitions related to immunogenicity. The Innovative Medicines Initiative (IMI; www.imi-europe.org), ABIRISK consortium [Anti-Biopharmaceutical (BP) Immunization Prediction and Clinical Relevance to Reduce the Risk; www.abirisk.eu] was formed by leading clinicians, academic scientists and EFPIA (European Federation of Pharmaceutical Industries and Associations) members to elucidate underlying causes, improve methods for immunogenicity prediction and mitigation and establish common definitions around terms and concepts related to immunogenicity. These efforts are expected to facilitate broader collaborations and lead to new guidelines for managing immunogenicity. To support alignment, an overview of concepts behind the set of key terms and definitions adopted to date by ABIRISK is provided herein along with a link to access and download the ABIRISK terms and definitions and provide comments (http://www.abirisk.eu/index_t_and_d.asp).

Adalimumab in patients with hand osteoarthritis refractory to analgesics and NSAIDs: a randomised, multicentre, double-blind, placebo-controlled trial.

AIM: To test the efficiency of tumour necrosis factor blockers (adalimumab) in patients with painful refractory (non-responders to analgesics and non-steroidal anti-inflammatory drugs (NSAIDs)) hand osteoarthritis (OA). METHODS: We performed a randomised, double-blind, placebo-controlled, parallel group, multicentre study. Patients were randomised to: 1/1 adalimumab 40 mg for two subcutaneous injections at a 15-day interval or placebo and monitored for 6 months. The primary outcome was the percentage of patients with an improvement of more than 50% in global pain (Visual Analogue Scale) between week 0 (W0) and week 6 (W6). Secondary outcomes included the number of painful joints, swollen joints, morning stiffness duration, patient and practitioner global assessments, functional indexes for hand OA, and consumption of analgesics. Analysis on the mean primary outcome measure was done on patients who received at least one injection. RESULTS: 99 patients were recruited and 85 patients were randomised. Among them, 37 patients in the placebo group and 41 in the adalimumab group received at least one injection and were evaluated at W6 (n=78) on the main efficacy outcome. Mean age was 62 years, 85% were women, and mean level of pain was 62 mm at W0. At W6, 35.1% in the adalimumab group versus 27.3% in the placebo group had a pain reduction ≥50% (RR 1.12 (95% CI 0.82 to 1.54; p=0.48). There were no statistical differences for all secondary end points. The rate of adverse events was similar in the two groups. CONCLUSIONS: Adalimumab was not superior to placebo to alleviate pain in patients with hand OA not responding to analgesics and NSAIDs. TRIALS REGISTRATION NUMBER: NCT00597623.

Microbiological diagnosis of vertebral osteomyelitis: relevance of second percutaneous biopsy following initial negative biopsy and limited yield of post-biopsy blood cultures.

The purpose of this investigation was to evaluate the microbiological diagnosis yield of post-biopsy blood cultures (PBBCs) and second percutaneous needle biopsy (PNB) following an initial negative biopsy in vertebral osteomyelitis (VO) without bacteremia. A retrospective multicenter study was performed. Patients with VO, pre-biopsy negative blood culture(s), ≥1 PNB, and ≥1 PBBC (0-4 h) were included. One hundred and sixty-nine PNBs (136 first and 33 following initial negative biopsy) were performed for 136 patients (median age = 58 years, sex ratio M/F = 1.9). First and second PNBs had a similar yield: 43.4 % (59/136) versus 39.4 % (13/33), respectively. Only two PBBCs (1.1 %) led to a microbiological diagnosis. The strategy with positive first PNB and second PNB following an initial negative result led to microbiological diagnosis in 79.6 % (74/93) of cases versus 44.1 % (60/136) for the strategy with only one biopsy. In the multivariate analysis, young age (odds ratio, OR [95 % confidence interval (CI)] = 0.98 [0.97; 0.99] per 1 year increase, p = 0.02) and >1 sample (OR = 2.4 ([1.3; 4.4], p = 0.007)) were independently associated with positive PNB. To optimize microbiological diagnosis in vertebral osteomyelitis, performing a second PNB (after an initial negative biopsy) could lead to a microbiological diagnosis in nearly 80 % of patients. PBBC appears to be limited in microbiological diagnosis.

Rituximab-induced T cell depletion in patients with rheumatoid arthritis: association with clinical response.

OBJECTIVE: Rituximab, a monoclonal antibody specifically targeting CD20, induces B cell depletion and is effective in the treatment of rheumatoid arthritis (RA). This study was undertaken to evaluate whether routine monitoring of lymphocyte subpopulations, especially T cells, may be useful in patients receiving rituximab for RA. METHODS: We examined data on all RA patients receiving rituximab between July 2007 and November 2012 in our center. Peripheral blood CD3+, CD4+, CD8+, CD3-CD56+, and CD19+ lymphocyte counts before and during the first course of rituximab were measured by flow cytometry. The Mann-Whitney nonparametric test was used to compare lymphocyte subpopulation counts before and during treatment. RESULTS: Data on 52 patients were examined. Rituximab induced unexpected and substantial depletion of T cells, mainly CD4+ cells, in most patients. The CD4+ cell count decreased by a mean ± SD of 37 ± 33% as compared to baseline at week 12, reaching <200 cells/µl in 3 patients. Importantly, lack of CD4+ cell depletion was associated with no clinical response. Therefore, the mechanism of action of rituximab may depend at least in part on T cells. CONCLUSION: Rituximab induces substantial T cell depletion, mainly of CD4+ cells, which is associated with the clinical response in RA. Routine monitoring of T cells may be useful in the clinical setting of RA.

Early decrease of serum biomarkers of type II collagen degradation (Coll2-1) and joint inflammation (Coll2-1 NO2 ) by hyaluronic acid intra-articular injections in patients with knee osteoarthritis: a research study part of the Biovisco study.

To measure the evolution of the serum levels of specific Osteoarthritis (OA) biomarker, Coll2-1 and Coll2-1 NO2 in knee osteoarthritic patients after viscosupplementation (VS). Fifty-one patients with unilateral symptomatic knee were recruited for this prospective open label study. They received three intra-articular injections of 2 ml of hyaluronic acid (Hylan GF-20) and were followed for 3 months. Walking pain was evaluated and serum samples were taken at each visit. Coll2-1 and Coll2-1 NO2 were measured in the serum using specific immunoassays. Variations over time of each parameter and predictive factor of response were studied. Forty-five patients were analyzed. The serum concentrations of Coll2-1 and Coll2-1 NO2 were significantly higher in KL III/IV patients compared to KL I/II patients at baseline and decreased systematically over time after VS. Its effect was ever more pronounced in patients with KL III/IV. The serum concentration of Coll2-1 was significantly lower at baseline in responders than in non-responders. This study suggests a rapid slowdown of type II collagen degradation and joint inflammation after VS with Hylan G-20 and gives additional information for the validation of accurate biomarkers for OA. The serum level of Coll2-1 appeared to be a predictive factor for response to treatment.

The value of individual or collective group exercise programs for knee or hip osteoarthritis. Clinical practice recommendations.

OBJECTIVE: To develop clinical practice guidelines concerning individual and group exercise therapy for knee and/or hip osteoarthritis (OA). METHOD: We used the SOFMER (French Physical Medicine and Rehabilitation Society) methodology, combining systematic literature review, collection of everyday clinical practice, and external review by a multidisciplinary expert panel, to develop the guidelines. RESULTS: Physical exercises are proposed for knee and hip OA. The benefit of individual exercises is low to moderate for pain, strength and ability to walk. The effectiveness is not maintained over time if the individual exercise program is not continued. The benefit of group exercise is also low to moderate for pain, strength, balance and ability to walk. There is no evidence of the superiority of one modality over the other (individual or group). CONCLUSION: More randomised controlled trials with good methodology are needed to compare the effectiveness of individual versus group exercise therapy for knee and hip OA.

[Eosinophilic fasciitis associated with Borrelia burgdorferi infection]. / Fasciite à éosinophiles survenue secondairement à une infection par Borrelia burgdorferi.

BACKGROUND: Eosinophilic fasciitis (Shulman syndrome) is defined by the association of sclerodermatous skin changes involving underlying fascia and hypereosinophilia. While the aetiology is unknown, some observations suggest an infectious origin. We report the association of eosinophilic fasciitis with an infection involving Borrelia burgdorferi. PATIENTS AND METHODS: A 54 year-old man consulted for a hardened oedema and stiffness of the calves associated with an oedema of the left hand evolving for 4 months. Routine blood tests showed hypereosinophilia at 1.01 G/l and moderate inflammatory syndrome. Diagnosis of eosinophilic fasciitis was confirmed by MRI and muscle biopsy. Since the patient had reported previous tick bites some months before onset, he was tested for Lyme disease. An ELISA test revealed IgG directed against Borrelia burgdorferi and this was confirmed by Western blot analysis. DISCUSSION: The association of eosinophilic fasciitis with Lyme disease raises the question of a real link or a fortuitous association between the two conditions. Similar cases have been described in the literature with or without isolation of the spirochete from skin or fascia lesions. The incidence of eosinophilic fasciitis remains low compared to the prevalence of the infection in endemic areas. We suggest that in some patients, perhaps genetically predisposed, infection with B. burgdorferi may be at the origin of fasciitis.

Optimal duration of antibiotic therapy in vertebral osteomyelitis.

OBJECTIVES: To compare the risk of relapse of vertebral osteomyelitis (VO), according to the duration of antibiotic therapy (< or =6 weeks versus >6 weeks). METHODS: We performed a 10-year retrospective study to assess the risk of VO relapse and to verify that this risk was not enhanced in patients who received 6 weeks of antibiotic therapy (Group 1) as compared with those who received a longer treatment (Group 2). VO was diagnosed based on clinical manifestations, magnetic resonance imaging and/or computed tomography findings, and isolation of a pyogenic organism in blood cultures and/or a discovertebral biopsy. Relapse was diagnosed based on isolation of the same organism in blood cultures and/or a discovertebral biopsy. Outcome was evaluated 6 months post-treatment and in December 2004. RESULTS: Group 1 included 36 patients (mean age, 58 +/- 15 years) and Group 2 included 84 patients (mean age, 67 +/- 15 years) (P = 0.003). Clinical data and microorganisms were comparable in the 2 groups. In the first 6 months, 6 (5%) patients died (Group 1, n = 2; Group 2, n = 4), and 5 (4%) in Group 2 relapsed, 2 with recurrent VO and 3 with recurrent bacteremia. In 2004, 91 patients were evaluated (mean follow-up, 40.6 +/- 31 months): 77 (85%) were cured, 13 (14%) died (Group 1, n = 3; Group 2, n = 10), 1 had VO due to a different microorganism (Group 2), and no long-term relapses occurred. CONCLUSION: Our results suggest that antibiotic therapy of VO could be safely shortened to 6 weeks without enhancing the risk of relapse.

Rat bite fever mimicking rheumatoid arthritis.

We report a case of Streptobacillus moniliformis polyarthritis mimicking a rheumatoid arthritis, in a pet shop employee. In culture of fluid joint growth a curious Gram-negative bacillus was identified by polymerase chain reaction as Streptobacillus moniliformis. The outcome was good after surgical debridment and rifampin-clindamycin combination during 4 weeks.

Quantitative ultrasound of bone in male osteoporosis.

Quantitative ultrasound (QUS) measurement, a different approach to bone fragility assessment, has already been attempted in women with osteoporosis but rarely in men. In order to test its value and ability to identify osteoporotic men, a case-control prospective study was conducted using the Lunar Achilles, a device that measures attenuation and velocity parameters. Broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (SI), a composite parameter, were assessed through the heel of 66 osteoporotic patients, and compared with the results in 35 controls. Patients had sustained a low-trauma fracture and/or had a lumbar and/or femoral bone mineral density (BMD) more than 2.5 SD below the young male reference value. As expected, all QUS parameters were statistically lower in patients, as were the dual-energy X-ray absorptiometry (DXA) measurements at the hip and lumbar spine. The two methods were compared for their ability to predict the risk of osteoporotic fractures. The odds ratios (ORs), with their 95% confidence limits, for fractures per 1 SD decrease were significant, especially for SOS and SI (OR = 2.3 [1.4-3.6] and 2.1 [1.3-3.3] respectively) and to a lesser extent for BUA (1.6 [1.0-2.4]). Our study suggests that QUS is associated with a history of low-trauma fracture in men; sensitivity is, however, less than when results are compared with BMD measurements (OR = 2.8 [1.6-5.0] and 3.4 [1.6-7.0] for lumbar spine and hip, respectively). Prospective studies are required before QUS can be recommended for clinical use in male osteoporosis.

Adeno-associated virus-mediated delivery of IL-4 prevents collagen-induced arthritis.

Immunomodulation of autoimmune inflammatory diseases like rheumatoid arthritis can be achieved by anti-inflammatory T2 cytokines such as interleukin (IL)-4 administered by gene therapy. In this study we investigated the efficiency of adeno-associated viruses (AAV) vectors in collagen-induced arthritis (CIA). After injection of AAV-LacZ in the tarsus area of mice, the expression of the transgene was localized in the deep muscles cells near the bone. LacZ expression was found in liver, heart and lung after i.m. injection of AAV-LacZ, showing a spread of the vector over the body. Anti-AAV neutralizing antibodies were detected in the serum after i.m. injection of AAV-LacZ, but they did not alter the transgene expression after re-administration of AAV-LacZ. Long-term IL-4 expression persisted 129 days after intra-muscular injection of 3.7 x 10(10) or 11.2 x 10(10) AAV-IL-4 p.p. (average 7.7 or 17.5 pg IL-4/mg proteins, respectively). More importantly, the treatment of CIA with AAV-IL-4 vector in mice produced a therapeutic benefit, since we show a diminished prevalence of the disease, a significant reduction in paw swelling, attenuated histological synovitis and a 10 days delayed onset of arthritis. This is the first evidence that AAV vector-mediated gene therapy using a T2 cytokine is efficient in an animal model of rheumatoid arthritis.