Lyme borreliosis and other tick-borne diseases. Guidelines from the French scientific societies (II). Biological diagnosis, treatment, persistent symptoms after documented or suspected Lyme borreliosis.

The serodiagnosis of Lyme borreliosis is based on a two-tier strategy: a screening test using an immunoenzymatic technique (ELISA), followed if positive by a confirmatory test with a western blot technique for its better specificity. Lyme serology has poor sensitivity (30-40%) for erythema migrans and should not be performed. The seroconversion occurs after approximately 6 weeks, with IgG detection (sensitivity and specificity both>90%). Serological follow-up is not recommended as therapeutic success is defined by clinical criteria only. For neuroborreliosis, it is recommended to simultaneously perform ELISA tests in samples of blood and cerebrospinal fluid to test for intrathecal synthesis of Lyme antibodies. Given the continuum between early localized and disseminated borreliosis, and the efficacy of doxycycline for the treatment of neuroborreliosis, doxycycline is preferred as the first-line regimen of erythema migrans (duration, 14 days; alternative: amoxicillin) and neuroborreliosis (duration, 14 days if early, 21 days if late; alternative: ceftriaxone). Treatment of articular manifestations of Lyme borreliosis is based on doxycycline, ceftriaxone, or amoxicillin for 28 days. Patients with persistent symptoms after appropriate treatment of Lyme borreliosis should not be prescribed repeated or prolonged antibacterial treatment. Some patients present with persistent and pleomorphic symptoms after documented or suspected Lyme borreliosis. Another condition is eventually diagnosed in 80% of them.

Lyme borreliosis and other tick-borne diseases. Guidelines from the French Scientific Societies (I): prevention, epidemiology, diagnosis.

Lyme borreliosis is transmitted en France by the tick Ixodes ricinus, endemic in metropolitan France. In the absence of vaccine licensed for use in humans, primary prevention mostly relies on mechanical protection (clothes covering most parts of the body) that may be completed by chemical protection (repulsives). Secondary prevention relies on early detection of ticks after exposure, and mechanical extraction. There is currently no situation in France when prophylactic antibiotics would be recommended. The incidence of Lyme borreliosis in France, estimated through a network of general practitioners (réseau Sentinelles), and nationwide coding system for hospital stays, has not significantly changed between 2009 and 2017, with a mean incidence estimated at 53 cases/100,000 inhabitants/year, leading to 1.3 hospital admission/100,000 inhabitants/year. Other tick-borne diseases are much more seldom in France: tick-borne encephalitis (around 20 cases/year), spotted-fever rickettsiosis (primarily mediterranean spotted fever, around 10 cases/year), tularemia (50-100 cases/year, of which 20% are transmitted by ticks), human granulocytic anaplasmosis (<10 cases/year), and babesiosis (<5 cases/year). The main circumstances of diagnosis for Lyme borreliosis are cutaneous manifestations (primarily erythema migrans, much more rarely borrelial lymphocytoma and atrophic chronic acrodermatitis), neurological (<15% of cases, mostly meningoradiculitis and cranial nerve palsy, especially facial nerve) and rheumatologic (mostly knee monoarthritis, with recurrences). Cardiac and ophtalmologic manifestations are very rarely encountered.

[Discontinuation or tapering strategies of biologics in rheumatoid arthritis in remission]. / Stratégies d'arrêt ou de réduction des biomédicaments dans la polyarthrite rhumatoïde en rémission.

The arrival of new drugs and new therapeutic strategies allowed to reach sustained remission in an increasing number of patients with rheumatoid arthritis. The study of biologic disease-modifying anti-rheumatic drugs (bDMARDs) adaptation strategies is a need to optimize the benefit/risk balance and cost/effectiveness ratio of these molecules. Current recommendations such as EULAR 2016 propose tapering bDMARDs, especially when combined with a csDMARD, when the patient is in remission after stopping persistent glucocorticoids. The analysis of literature comprising 22 studies shows that a bDMARD adaptation is possible in established rheumatoid arthritis when clinico-biological and ultrasound remission is maintained over six months. Priority should be given to a progressive tapering strategy doses controlled by disease activity while maintaining "tight control" to identify and effectively treat a relapse, a retreatment being usually favorable.

Biosimilar infliximab for the management of rheumatoid arthritis in France: what are the expected savings?

OBJECTIVES: Biosimilar infliximab, the first similar biological medicinal product containing monoclonal antibodies to be commercialised, is likely to contribute to a significant reduction in healthcare costs. We aimed to assess the cost savings potential over 1 year of the use of biosimilar infliximab for the treatment of rheumatoid arthritis (RA) patients in Alsace and in France, in a real-life setting. METHODS: The analysis was based on a previously conducted observational study which evaluated the annual cost of the care of patients with RA treated with biological therapies in 2012 in Alsace. Average annual costs to manage RA patients were calculated, taking into account the decrease in the retail price between 2012 and 2015 (as given in the official national price list) and the local negotiated price for biosimilar infliximab. Annual cost savings for different biosimilar prescription scenarios were calculated using 2015 prices. RESULTS: Management of RA patients with biosimilar infliximab was significantly cheaper than with adalimumab or etanercept (€11 907 vs €12 981 and €13 551, respectively). The projected annual cost savings reached €13.6 million nationally, if all adult RA patients treated with the originator infliximab switched to the biosimilar drug. These savings, if fully reallocated for the treatment of RA, would enable the treatment of 1141 additional patients. CONCLUSIONS: The study showed a positive financial impact of introducing biosimilar infliximab for the treatment of RA patients in France. Such savings could contribute to improved patient care by allowing more patients to be treated without more money being spent.

Physiological plasticity of Dictyota kunthii (Phaeophyceae) to copper excess.

The brown alga Dictyota kunthii is one of the dominant species in the coastal areas of northern Chile affected by copper enrichment due to accumulated mining wastes. To assess its physiological plasticity in handling copper-mediated oxidative stress, 4-days copper exposure (ca. 100 µg/L) experiments were conducted with individuals from a copper impacted area and compared with the responses of plants from a non-impacted site. Several biochemical parameters were then evaluated and compared between populations. Results showed that individuals from the copper-impacted population normally displayed higher levels of copper content and antioxidant enzymes activity (catalase (CAT), ascorbate peroxidase (AP), dehydroascorbate reductase (DHAR), glutathione peroxidase (GP) and peroxiredoxins (PRX)). After copper exposure, antioxidant enzyme activity increased significantly in plants from the two selected sites. In addition, we found that copper-mediated oxidative stress was associated with a reduction of glutathione reductase (GR) activity. Moreover, metabolic profiling of extracellular metabolites from both populations showed a significant change after plants were exposed to copper excess in comparison with controls, strongly suggesting a copper-induced release of metabolites. The copper-binding capacity of those exudates was determined by anodic stripping voltammetry (ASV) and revealed an increased ligand capacity of the medium with plants exposed to copper excess. Results indicated that D. kunthii, regardless their origin, counteracts copper excess by various mechanisms, including metal accumulation, activation of CAT, AP, DHAR, GP and PRX, and an induced release of Cu binding compounds. Thus, plasticity in copper tolerance in D. kunthii seems constitutive, and the occurrence of a copper-tolerant ecotype seems unlikely.

[Intra-articular osteoid osteoma in the left elbow]. / Ostéome ostéoïde du coude : un mode de révélation trompeur.

Intra-articular osteoid osteoma (OO) is a rare and difficult diagnosis. We report the case of an 11-year-old boy who presented with inflammatory monoarticular arthritis in the left elbow. This monoarthritis was resistant to all types of treatment. He had an OO, diagnosed late because the first symptoms developed subsequent to the ablation of a wart in the same elbow and were suggestive of arthritis.

[Arthritis revealing an osteoid osteoma in a patient with spondylarthropathy]. / Arthrite au cours d'une spondylarthropathie révélatrice d'un ostéome ostéoïde.

Intra-articular osteoid osteoma is rare and difficult to diagnose. We report a 38-year-old woman who presented with an inflammatory monoarticular arthritis in the right ankle in the context of a spondylarthropathy, otherwise well-controlled by leflunomide. This monoarthritis was resistant to all types of treatment. Investigations led to the diagnosis of an intra-articular osteoid osteoma. This original observation is the first description of an osteoid osteoma developing in a patient already known to have inflammatory rheumatism. All previous reported cases were monoarthritis consecutive to the osteoid osteoma itself and interpreted as incipient inflammatory rheumatism.

Characteristics and survival of 26 patients with paraneoplastic arthritis.

OBJECTIVE: To date, only a few series of patients with paraneoplastic arthritis have been published. The charts of patients with cancer-associated arthritis were collected in order to describe characteristics of this rheumatism. METHODS: A questionnaire was created for this study and validated by experts based on specific criteria of inclusion and exclusion. Histology of neoplasia was included. RESULTS: In all, 16 males and 10 females with a mean (range) age of 57.5 years (28-85) were recruited from 17 nationwide centres in France. Patients presented with symmetric polyarthritis involving wrists and hands (85%) and extra-articular symptoms were frequent (84%). There was no specific biologic or radiographic feature. The mean (range) delay between the diagnosis of rheumatism and neoplasia was 3.6 months (0-21.2). Tumours were usually diagnosed after articular symptoms occurred (88.5%). Twenty patients had a solid cancer, and six a haematological malignancy. Adenocarcinoma of the lungs was the most frequent type of solid cancer (60%). Tumours were diagnosed at an early stage, which may explain the good median survival of 1.21 years (range 0.64-present) with a mean follow-up of 1.9 years (range 0.16-10). The percentage of articular symptoms resolution was significantly higher in patients with solid tumours, as compared to patients with haemopathy (p = 0.007). In cases of tumour relapse, rheumatic symptoms did not recur for 75% of patients. CONCLUSIONS: Underlying neoplasia should be considered in male patients with new onset polyarthritis, smokers, and particularly in patients chronically ill. Additional investigations should then be performed to diagnose cancer at an early stage.

[Hospital infection control--beyond the hospital]. / Hygiène hospitatière--au-delà de l'hôpital.

Health care related infections are expensive untoward events, not only in terms of morbidity and mortality, but also cost. Prevention is essential, as well as limiting dissemination. Specify measures refer usually to hospital hygiene. However, health care tend to be provided more and more outside of the acute care hospital, with increasing complexity and thus risk for health care related infections. This risk varies according to patient's characteristics as well as environmental parameters. Consequently, it is essential to adapt preventive measures to situations such as home health care or nursing homes. We describe a model of regional organization for infection control in various health care settings.

Serum immunoglobulin free light chain assessment in rheumatoid arthritis and primary Sjogren's syndrome.

BACKGROUND: B cell activation may result in an increased secretion of immunoglobulin free light chains (FLCs) in autoimmune diseases. OBJECTIVE: To analyse serum FLC levels in patients with rheumatoid arthritis and in those with primary Sjögren's syndrome (pSS). PATIENTS AND METHODS: Blood samples were collected from 80 healthy blood donors, 50 patients with rheumatoid arthritis and 139 patients with pSS. Serum FLC level was measured using a new quantitative immunoassay. RESULTS: Mean (standard error (SE)) serum kappa and lambda FLC levels were significantly higher in patients with rheumatoid arthritis and in those with pSS than in controls (kappa : 18.9 (1.1) and 16.3 (1.4) v 10.5 (0.4) mg/l, p<0.001 and p = 0.001, respectively; lambda: 16.7 (1.2) and 19.3 (1.5) v 11.6 (0.6) mg/l, p<0.001 for both). 18 (36%) patients with rheumatoid arthritis and 31 (22.3%) patients with pSS had abnormal serum FLC levels (increased kappa or lambda levels and abnormal ratio of kappa:lambda). Serum kappa and lambda levels were correlated with other B cell activation markers in both diseases. FLC levels increased with disease activity, because, unlike total gammaglobulin and immunoglobulin G levels, they were significantly correlated with Disease Activity Score 28 in patients with rheumatoid arthritis (p = 0.004 for kappa, p = 0.05 for lambda) and with extraglandular involvement in pSS (p = 0.01 for kappa, p = 0.04 for lambda). CONCLUSION: FLC levels are increased and correlate with disease activity in patients with rheumatoid arthritis and in those with pSS, two diseases in which increased risk of lymphoma could result from persistent B cell activation and disease activity. Further studies are required to determine whether FLC assessment could represent a relevant biomarker for response to treatment (especially B cell depletion) and for the risk of lymphoma in autoimmune diseases.

Systemic sclerosis-associated Sjögren's syndrome and relationship to the limited cutaneous subtype: results of a prospective study of sicca syndrome in 133 consecutive patients.

OBJECTIVE: To determine the prevalence of sicca symptoms and Sjögren's syndrome (SS) in a 2-center prospective series of patients with systemic sclerosis (SSc), using the American-European Consensus Group criteria for SS. METHODS: Consecutive SSc patients hospitalized for followup care were evaluated for sicca symptoms. When the initial clinical evaluation yielded positive findings, a labial salivary gland biopsy was performed; histologic analysis evaluated focal lymphocytic sialadenitis and/or glandular fibrosis. Computed tomography and respiratory function tests were used to assess pulmonary fibrosis. RESULTS: We included 133 SSc patients (mean +/- SD age 55 +/- 13 years; mean +/- SD disease duration 6.5 +/- 6 years). Eighty-one patients had limited cutaneous SSc (lcSSc). Ninety-one patients (68%) had sicca syndrome. Histologic analysis revealed fibrotic involvement in 50 of these 91 patients, but labial salivary gland fibrosis was not associated with any organ involvement we evaluated. Nineteen of the 133 patients (14%) had SS. In this subgroup, lcSSc was present at a significantly higher frequency (18 of 19 patients) than in the remaining patients with sicca syndrome (39 of 72 patients) and the patients without sicca syndrome (24 of 42 patients). This subgroup also had a significantly higher frequency of anticentromere antibodies (18 of 19 patients) than did the remaining patients with sicca syndrome (19 of 72 patients) and the patients without sicca syndrome (5 of 42 patients). In addition, this subgroup had a significantly lower prevalence of pulmonary fibrosis (2 of 19 patients) than did the remaining patients with sicca syndrome (29 of 72 patients) and the patients without sicca syndrome (19 of 42 patients). CONCLUSION: There was a 68% prevalence of sicca syndrome in this prospective series of SSc patients. Sicca syndrome was related primarily to glandular fibrosis, the hallmark of SSc. The prevalence of secondary SS, as defined by the American-European Consensus Group criteria, was 14% and was markedly associated with lcSSc. We believe that lcSSc should be regarded as a specific autoimmune subgroup of SSc.

Anti-pm/scl antibodies in connective tissue disease: Clinical and biological assessment of 14 patients.

INTRODUCTION: Anti-PM/Scl antibodies (Anti-PM/Scl) represent a rarely encountered type of antinuclear antibodies. They have mainly been reported in association with idiopathic inflammatory myositis - systemic sclerosis overlap syndromes (also called scleromyositis or sclerodermatomyositis) but also with polymyositis, dermatomyositis and systemic sclerosis without features of overlap syndromes. Studies concerning characteristics of patients with anti-PM/SCl are rare and include small numbers of patients. PATIENTS AND METHODS: Retrospective review of clinical and biological characteristics of 14 patients with anti-PM/Scl in two University Hospitals: one in Belgium (Erasme Hospital, Bruxelles) and one in France (Hautepierre Hospital, Strasbourg). RESULTS: Seven patients were identified in Erasme and 7 in Strasbourg: 5 with systemic sclerosis-(dermato)myositis overlap syndromes, 4 with dermatomyositis, 1 with polymyositis, 3 with systemic sclerosis, 1 with primary Sjögren's syndrome. The most frequently observed clinical characteristics (85% of patients) were: pulmonary interstitial disease and arthralgia or arthritis. No patient of our series died or developed cancer (mean follow-up:6.1 years). CONCLUSIONS: Our study failed to identify an homogeneous clinical pattern in patients with anti-PM/Scl, except for 2 characteristics shared by 85% of the patients. This lack of homogeneity is in agreement with preceding literature. We confirm the favourable prognosis associated with the presence of anti-PM/Scl, despite the high incidence of interstitial pulmonary disease. The absence of cancer associated with presence of anti-PM/Scl represents a partial explanation. Finally, we report herein the second case of primary Sjögren's syndrome associated with anti-PM/Scl.

The usefulness of bone remodelling markers in predicting the efficacy of pamidronate treatment in SAPHO syndrome.

OBJECTIVES: Pamidronate has recently been used in SAPHO syndrome due to its anti-osteoclastic effect. The aim of this study is to determine the usefulness of bone remodelling markers for determining the efficacy of pamidronate treatment. METHODS: Thirteen patients with SAPHO syndrome were treated with pamidronate. The treatment evaluation was done using a visual analogue scale (VAS) and also erythrocyte sedimentation rate, C-reactive protein, serum crosslaps (sCTX) and osteocalcin initially and after 3 months. A relevant clinical response was defined as an improvement in VAS of at least 40%. RESULTS: At 3 months, 7 of 13 patients had a good clinical response, as previously defined. Five of the seven patients maintained the good response over 6 months. Before the first perfusion 6 of the 13 patients had increased sCTX (upper 3250 pmol/l). In this small cohort we tried to analyse whether the increase in bone remodelling markers was associated with a good clinical response. In the responders group the mean levels of sCTX and osteocalcin at baseline were 6783.17 and 24.66, respectively, and in the non-responders group the levels were 2152 and 11.8, respectively. There was a significant difference in sCTX between the responders and the non-responders (P = 0.0044). CONCLUSION: Infusion of pamidronate is effective in SAPHO in some patients. Increased sCTX might be a prognostic marker for a good clinical response but results have to be confirmed in a larger cohort.

Diagnostic value of serum and synovial procalcitonin in acute arthritis: a prospective study of 42 patients.

OBJECTIVE: To determine the diagnostic value of serum and synovial procalcitonin (PCT) for bacterial arthritis and to determine the cellular origin of synovial PCT. METHODS: A prospective study enrolled 42 patients with acute arthritis including 11 bacterial arthritis, 18 rheumatoid arthritis and 13 crystal induced arthritis. Diagnostic values of serum and synovial PCT levels were determined by a immunoluminometric assay (Lumitest PCT) and compared to those of classical inflammatory markers (C-reactive protein, erythrocyte sedimentation rate, synovial fluid cellularity and both serum and synovial IL-6 and TNF alpha). Using fibroblast-like synoviocyte (FLS) cultures derived from rheumatoid arthritis (n = 4) and osteo-arthritis (n = 3) synovium, with or without stimulation by lipopolysaccharid or recombinant streptococcal protein 1/II, we attempted to determine whether synovial cells could be a source of PCT. RESULTS: Serum PCT was the best parameter to distinguish patients with acute bacterial arthritis from patients with crystal induced arthritis or rheumatoid arthritis. In setting of an acute arthritis serum PCT (> 0.5 ng/mL) achieved 55% sensitivity and 94% specificity for the diagnosis of bacterial arthritis, while CRP (> 50 mg/L) had 100% sensitivity but poor specificity (40%). Serum PCT appeared to be higher in patients with septic arthritis resulting from "systemic infection" than in cases resulting from direct inoculation. Synovial PCT was not useful to discriminate between infectious and non infectious arthritis in clinical practice. PCT could not be detected at significant levels in the conditioned medium from fibroblast-like synoviocyte cultures. CONCLUSION: Serum PCT is a poorly sensitive but specific marker of bacterial arthritis. Use of serum PCT in association with CRP could nevertheless be useful in an emergency situation for the diagnosis of bacterial arthritis.

[Rituximab: a original biotherapy in auto-immune disorders]. / Le rituximab: une biothérapie originale dans les maladies auto-immunes.

SUBJECT: After several decades of hegemony of the T lymphocyte, recent work has suggested the importance of the B lymphocyte in auto-immune diseases. As a consequence, there has emerged over the last few years the idea of using anti-B lymphocyte therapy, in particular rituximab (a chimeric anti-CD20 monoclonal antibody). CURRENT TOPICS AND IMPORTANT RESULTS: This review addresses various current topics: a) the role of B lymphocytes in auto-immune diseases, notably their capacity to be antigen presenting cells and to be activated by original systems like Blys/Baff; b) the mechanism of action of rituximab (apoptosis, complement-dependent cytotoxicity and antibody-dependent cell cytotoxicity) and the phenomena explaining failures and cases escaping treatment, in particular among lymphoproliferations; c) The results include efficacy and tolerance data for the principal auto-immune affections. Among these, the most promising indications would seem to be for rheumatoid polyarthritis and systemic lupus erythematosis, although some preliminary open studies point to an effect in Goujerot-Sjögren's syndrome, neuropathies, auto-immune cytopenia, idiopathic thrombocytopenic purpura, cryoagglutinins, blistering cutaneous affections... PERSPECTIVES AND PROJECTS: Controlled studies will be required to determine the true efficacy and tolerance of this molecule, as it is imperative to validate these new immunotherapeutic strategies, above all when they concern innovative and expensive therapy. Nevertheless, these different observations arouse great hopes and at the same time exciting questions, notably as to the role of B lymphocytes in auto-immune diseases.