Methotrexate osteopathy: five cases and systematic literature review.

INTRODUCTION: Methotrexate (MTX)-related osteopathy is rare, defined by the triad of pain, osteoporosis, and "atypical fractures" when it was first described in the 1970s in children treated with high doses MTX for acute leukemia. Since then, several cases have been reported in patients treated with low-dose MTX for inflammatory diseases. METHODS: A systematic research of cases of MTX-related osteopathy was performed in records of Rheumatology Department of Rennes University Hospital. Data collection focused on demographic data, corticosteroid doses, MTX doses and intake method, cumulative doses, year of diagnosis, fracture location, bone densitometry value, and osteoporosis treatment if necessary. A literature review was also conducted to identify other cases in literature and try to understand the pathophysiological mechanisms of this rare entity. RESULTS: We report 5 cases identified between 2011 and 2019, which represents the largest cohort described excluding oncology cases. Fracture locations were atypical for osteoporotic fractures. All patients improved in the following months with MTX withdrawal. All patients except one were treated with antiresorptives (bisphosphonates, denosumab). Two patients, treated with bisphosphonates, had a recurrence of fracture, once again of atypical location. Twenty-five cases were collected in literature with similar clinical presentation. The cellular studies that investigated the bone toxicity of MTX mainly showed a decrease in the number of osteoblasts, osteocytes, and chondrocytes in the growth plate and an increase in the number and activity of osteoclasts. In vitro, consequences of mechanical stimulation on human trabecular bone cells in the presence of MTX showed an alteration in mechano-transduction, with membrane hyperpolarization, acting on the integrin pathway. In contrast with our report, the cases described in the literature were not consistently associated with a decrease in bone mineral density (BMD). CONCLUSION: MTX osteopathy while rare must be known by the rheumatologist, especially when using this treatment for inflammatory conditions. The mechanisms are still poorly understood, raising the question of a possible remnant effect of MTX on osteo-forming bone cells, potentially dose-dependent. Methotrexate (MTX) osteopathy, described as a clinical triad, pain, osteoporosis, and atypical stress fractures, while rare, must be known by the rheumatologist. Our cohort of 5 cases represent the largest series of the literature. Pathophysiological studies raised the question of a dose-dependent remnant effect of MTX on osteo-forming bone cells.

Etiology of avascular osteonecrosis of the femoral head.

Avascular osteonecrosis of the femoral head (ONFH) is one of the causes of hip pain that clinicians need to know about. In many cases, it is a fortuitous discovery when pelvic X-rays is performed for another reason. In the other cases, pain reveals the disease. For the rheumatologist, a major part of the job is to look for a cause. An etiology can be found to ONFH in about 70% of the cases. Some of them are evident and the context give the diagnosis (corticosteroids, alcohol abuse…). However, in many cases, additional tests to imaging are required to make the causal diagnosis. In some cases, the treatment of the cause can prevent the recurrence of the disease.

External validation of Gout-calculator performance on a cohort of acute arthritis (SYNOLACTATE) sparing distal joints such as hallux and midfoot. A cross-sectional study of 170 patients.

OBJECTIVE: To evaluate the performance of the Gout-calculator in a cohort of consecutive acute arthritis affecting large and intermediate joints (without an attack on hallux or midfoot joints). METHODS: A retrospective study. Gout-calculator data were collected in medical records of patients included in the prospective consecutive cohort of acute arthritis called SYNOLACTATE. The diagnosis of gout was defined by the presence of sodium urate crystals in synovial fluid. The diagnostic performance of the Gout-calculator was studied by performing an ROC curve with the calculation of its AUC (95% CI) as well as the calculation of Sensitivity (Se), Specificity (Sp), and positive likelihood ratio (LR+). RESULTS: 170 patients with acute arthritis were included. Variables associated with the diagnosis of gout were as follows: serum uric acid > 350 µmol/L (OR 5.52 (2.52-12.1), p < 0.001), joint redness (OR 5.08 (1.85-14.0), p = 0.001), previous patient-reported arthritis attack (OR 4.04 (1.92-8.49), p < 0.001), male (OR 3.00 (1.17-7.69), p = 0.02), hypertension or cardiovascular disease (OR 2.33 (1.07-5.06), p = 0.03). The median (IQR) of Gout-calculator was significantly higher in gouty arthritis (7.0 [5.5-8.1]) than in associated-CPP acute arthritis (4.0 [2.0-5.8]), septic arthritis (3.0 [2.0-5.1]), or others arthritis (3.5 [2.0-5.5]). The AUC was 0.833 (0.768-0.897) with for the threshold ≥ 8, a Se at 27.5% (0.161-0.428), Sp 97.7% (0.934-0.992), and LR+ 11.9 (3.5-40). CONCLUSION: Despite diagnostic performances close to those published, the use of the Gout-calculator is not sufficient for the diagnosis of gout or to exclude the differential diagnosis of septic arthritis in the SYNOLACTATE cohort. KEY POINTS: • For a Gout-calculator threshold of ≤ 4, Sensitivity is 92.5%, Specificity 50.8% and LR- 0.15 to the gout diagnosis. • For a Gout-calculator threshold of > = 8, Sensitivity is 27.5%, Specificity 97.7% and LR+ 11.9 to the gout diagnosis. • In a population of acute arthritis affecting large joints, Gout-calculator is not sufficient to discriminate between gouty arthritis and septic arthritis.

Towards a better understanding of the genetic and physiological basis for nitrogen use efficiency in maize.

To enhance our understanding of the genetic basis of nitrogen use efficiency in maize (Zea mays), we have developed a quantitative genetic approach by associating metabolic functions and agronomic traits to DNA markers. In this study, leaves of vegetative recombinant inbred lines of maize, already assessed for their agronomic performance, were analyzed for physiological traits such as nitrate content, nitrate reductase (NR), and glutamine synthetase (GS) activities. A significant genotypic variation was found for these traits and a positive correlation was observed between nitrate content, GS activity and yield, and its components. NR activity, on the other hand, was negatively correlated. These results suggest that increased productivity in maize genotypes was due to their ability to accumulate nitrate in their leaves during vegetative growth and to efficiently remobilize this stored nitrogen during grain filling. Quantitative trait loci (QTL) for various agronomic and physiological traits were searched for and located on the genetic map of maize. Coincidences of QTL for yield and its components with genes encoding cytosolic GS and the corresponding enzyme activity were detected. In particular, it appears that the GS locus on chromosome 5 is a good candidate gene that can, at least partially, explain variations in yield or kernel weight. Because at this locus coincidences of QTLs for grain yield, GS, NR activity, and nitrate content were also observed, we hypothesize that leaf nitrate accumulation and the reactions catalyzed by NR and GS are coregulated and represent key elements controlling nitrogen use efficiency in maize.