Lymphoma complicating rheumatoid arthritis: results from a French case-control study.

OBJECTIVES: To study the characteristics of B-cell non-Hodgkin's lymphoma (NHL) or Hodgkin lymphoma complicating rheumatoid arthritis (RA) and to identify RA-related factors associated with their occurrence. METHODS: A multicentre case-control study was performed in France. Cases were patients with RA fulfilling ACR-EULAR 2010 criteria in whom B-cell NHL or Hodgkin lymphoma developed after the diagnosis of RA. For each case, 2 controls were assigned at random from the ESPOIR cohort and were matched on age at lymphoma diagnosis (cases)/age at the 10-year follow-up visit in the cohort (controls). Case and control characteristics were compared to identify parameters associated with the occurrence of lymphoma. RESULTS: 54 cases were included and matched to 108 controls. Lymphomas were mostly diffuse large B-cell lymphoma (DLBCL, n=27, 50.0%). On immunochemistry, 4 of 27 (14.8%) lymphoma cases were positive for Epstein-Barr virus. On univariate analysis, factors associated with the occurrence of lymphoma were male sex (OR 3.3, 95% CI 1.7 to 6.7), positivity for ACPA (OR 5.1, 95% CI 2.0 to 15.7) and rheumatoid factor (OR 3.9, 95% CI 1.6 to 12.2), and erosions on radiographs (OR 3.8, 95% CI 1.7 to 8.3) and DAS28 (OR 2.0, 95% CI 1.5 to 2.7), both at the time of matching. Methotrexate, TNF blockers and a number of previous biologics were not associated with the occurrence of lymphoma. On multivariable analysis, erosions and DAS28 remained significantly associated with increased risk of lymphoma. CONCLUSION: Lymphomas complicating RA are mostly DLBCL. Risk of lymphoma in patients with RA was increased with markers of disease activity and severity, which supports the paradigm of a continuum between autoimmunity and lymphomagenesis in RA.

Therapeutic Maintenance of Baricitinib and Tofacitinib in Real Life.

BACKGROUND: Janus kinase inhibitors (JAKis) represent a new alternative to treat rheumatoid arthritis (RA). The objective of this study was to evaluate the effectiveness, tolerance profile, and maintenance of these treatments (tofacitinib and baricitinib) in real life. METHODS: All patients in the rheumatology department of Amiens University Hospital treated by JAKis for RA were included from 1 October 2017 to 20 May 2020. Clinical and biological data were provided retrospectively in this observational and single-center study. We aimed to study the JAKi maintenance rate at 12 months and their clinical and biological safety profiles. RESULTS: Fifty-five patients were included. Drug maintenance at 12 months was 67.6%. Factors associated with poorer maintenance were a higher Charlson comorbidity index (HR 1.311 (1.089-1.579); p = 0.0042), a higher age (HR 1.055 (1.015-1.096); p = 0.0067), and corticosteroids therapy at initiation (HR 2.722 (1.006-7.365); p = 0.0487). The clinical and biological safety profile was generally good. CONCLUSIONS: Our study found that a higher Charlson index, age, and corticosteroids appeared to be associated with the earlier discontinuation of treatment. JAKis had a response and tolerance profile in real life at least equivalent to that of biological disease-modifying antirheumatic drugs (bDMARDs).

Worsening and newly diagnosed paraneoplastic syndromes following anti-PD-1 or anti-PD-L1 immunotherapies, a descriptive study.

BACKGROUND: Paraneoplastic syndromes (PNS) are autoimmune disorders specifically associated with cancer. There are few data on anti-PD-1 or anti-PD-L1 immunotherapy in patients with a PNS. Our objective was to describe the outcome for patients with a pre-existing or newly diagnosed PNS following the initiation of anti-PD-1 or anti-PD-L1 immunotherapy. METHODS: We included all adult patients (aged ≥18) treated with anti-PD-1 or anti-PD-L1 immunotherapy for a solid tumor, diagnosed with a PNS, and registered in French pharmacovigilance databases. Patients were allocated to cohorts 1 and 2 if the PNS had been diagnosed before vs. after the initiation of immunotherapy, respectively. FINDINGS: Of the 1304 adult patients screened between June 27th, 2014, and January 2nd, 2019, 32 (2.45%) had a PNS and were allocated to either cohort 1 (n = 16) or cohort 2 (n = 16). The median (range) age was 64 (45-88). The tumor types were non-small-cell lung cancer (n = 15, 47%), melanoma (n = 6, 19%), renal carcinoma (n = 3, 9%), and other malignancies (n = 8, 25%). Eleven (34%) patients presented with a neurologic PNS, nine (28%) had a rheumatologic PNS, eight (25%) had a connective tissue PNS, and four (13%) had other types of PNS. The highest severity grade for the PNS was 1-2 in 10 patients (31%) and ≥ 3 in 22 patients (69%). Four patients (13%) died as a result of the progression of a neurologic PNS (encephalitis in three cases, and Lambert-Eaton syndrome in one case). Following the initiation of immunotherapy, the PNS symptoms worsened in eight (50%) of the 16 patients in cohort 1. INTERPRETATION: Our results show that PNSs tend to be worsened or revealed by anti-PD-1 or anti-PD-L1 immunotherapy. Cases of paraneoplastic encephalitis are of notable concern, in view of their severity. When initiating immunotherapy, physicians should carefully monitor patients with a pre-existing PNS.

Mobile Phone Text Messages and Effect on Treatment Adherence in Patients Taking Methotrexate for Rheumatoid Arthritis: A Randomized Pilot Study.

OBJECTIVE: To assess the impact of weekly text messages on adherence in patients taking methotrexate (MTX) for rheumatoid arthritis (RA). METHODS: This prospective, randomized pilot, single-site study included patients with RA stabilized using MTX alone or combined with biologics. Participants were randomized to 3 interventions: a standard consultation (controls), a 15-minute pharmacist-led counseling session, or the receipt of text message reminders. The change over time in the Compliance Questionnaire Rheumatology (CQR-19) score between baseline and 6 months was defined as the primary outcome for adherence. Multivariable analyses and final adherence (as a composite outcome of the CQR-19 score, the Girerd score, and the medication possession ratio) were probed in sensitivity tests. Rheumatologic scales, inflammation, and patient satisfaction were also analyzed. RESULTS: A total of 96 patients (mean ± SD Disease Activity Score in 28 joints 2.42 ± 1.03) were monitored. The change over time in the CQR-19 score was significantly higher in the text message group (mean ± SD 3.32 ± 5.66; P = 0.02) than in the control group (mean ± SD 0.22 ± 6.56) and the pharmacist-led counseling group (mean ± SD -0.14 ± 7.56). Multivariable logistic regression showed that text messages remained associated with an increase in the CQR-19 score, independently of the baseline CQR-19 score (odds ratio 3.63 [95% confidence interval 1.26-10.49]; P = 0.017). In the text message group, the increase in the CQR-19 score was correlated with the Health Assessment Questionnaire score (r = -0.405, P = 0.021), and patient satisfaction was significantly higher (P < 0.01) than in the control group. CONCLUSION: Our results showed evidence of a positive impact of text messages on adherence to MTX treatment for RA. The clinical benefit and the ideal target patient remain to be determined.

Morbimortality in adult patients with septic arthritis: a three-year hospital-based study.

BACKGROUND: The objective of this ambispective study was to determine outcomes and associated factors for adult patients with confirmed septic arthritis (SA). METHODS: All adult patients admitted to Amiens University Hospital between November 2010 and December 2013 with confirmed SA were included in the study. Patients with prosthetic joint infections were excluded. A statistical analysis was performed in order to identify risk factors associated with a poor outcome (including mortality directly attributable to SA). RESULTS: A total of 109 patients (mean ± SD age: 60.1 ± 20.1; 74 male/35 females) were diagnosed with SA during the study period. The most commonly involved sites were the small joints (n = 34, 31.2 %) and the knee (n = 25, 22.9 %). The most frequent concomitant conditions were cardiovascular disease (n = 45, 41.3 %) and rheumatic disease (n = 39, 35.8 %). One hundred patients (91.7 %) had a positive microbiological culture test, with Staphylococcus aureus as the most commonly detected pathogen (n = 59, 54.1 %). Mortality directly attributable to SA was relatively infrequent (n = 6, 5.6 %) and occurred soon after the onset of SA (median [range]: 24 days [1-42]). Major risk factors associated with death directly attributable to SA were older age (p = 0.023), high C-reactive protein levels (p = 0.002), diabetes mellitus (p = 0.028), rheumatoid arthritis and other inflammatory rheumatic diseases (p = 0.021), confusion on admission (p = 0.012), bacteraemia (p = 0.015), a low creatinine clearance rate (p = 0.009) and the presence of leg ulcers/eschars (p = 0.003). The median duration of follow-up (in patients who survived for more than 6 months) was 17 months [6-43]. The proportion of poor functional outcomes was high (31.8 %). Major risk factors associated with a poor functional outcome were older age (0.049), hip joint involvement (p = 0.003), the presence of leg ulcers/eschars (p = 0.012), longer time to presentation (0.034) and a low creatinine clearance rate (p = 0.013). CONCLUSIONS: In a university hospital setting, SA is still associated with high morbidity and mortality rates.

Decrease of Tocilizumab Dose in Patients with Rheumatoid Arthritis: A Pilot Study.

BACKGROUND: The efficacy and safety of tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) are well demonstrated. Doses of 4 and 8 mg/kg are used intravenously. The objective of our study was to report the efficacy and safety for a set of patients who had an 8 mg/kg doze of TCZ and for another set who had this treatment first at a dose of 8 followed by 4 mg/kg. METHODS: All RA patients treated with TCZ in a University Hospital Centre Department of Rheumatology between January 2010 and December 2014 were included. Sixty-three patients received TCZ at a dose of 8 mg/kg and 19 patients received this treatment first receiving a dose of 8 mg/kg decreased to 4 mg/kg. The demographic characteristics, the clinical response and adverse events were reported. RESULTS: At the end of follow-up, 48% of patients were in clinical remission defined by disease activity score based on 28 joints with an erythrocyte sedimentation rate <2.6 in the 8 mg/kg group and 74% of patients in the 8-4 mg/kg. The rates of severe infections were 4.8 per 100 patients-years (PY) in the 8 mg/kg group and 2.9 per 100 PY in the 8 then 4 mg/kg. The infections were mainly pulmonary, ENT and skin infections. CONCLUSION: Our study reported the efficacy and safety of the TCZ in patients with RA in 'real life' with the dose of 8 mg/kg or 8 then 4 mg/kg.

Difficulties in the diagnosis of vertebral fracture in men: agreement between doctors.

UNLABELLED: The agreement for vertebral fracture (VF) diagnosis in men, between doctors is poor. OBJECTIVES: To assess the agreement for VF diagnosis, in men, on standard radiographs, between experts, before and after consensual workshop and establishing an algorithm. METHODS: The agreement between thirteen experimented rheumatologists has been calculated in thirty osteoporotic men. Then, the group discussed in a workshop and 28 other radiograph sets of osteoporotic men with follow-up radiographs and incident confirmed VF, have been reviewed. The experts identified and hierarchised 18 pathological features of vertebral deformation and established an algorithm of VF diagnosis. Eleven experts have realized a second reading of the first set of radiographs. We compared the agreement between the 2 readings without and with the algorithm. RESULTS: After consensus and the use of the algorithm the results are: number of fractured patients (with at least 1 VF) according to the experts varies from 13 to 26 patients out of 30 (13 to 28 during the first reading). The agreement between the experts at the patient level is 75% (70% at the first reading). Among the 390 vertebrae analyzed by the experts, the number of VF detected varies from 18 to 59 (18 to 98 at the first reading). The agreement between the experts at the vertebral level is 92% (89% at the first reading). The algorithm allows a good improvement of the agreement, especially for 8 of the 11 experts. Discrepancies for the VF diagnosis between experts exist. The algorithm improves the agreement.

Treatment persistence and changes in fracture risk, back pain, and quality of life amongst patients treated with teriparatide in routine clinical care in France: results from the European Forsteo Observational Study.

OBJECTIVES: The European Forsteo Observational Study assessed the clinical fracture incidence, back pain, quality of life (QoL), and treatment persistence amongst post-menopausal women, who were prescribed teriparatide in routine care in eight European countries. We present the results for France, with health-insurance reimbursement criteria channel teriparatide to women with severe disease and limit treatment to 18 months. METHODS: A representative sample of women initiating teriparatide in France was followed in routine care for 36 months. We described patients' characteristics at baseline and persistence to teriparatide (Kaplan-Meier analysis), fracture incidence, back pain, and QoL (EQ-5D) at baseline, 18 and 36 months follow-up (last-observation-carried-forward (LOCF) and mixed-models-for-repeated-measures (MMRM). RESULTS: One hundred and sixteen rheumatologists included 309 patients, of whom 290 (93.9%) had at least one follow-up visit. Women's mean age (standard deviation) was 74.5 years (7.4) and 296 (95.8%) had greater or equal to two vertebral fractures prior to teriparatide initiation. Clinical fracture incidence, mainly vertebral fractures, decreased around 6 months after teriparatide initiation, and was sustained at 36 months (P=0.013) when most patients were treated by anti-resorptives. Back pain and EQ-5D measures improved significantly at 18 and 36 months (P<0.0001) in the LOCF analyses but did not improve in the EQ-5D VAS measure after covariate adjustment in the MMRM model. Median treatment duration was 17.4 months. CONCLUSION: French women initiating teriparatide in routine care had severe osteoporosis and showed good treatment persistence, consistent with France's insurance reimbursement criteria. Improvements in fracture risk and back pain began soon after treatment and was maintained at 36 months follow-up.

Musculoskeletal ultrasonography in healthy subjects and ultrasound criteria for early arthritis (the ESPOIR cohort).

OBJECTIVE: To confirm the occurrence of bone erosions and synovitis in healthy subjects detectable by ultrasound (US) and to establish US criteria for early arthritis. METHODS: Our study involved 127 healthy subjects matched with a cohort of patients with early arthritis (the ESPOIR cohort). The second and fifth metacarpophalangeal (MCP) joints and the fifth metatarsophalangeal (MTP) joint of both hands and feet were assessed with US to detect bone erosion; and the second, third, fourth, and fifth MCP and the fifth MTP were evaluated for synovial thickening in B-mode US and synovial vascularity in power Doppler. Bone erosion and synovitis were defined according to the Outcome Measures in Rheumatology Clinical Trials consensus. RESULTS: Bone erosion and grade 2-3 synovial thickening in B-mode were detected in 11% and 9% of healthy subjects. To consider the diagnosis of early arthritis, a cutoff at 1 case of synovial thickening in B-mode enabled discrimination between patients with early arthritis and healthy subjects, with a good sensitivity of 74.8% (95% CI 67.2%-82.3%) and a high specificity of 90.5% (95% CI 85.4%-95.6%). If higher specificity is required to confirm the diagnosis of early arthritis, cutoff at 2 cases of synovial thickening in B-mode or at 2 cases of bone erosion gave optimal results, with specificity of 98.4% (95% CI 96.2%-100%) and 100%, respectively, and lower sensitivity of 59.8% (95% CI 51.2%-68.3%) and 17% (95% CI 10.5%-23.5%) (area under the curve = 0.85 for synovitis and 0.63 for bone erosion). Neither the combination of power Doppler signal plus bone erosion, nor bone erosions plus synovial thickening on the same joint, were seen in healthy subjects. CONCLUSION: A single case of bone erosion or synovial thickening in B-mode is common in healthy subjects. However, more than 1 case of synovial thickening in B-mode or bone erosion is a strong argument for the diagnosis of early inflammatory arthritis.

First case of human spondylodiscitis due to Shewanella algae.

We present the first case of human spondylodiscitis due to Shewanella algae. Our patient did not have any predisposing factors. The portal of entry was probably a cutaneous lesion on the leg, exposed to seawater. Bacteria were isolated in pure culture from a needle biopsy specimen of the vertebral disk. Automated identification systems identified the organism as Shewanella putrefaciens. However, molecular biology identified it as S. algae. Treatment with ceftriaxone and amikacin, then ciprofloxacin successfully addressed the infection. We also review four published cases of human osteoarticular infections caused by Shewanella spp: two cases of arthritis and two cases of osteomyelitis. Two patients had predisposing factors, and contact with water was found in two cases. The clinical, radiological and biological characteristics of S. algae spondylodiscitis are indistinguishable from those of spondylodiscitis of other causes. A cutaneous lesion with exposure to water is a potential portal of entry. Molecular typing is necessary to obtain a precise bacteriological identification.

Hematogenous Staphylococcus aureus discitis in adults can start outside the vertebral body.

BACKGROUND: Textbooks describe hematogenous discitis in adults as starting in the anterior vertebral body near the endplates. CASE REPORT: Hematogenous Staphylococcus aureus discitis developed at L1-L2 in an 81-year-old woman. On the first magnetic resonance imaging (MRI) scan performed 4 days after symptom onset, the only abnormalities were high signal from the disk on T2-weighted images, gadolinium enhancement of the soft tissues anterior to L1-L2, and epidural involvement. The endplates and vertebral bodies were normal. A subsequent MRI scan showed features typical of infectious discitis. DISCUSSION: We found a single similar case report in the medical literature, indicating that discitis starting outside the anterior vertebral body is rare. Nevertheless, an increasing number of similar cases may be diagnosed in the future, as MRI is being performed increasingly early in patients with a clinical suspicion of infectious discitis. CONCLUSION: Hematogenous infectious discitis in adults may start in some patients within the disk, soft tissues anterior to the disk, or epidural space. To avoid diagnostic and therapeutic delays, physicians should be aware of this unusual presentation of infectious discitis on very early MRI scans. When the clinical picture suggests discitis and findings from the early MRI scan are atypical, a repeat MRI scan should be obtained 1 week later to confirm the diagnosis.

Radiographic methods for evaluating osteoporotic vertebral fractures.

UNLABELLED: Reproducible methods for the radiological assessment of osteoporotic vertebral fractures, defined based on accurate criteria, are needed in everyday practice and in therapeutic trials and epidemiological studies. OBJECTIVES: To describe and to evaluate methods for osteoporotic vertebral fracture assessment based on standard radiographs or dual-energy X-ray absorptiometry (DXA) and to determine the role for each method in clinical practice, therapeutic trials, and epidemiological studies. METHODS: A review written by a rheumatologist based on his clinical experience and on a literature review was submitted to four experts. Studies in English or French published between 1975 and February 2008 were retrieved from Medline using the keywords vertebral fracture, osteoporosis, vertebral deformity, and vertebral fracture assessment. RESULTS: One hundred forty-nine articles were selected and read in their full-text version. There was no consensus regarding the definition of osteoporotic vertebral fractures. The following methods were evaluated: visual assessment, Genant's semi-quantitative assessment, Jiang's algorithm-based qualitative method, morphometric radiography, and DXA of the spine. In everyday practice, Genant's semi-quantitative assessment on standard radiographs may provide useful information on the severity and prognosis of osteoporosis. DXA done for bone mineral density measurement may detect vertebral fractures in asymptomatic patients. Assessment of standard radiographs remains the reference standard for diagnosing vertebral fractures in patients with suggestive symptoms (e.g., pain in the thoracic or lumbar spine, height loss, or thoracic kyphosis). For therapeutic trials and epidemiological studies, Genant's semi-quantitative assessment used by a trained and experienced observer is the preferred method, based on its good reproducibility and ability to differentiate fractures from other deformities. However, thousands of radiographs may be needed, making routine interpretation by an expert impractical. A visual semi-quantitative method may be used to separate normal radiographs from radiographs showing possible or obvious fractures, which can then be read by an expert. Alternatively, radiomorphometric indices can be determined on digitized radiographs in combination with a semi-quantitative assessment, with discordant cases being reviewed by an expert. We do not recommend Jiang's method at present, as it is still undergoing validation.

Discitis due to Clostridium perfringens.

INTRODUCTION: A combination of disk space narrowing and vacuum phenomenon on radiographs of the spine is usually considered a reliable indicator of degenerative disk disease. We report a case in which vacuum phenomenon was related to Clostridium perfringens discitis. METHODS: A 79-year-old woman was admitted for inflammatory low back pain that had worsened steadily over the last 2 months. Her body temperature was normal, laboratory tests showed inflammation (erythrocyte sedimentation rate, 61 mm/h; and C-reactive protein, 13 mg/L), and blood cultures were negative. Imaging studies (radiographs, computed tomography [CT], and magnetic resonance imaging) indicated L4-L5 discitis. Vacuum phenomenon within the L4-L5 disk was seen on radiographs and CT scans. C. perfringens was recovered by fine-needle biopsy of the disk. Diverticular disease of the colon was the only identifiable portal of entry. Amoxicillin therapy ensured a full recovery. DISCUSSION: C. perfringens discitis is rare, with only 7 published cases in humans. A gastrointestinal portal of entry was identified in 70% of cases. Radiographs or CT scans visualized vacuum phenomenon in 80% of cases. Positive blood cultures were noted in 75% of cases. The outcome was favorable with antibiotic therapy, even when a single-drug was used. The other characteristics of C. perfringens discitis were indistinguishable from those of discitis caused by the usual organisms. CONCLUSION: Presence of gas within the disk does not rule out infectious discitis and may indicate C. perfringens discitis.

Suggestions for managing pyogenic (non-tuberculous) discitis in adults.

OBJECTIVES: To develop recommendations about identifying the causative organism, obtaining imaging studies, and selecting pharmacological and non-pharmacological treatments in adults with pyogenic discitis and vertebral osteomyelitis (PDVO). METHODS: A rheumatologist and an infectiologist drafted recommendations based on their personal experience and a review of studies in English or French retrieved on Medline using the following search terms: "infectious spondylodiscitis", "infectious spondylitis", "spondylodiscitis", "discitis", "vertebral osteomyelitis", "spine infection", and "bone and joint infections". The recommendations were submitted to four experts for validation. RESULTS: 85 articles were selected for detailed review. No prospective randomized controlled trials were identified. Antimicrobial therapy should be initiated only after recovery of the causative organism in blood cultures or percutaneous disk biopsy specimens, except in patients with neutropenia or severe sepsis. The initial treatment rests on a combination of two bactericidal and synergistic antimicrobials in high dosages. The total duration of antimicrobial therapy should be 12 weeks at least. Radiographs of the spine and chest and magnetic resonance imaging (MRI) of the spine should be performed routinely during the initial evaluation. In PDVO due to hematogenous dissemination of a streptococcus or staphylococcus, routine echocardiography may be in order. Radiographs centered on the affected disk should be obtained 1 and 3 months into antimicrobial therapy and 3 months after treatment discontinuation. Follow-up MRI is usually unnecessary when the clinical and laboratory abnormalities respond to treatment. If not, or if the initial investigations show a collected abscess, a repeat MRI after 1 month of antimicrobial treatment may be useful. Clinical and laboratory follow-up is mandatory throughout antimicrobial therapy and during the first 6 months after treatment discontinuation. CONCLUSIONS: Recommendations based on descriptive studies and expert opinion were developed. They can be expected to improve the quality and uniformity of PDVO management. Further studies are needed to improve the level of evidence that is available for developing recommendations. In particular, prospective randomized multicenter studies should be performed to compare the intravenous to the oral route for initial antimicrobials administration and to compare different treatment durations.

Osteoarticular side effects of BCG therapy.

Although osteoarticular side effects of the Bacillus Calmette-Guérin (BCG) are rare compared to the number of administrations, BCG vaccination and cancer therapy are so widely used that the absolute number of cases is not negligible. Osteoarticular infection is an exceedingly rare complication of vaccination with the BCG. Intravesical BCG instillations used to treat superficial bladder cancer may cause arthralgia, reactive arthritis or osteoarticular infections. Intradermal BCG therapy used to treat a number of malignancies can cause osteoarticular infections or bilateral symmetric polyarthritis predominating in the wrists and fingers. In practice, when intravesical BCG instillation is followed by arthritis, hyperthermia is unhelpful for distinguishing septic arthritis from reactive arthritis. Arguments pointing to reactive arthritis include oligo- or polyarticular involvement and onset a few weeks (as opposed to a few months) after the last instillation. Nevertheless, joint fluid examination is in order to rule out septic arthritis. BCG-induced reactive arthritis usually responds well to nonsteroidal anti-inflammatory drugs. Osteoarticular infections related to BCG therapy should be treated by rifampin, isoniazid and ethambutol for 2 months, followed by rifampin and isoniazid for 10 months.