Relevance of circulating Semaphorin 4A for rheumatoid arthritis response to treatment.

The lack of validated tools to predict rheumatoid arthritis (RA) disease course warrants the development of new reliable biomarkers. Our aim was to evaluate the merit of circulating SEMA4A for the prediction of outcomes in patients with RA. In a first cohort of 101 consecutive RA patients followed up for 41 ± 15 months, increased baseline SEMA4A levels were identified as an independent predictor of treatment failure (hazard ratio, HR 2.71, 95% CI 1.14-6.43), defined by the occurrence of patient-reported flares and initiation or change of targeted therapy. The highest predictive value of treatment failure was obtained with the combination of increased circulating SEMA4A and/or Disease Activity Score (DAS) 28-CRP > 3.2 and/or active synovitis on doppler ultrasound (HR 10.42, 95% CI 1.41-76.94). In a second independent cohort of 40 consecutive RA patients who initiated new therapy because of insufficient disease control, baseline SEMA4A levels were significantly higher in patients who further experienced none or moderate response, and SEMA4A concentrations were markedly decreased in the group of patients with good clinical response as compared to non-responders. Circulating SEMA4A appears as an appealing biomarker in RA with ability to predict treatment failure, and with association with response to therapy.

Risk of liver fibrosis induced by methotrexate and other rheumatoid arthritis medications according to the Fibrosis-4 Index.

OBJECTIVES: We aimed to estimate the amount of scarring in the liver with the fibrosis-4 (FIB-4) index in patients with rheumatoid arthritis (RA) with special interest in methotrexate (MTX) influence. METHODS: This was a cross-sectional monocentric study including successive RA patients recruited for a 12-month period. Data on liver function, disease activity, hepatotoxic and cardiovascular risk factors were systematically collected. The FIB-4 index was calculated according the following formula: (age(years)× AST(U/L)/platelet (PLT) (109/L)×√ALT(U/L)). RESULTS: We included 170 patients with established RA: 141 (83%) were women with a mean age of 59±12 years and mean disease duration of 15±11 years. The FIB-4 was low and not significantly different between patients receiving MTX (n=102), patients previously treated with MTX (n=39) and patients never treated with MTX (n=29). No correlation was observed between FIB-4 values and cumulative MTX dose (r=0.09, p=0.271). No relationship was observed between FIB-4 and MTX treatment duration. The FIB-4 index was found significantly increased in patients receiving leflunomide (n=24), (median (range) 1.58 (0.46-3.16) vs. 1.18 (0.54-3.40), p=0.019) and tocilizumab (n=14), (median (range) 1.82 (0.75-3.73) vs. 1.18 (0.54-3.40), p=0.005) compared to patients not receiving DMARDs (n=29). Multivariate logistic regression analyses revealed an independent association between increased FIB-4 (>1.45) and male gender, low disease activity, and treatment with leflunomide and tocilizumab. CONCLUSIONS: RA patients with long-term maintenance MTX therapy have low FIB-4 values suggesting that MTX is not associated with an increased risk of advanced liver fibrosis. Increased FIB-4 values have been detected in leflunomide- and tocilizumab-treated patients, which will deserve dedicated further investigations.

Systematic assessment of the humoral response against SARS-CoV-2 in a French cohort of 283 patients with rheumatic diseases.

OBJECTIVES: To estimate the seroprevalence of SARS-CoV-2 infection in patients with rheumatic diseases and to specify the proportion of asymptomatic and symptomatic forms of COVID-19. METHODS: We screened for SARS-CoV-2 infection among spondyloarthritis (SpA, n=143) or rheumatoid arthritis (RA, n=140) patients in our outpatient clinic at Cochin Hospital in Paris between June and August 2020. We performed a qualitative SARS-CoV-2 serological test which detects IgG directed against the N nucleocapsid protein (anti-N) and, for some patients, against the Spike protein (anti-S). Descriptive analyses were managed. RESULTS: During June-August 2020, the SARS-CoV-2 seroprevalence rate in our population was 2.83% (8/283 patients) without significant difference between RA and SpA patients (2.14% and 3.5%, respectively). We report 11 out of 283 patients (3.8%) with a diagnosis of SARS-CoV-2 infection. Among these 11 patients, 1 patient was asymptomatic (9%) with a confirmed diagnosis of COVID-19 by anti-S serology. Of the 283 patients, 85% were under bDMARDs, mainly on rituximab (RTX) (n=44) and infliximab (IFX) (n=136). CONCLUSIONS: The seroprevalence of SARS-CoV-2 in patients with rheumatic diseases, mainly under bDMARDs treatments, was 2.83%. Among infected patients, 9% were asymptomatic. Detecting SARS-CoV-2 infections could be based on the strategy using patients' interview and anti-N serology.

Intervertebral disc therapies for non-specific chronic low back pain: a systematic review and meta-analysis.

OBJECTIVES: We aim to evaluate the benefits and harms of intervertebral disc therapies (IDTs) in people with non-specific chronic low back pain (NScLBP). METHODS: We conducted a systematic review and meta-analysis of randomized trials of IDTs versus placebo interventions, active comparators or usual care. EMBASE, MEDLINE, CENTRAL and CINHAL databases and conference abstracts were searched from inception to June 2020. Two independent investigators extracted data. The primary outcome was LBP intensity at short term (1 week-3 months), intermediate term (3-6 months) and long term (after 6 months). RESULTS: Of 18 eligible trials (among 1396 citations), five assessed glucocorticoids (GCs) IDTs and were included in a quantitative synthesis; 13 assessed other products including etanercept (n = 2), tocilizumab (n = 1), methylene blue (n = 2), ozone (n = 2), chymopapaine (n = 1), glycerol (n = 1), stem cells (n = 1), platelet-rich plasma (n = 1) and recombinant human growth and differentiation factor-5 (n = 2), and were included in a narrative synthesis. Standardized mean differences (95% CI) for GC IDTs for LBP intensity and activity limitations were -1.33 (-2.34; -0.32) and -0.76 (-1.85; 0.34) at short term, -2.22 (-5.34; 0.90) and -1.60 (-3.51; 0.32) at intermediate term and -1.11 (-2.91; 0.70) and -0.63 (-1.68; 0.42) at long term, respectively. Odds ratios (95% CI) for serious and minor adverse events with GC IDTs were 1.09 (0.25; 4.65) and 0.97 (0.49; 1.91). CONCLUSION: GC IDTs are associated with a reduction in LBP intensity at short term in people with NScLBP. Positive effects are not sustained. IDTs have no effect on activity limitations. Our conclusions are limited by high heterogeneity and a limited methodological quality across studies. REGISTRATION: PROSPERO: CRD42019106336.

Effect of Osteopathic Manipulative Treatment vs Sham Treatment on Activity Limitations in Patients With Nonspecific Subacute and Chronic Low Back Pain: A Randomized Clinical Trial.

Importance: Osteopathic manipulative treatment (OMT) is frequently offered to people with nonspecific low back pain (LBP) but never compared with sham OMT for reducing LBP-specific activity limitations. Objective: To compare the efficacy of standard OMT vs sham OMT for reducing LBP-specific activity limitations at 3 months in persons with nonspecific subacute or chronic LBP. Design, Setting, and Participants: This prospective, parallel-group, single-blind, single-center, sham-controlled randomized clinical trial recruited participants with nonspecific subacute or chronic LBP from a tertiary care center in France starting February 17, 2014, with follow-up completed on October 23, 2017. Participants were randomly allocated to interventions in a 1:1 ratio. Data were analyzed from March 22, 2018, to December 5, 2018. Interventions: Six sessions (1 every 2 weeks) of standard OMT or sham OMT delivered by nonphysician, nonphysiotherapist osteopathic practitioners. Main Outcomes and Measures: The primary end point was mean reduction in LBP-specific activity limitations at 3 months as measured by the self-administered Quebec Back Pain Disability Index (score range, 0-100). Secondary outcomes were mean reduction in LBP-specific activity limitations; mean changes in pain and health-related quality of life; number and duration of sick leaves, as well as number of LBP episodes at 12 months; and consumption of analgesics and nonsteroidal anti-inflammatory drugs at 3 and 12 months. Adverse events were self-reported at 3, 6, and 12 months. Results: Overall, 200 participants were randomly allocated to standard OMT and 200 to sham OMT, with 197 analyzed in each group; the median (range) age at inclusion was 49.8 (40.7-55.8) years, 235 of 394 (59.6%) participants were women, and 359 of 393 (91.3%) were currently working. The mean (SD) duration of the current LBP episode was 7.5 (14.2) months. Overall, 164 (83.2%) patients in the standard OMT group and 159 (80.7%) patients in the sham OMT group had the primary outcome data available at 3 months. The mean (SD) Quebec Back Pain Disability Index scores for the standard OMT group were 31.5 (14.1) at baseline and 25.3 (15.3) at 3 months, and in the sham OMT group were 27.2 (14.8) at baseline and 26.1 (15.1) at 3 months. The mean reduction in LBP-specific activity limitations at 3 months was -4.7 (95% CI, -6.6 to -2.8) and -1.3 (95% CI, -3.3 to 0.6) for the standard OMT and sham OMT groups, respectively (mean difference, -3.4; 95% CI, -6.0 to -0.7; P = .01). At 12 months, the mean difference in mean reduction in LBP-specific activity limitations was -4.3 (95% CI, -7.6 to -1.0; P = .01), and at 3 and 12 months, the mean difference in mean reduction in pain was -1.0 (95% CI, -5.5 to 3.5; P = .66) and -2.0 (95% CI, -7.2 to 3.3; P = .47), respectively. There were no statistically significant differences in other secondary outcomes. Four and 8 serious adverse events were self-reported in the standard OMT and sham OMT groups, respectively, though none was considered related to OMT. Conclusions and Relevance: In this randomized clinical trial of patients with nonspecific subacute or chronic LBP, standard OMT had a small effect on LBP-specific activity limitations vs sham OMT. However, the clinical relevance of this effect is questionable. Trial Registration: ClinicalTrials.gov Identifier: NCT02034864.

Lumbosacral immobilization following glucocorticoid intradiscal injection in patients with chronic low back pain and active discopathy: A feasibility study.

BACKGROUND: In people with chronic low back pain (cLBP) and active discopathy, glucocorticoid intradiscal injection (GC IDI) reduces LBP in the short-term. Lumbosacral immobilization may be useful to obtain long-term results. OBJECTIVE: To assess the feasibility of a lumbosacral immobilization using a pantaloon cast following GC IDI in people with cLBP sand active discopathy. METHODS: We conducted a retrospective feasibility study. Participants were allocated to experimental or control groups by preferences. The experimental group received lumbosacral immobilization using a custom-made pantaloon cast worn continuously for one week following a GC IDI of 25 mg of prednisolone acetate. The control group received GC IDI alone. The primary endpoint was the feasibility of lumbosacral immobilization assessed by the rate of refusal and early withdrawal of the cast. RESULTS: Twelve patients were offered lumbosacral immobilization following GC IDI: the rate of refusal was 3/12 (25.0%) and was 3/9 (33.3%) of early withdrawal. Mean (95% CI) acceptability of the procedure was 55.0 (26.9-83.1)/100 in the experimental group (N= 6) and 61.6 (25.1-98.2)/100 in the control group (N= 6). CONCLUSIONS: We found high rates of refusal and early withdrawal of the lumbosacral immobilization using a pantaloon cast following GC IDI in people with nonspecific cLBP and active discopathy.

Serum biomarkers in people with chronic low back pain and Modic 1 changes: a case-control study.

We aimed to compare serum biomarkers of inflammation, redox status and cartilage degradation between chronic low back pain (cLBP) patients with and without Modic 1 changes. We used a convenience sample of patients recruited from a single center, case-control study, conducted in a tertiary care center. From December, 2014 to May, 2016, 2,292 patients were consecutively screened, 34 met inclusion criteria and were prospectively enrolled in the present study. Cases (n = 13) were defined as patients with Modic 1 changes detected on MRI and controls (n = 21) as cLBP patients without (Modic 0). To assess serum biomarkers of inflammation, redox status and cartilage degradation, fasting serum samples were collected in a standardized manner and analyzed by immunoassays and spectrophotometry. Mean (95% CI) age was 44.1 (40.0-48.1) years and mean LBP duration was 72.5 (53.0-91.9) months. Serum biomarkers of inflammation (IL-1ß, IL-6, IL-8 and TNF-α), redox status (total thiols, advanced oxidation protein products and carbonyl groups) and cartilage degradation (Coll2-1 and Coll2-1NO2) did not differ between cLBP patients with and without Modic 1 changes. In summary, we did not find any differences in serum biomarkers between cLBP patients with and without Modic 1 changes. Interpretation is limited by convenience sampling and small sample size.

Active discopathy: a clinical reality.

In the late 1980s, the description by Modic and colleagues of elementary discovertebral changes detected on MRI (Modic classification) suggested for the first time a possible correlation between anatomical and clinical features in a subgroup of patients with non-specific chronic low back pain. Degenerative disc disease is frequent and usually asymptomatic, but Modic 1 changes in the vertebral endplates adjacent to a degenerated disc are associated with inflammatory-like chronic low back pain and low-grade local and systemic inflammation, which led to the concept of 'active discopathy'. Active discopathy shares some similarities with acute flares of peripheral osteoarthritis. Likewise, what triggers disc activation and how it self-limits remain unknown. A better understanding of mechanisms underlying disc activation and its self-limitation is of clinical relevance because it may enable the design of more targeted pharmacological and non-pharmacological interventions for the subgroup of patients with chronic low back pain and active discopathy. Here, we narratively review current disc-centred biomechanical and biochemical hypotheses of disc activation and discuss evidence of interactions with adverse personal and environmental factors.