[Low-dose methotrexate: Indications and side effects, particularly in cases of diffuse interstitial pneumonia]. / Méthotrexate à faible dose : indications et effets secondaires, en particulier en cas de pneumopathie interstitielle diffuse.

INTRODUCTION: Methotrexate (MTX) is a folate antagonist used as an immunosuppressant in a number of conditions, including rheumatoid arthritis (RA). Low-dose MTX (MTX-LD) is associated with a risk of haematological, hepatic, gastrointestinal and pulmonary toxicity, which may up until now have limited its use. STATE OF THE ART: In RA, data from retrospective cohorts have reported a possible excess risk of methotrexate toxicity in cases of underlying interstitial lung disease (ILD). However, recent prospective and retrospective multicentre studies have found no such increased risk, and have reassuringly concluded that MTX-LD can be prescribed in cases of RA-associated ILD (RA-ILD). PERSPECTIVES AND CONCLUSIONS: Current recommendations are not to delay the introduction of MTX in patients with RA at risk of developing ILD or in the presence of RA-ILD with mild to moderate respiratory impairment.

Burden of comorbidities: Osteoporotic vertebral fracture during non-small cell lung cancer - the BONE study.

INTRODUCTION: Immunotherapy and targeted therapy have extended life expectancy in non-small cell lung cancer (NSCLC) patients, shifting it into a chronic condition with comorbidities, including osteoporosis. This study aims to evaluate the prevalence and incidence of osteoporotic vertebral fracture (OPVF) during NSCLC follow-up, identify risk factors of OPVF, and determine the impact on overall survival (OS). METHODS: We performed a longitudinal single-center retrospective cohort study involving patients with histologically proven NSCLC of any stage. Chest-abdomen-pelvis computed tomography (CAP CT) at diagnosis and during follow-up were double-blind reviewed to determine OPVF site, count, type, time to incident OPVF, and trabecular volumetric bone density (TVBD). An institutional expert committee adjudicated discrepancies. Binary logistic regression was used to predict the occurrence of incident OPVF. OS was calculated using the Kaplan-Meier method. RESULTS: We included 289 patients with a median follow-up of 29.7 months. OPVF prevalence was 10.7% at inclusion and 23.2% at the end of follow-up. Cumulative incidence was 12.5%, with an incidence rate of 4 per 100 patient-years. Median time to incident OPVF was 13 months (IQR: 6.7-21.2). Seven of the 36 patients with incident OPVF received denosumab or bisphosphonates. In multivariable analysis, independent risk factors for incident OPVF were BMI < 19 kg/m2 (OR: 5.62, 95%CI 1.84-17.20, p = 0.002), lower TVBD (OR: 0.982 per HU, 95%CI 0.97-0.99, p = 0.001) and corticosteroid use (OR: 4.77, 95%CI: 1.76-12.89, p = 0.001). OPVF was not significantly associated with OS. CONCLUSIONS: Osteoporosis should be screened for in NSCLC patients. Thoracic oncologists must broaden the use of steroid-induced osteoporosis recommendations.

Rheumatological evaluation of patients with interstitial lung disease.

Objective: Interstitial lung disease (ILD) is a common feature of connective tissue disease (CTD). The diagnosis of CTD-ILD can be challenging and is important for therapeutic decisions. In this study, we aimed to determine whether a systematic rheumatological assessment could help pulmonologists in the diagnosis and care of ILD patients.Method: We conducted an observational single-centre study of patients with ILD. All patients underwent standardized pulmonary and rheumatological evaluations, including clinical evaluation (pulmonary symptoms and musculoskeletal signs), immunological screening, chest high-resolution computed tomography, pulmonary function tests, and ultrasonography (US) of joints and major salivary glands.Results: We included 100 consecutive ILD patients (47% women, mean ± sd age 67 ± 14 years); 15 patients already had CTD. The main extrapulmonary symptoms were joint pain (n = 52), joint swelling (n = 26), and sicca syndrome (n = 33). US of joints revealed synovitis, bone erosion, and tenosynovitis in 37, 17, and 13 patients, respectively. US of major salivary glands detected features associated with Sjögren's syndrome in 13 patients. After rheumatological evaluation, CTD-ILD was confidently diagnosed in 39 patients; diseases were mainly rheumatoid arthritis (n = 20), primary Sjögren's syndrome (n = 17), and inflammatory myopathies (n = 7). The diagnosis of CTD-ILD was associated with the presence of musculoskeletal symptoms and immunological and US abnormalities. The CTD diagnosis led to a therapeutic change in 21 patients.Conclusion: Our findings suggest that musculoskeletal symptoms are frequent in ILD patients, which supports multidisciplinary management, involving the rheumatologist, for evaluating patients with ILD.

Lung ultrasonography in patients with COVID-19: comparison with CT.

AIM: To determine whether findings from lung ultrasound and chest high-resolution computed tomography (HRCT) correlate when evaluating COVID-19 pulmonary involvement. MATERIALS AND METHODS: The present prospective single-centre study included consecutive symptomatic patients with reverse transcription polymerase chain reaction (RT-PCR)-proven COVID-19 who were not in the intensive care unit. All patients were assessed using HRCT and ultrasound of the lungs by distinct operators blinded to each other's findings. The number of areas (0-12) with B-lines and/or consolidations was evaluated using ultrasound and compared to the percentage and classification (absent or limited, <10%; moderate, 10-25%; extensive, 25-50%; severe, 50-75%; critical, >75%) of lung involvement on chest HRCT. RESULTS: Data were analysed for 21 patients with COVID-19 (median [range] age 65 [37-90] years, 76% male) and excellent correlation was found between the ultrasound score for B-lines and the classification (p<0.01) and percentage of lung involvement on chest HRCT (r=0.935, p<0.001). In addition, the ultrasound score correlated positively with supplemental oxygen therapy (r=0.45, p=0.041) and negatively with minimal oxygen saturation at ambient air (r=-0.652, p<0.01). CONCLUSION: The present study suggests that among COVID-19 patients, lung ultrasound and HRCT findings agree in quantifying lung involvement and oxygen parameters. In the context of the COVID-19 pandemic, lung ultrasound could be a relevant alternative to chest HRCT.

Predictors of hypogammaglobulinemia during rituximab maintenance therapy in rheumatoid arthritis: A 12-year longitudinal multi-center study.

OBJECTIVE: Rituximab (RTX) is an anti-CD20 monoclonal antibody that selectively depletes B-cell population. Thus, it presents a potential risk for the development of hypogammaglobulinemia and related infectious events. Our aim was to identify predictors of hypogammaglobulinemia in RA patients long-term treated with RTX. METHODS: Multicenter observational usual care study of patients with RA on RTX maintenance therapy (minimal exposition of 30 months). Serum protein electrophoresis was performed before each RTX infusion. Hypogammaglobulinemia and severe hypogammaglobulinemia were defined as total gammaglobulin <6g/L and <4g/L, respectively. The primary outcome was the occurrence within the follow-up period of hypogammaglobulinemia. RESULTS: 134 patients met inclusion criteria and were followed-up for 79.5 ± 24.6 months. Hypogammaglobulinemia occurred during the follow-up period in 23 patients (2.7 events per 100 pt-yrs). The mean time to development of hypogammaglobulinemia was 64 ± 23 months. Patients who developed hypogammaglobulinemia were more likely to experience severe infections (26.1% vs. 6.3%, P = 0.033). Multivariate Cox analysis identified gammaglobulin levels <8g/L at baseline as an independent predictor of hypogammaglobulinemia (HR 7.34 [95% CI: 2.00-26.90], P = 0.003). Concomitant methotrexate (MTX) intake was also predictive of a reduced risk of hypogammaglobulinemia occurrence (HR 0.26 [95% CI: 0.08-0.87], P = 0.03). CONCLUSION: Our results show that gammaglobulin levels of less than 8g/L at baseline is a strong independent risk factor for developing subsequent hypogammaglobulinemia, whereas concomitant MTX therapy seems to be a protective factor in RA patients treated long-term with RTX.

Association between RANK, RANKL and OPG polymorphisms with ACPA and erosions in rheumatoid arthritis: results from a meta-analysis involving three French cohorts.

OBJECTIVES: The RANK/RANKL/osteoprotegerin (OPG) system plays a central role in the pathogenesis of bone erosions in rheumatoid arthritis (RA). The aim of this study was to test the association between 11 single-nucleotide polymorphisms (SNPs) located on RANK, RANKL and OPG genes and anticitrullinated peptide antibody (ACPA) presence or erosions in RA. PATIENTS: This work was performed on three independent samples of French patients with RA: the Etude de Suivi des PolyArthrites Indifférenciées Récentes (ESPOIR) (n=632), Rangueil Midi-Pyrénées (RMP) (n=249) and French Rheumatoid Arthritis Genetic Consortium (FRAGC) (n=590) cohorts. Genotyping: the genotyping of 11 SNPs located on RANK, RANKL and OPG were performed by PCR. STATISTICAL ANALYSES: The association between the genotypes with ACPA or erosions was first tested in the ESPOIR cohort using a χ(2) test and, in the case of significant association, replicated in the RMP and FRACG cohorts. A meta-analysis on the three cohorts was performed using the Mantel-Haenszel method. RESULTS: One SNP on RANK (rs8086340) and three SNPs on RANKL (rs7984870, rs7325635, rs1054016) were significantly associated with ACPA presence, while one SNP on OPG (rs2073618) and one SNP on RANKL (rs7325635) were significantly associated with erosions in the ESPOIR cohort. Following meta-analysis performed on the three samples, the SNP on RANK and the GGG haplotype of the three SNPs located on RANKL were both significantly associated with ACPA presence, while only the SNP on OPG remained significantly associated with erosions. CONCLUSIONS: This study identified one SNP located on RANK, one haplotype on RANKL associated with ACPA presence, and one SNP located on OPG associated with erosions in three different samples of French patients with RA.

Body mass index and response to tocilizumab in rheumatoid arthritis: a real life study.

Several studies have suggested that obesity could have a negative effect on response to anti-tumor necrosis factor α (anti-TNFα) in rheumatoid arthritis (RA). Little is known about the impact of body mass index (BMI) on other biologic agents. We aimed to evaluate the effect of BMI on response to tocilizumab (TCZ) in RA. RA patients treated with TCZ were included in this multicenter retrospective study. BMI was calculated at the initiation of treatment. After 6 months of treatment, change from baseline in DAS28, pain on a visual analog scale, erythrocyte sedimentation rate and C-reactive protein level, and tender and swollen joints were analyzed. The primary endpoint was decrease in DAS28 ≥ 1.2. Secondary outcomes were good response and remission by EULAR criteria. At baseline, among 115 RA patients included, the median (interquartile range) BMI was 25.4 (22.0-28.8) kg/m(2). The number of patients with normal weight, overweight, and obesity was 53 (46 %), 37 (32 %), and 25 (22 %), respectively. Baseline characteristics did not differ between the three subgroups of BMI. The median BMI did not differ between responders and non-responders for DAS28 decrease ≥1.2 (25.7 [22.1-29.9] vs 24.9 [22.0-27.1], P = 0.38), EULAR good response (25.9 [22.8-30.0] vs 25.4 [22.0-28.4], P = 0.61), and remission (25.1 [22.5-28.6] vs 25.4 [22.0-28.9], P = 0.76). BMI did not affect the response to TCZ in RA. If confirmed, these results could be helpful for the selection of a biologic agent in obese RA patients.

Disabling chronic low back pain with Modic type 1 MRI signal: acute reduction in pain with intradiscal corticotherapy.

OBJECTIVES: The objective of the current study was to compare short- and long-term effect on chronic low back pain of intradiscal injection of methylprednisolone with or without presence of Modic type 1 MRI changes. PATIENTS AND METHODS: Medical charts of patients receiving intradiscal injection of methylprednisolone from January 1, 1995 to December 31, 1998 were retrospectively reviewed. Clinical parameters were recorded at baseline, 24h after injection and at follow-up (12-14 months). Patients were studied in three groups: Modic I-a, if patients had Modic type 1 changes with no previous surgery or nucleolysis (n=30); Modic I-b, if patients had Modic type 1 changes at the level of previous surgery or nucleolysis (n=37); Control, if patients had no Modic type 1 changes (n=30). RESULTS: Twenty-four hours after methylprednisolone injection, higher proportion of patients with self-assessed improvement was observed in Modic I-a (90%) and Modic I-b (71%) than in Control (30%). Low back pain decreased in both Modic groups. Low back pain did not vary from baseline in controls. No effect was detected in three groups, neither for radiating pain 24h after injection, nor for any outcome parameters at the latest follow-up. CONCLUSIONS: We suggest that patients with disabling chronic low back pain and Modic type 1 MRI changes have specific acute response to intradiscal injection of methylprednisolone. Clinical studies are however necessary to further investigate the effectiveness and safety of such injections.

Evidence of the contribution of the X chromosome to systemic sclerosis susceptibility: association with the functional IRAK1 196Phe/532Ser haplotype.

OBJECTIVE: Several autoimmune disorders, including systemic sclerosis (SSc), are characterized by a strong sex bias. To date, it is not known whether genes on the sex chromosomes influence SSc susceptibility. Recently, an IRAK1 haplotype that contains the 196Phe functional variant (rs1059702), located on Xq28, was found to confer susceptibility to systemic lupus erythematosus (SLE). This study was undertaken to test for an association between SSc and the IRAK1 SLE risk haplotype. METHODS: We tested for an association with the IRAK1 SLE risk haplotype in a discovery set of 849 SSc patients and 625 controls. IRAK1 rs1059702 was further genotyped in a replication set, which included Caucasian women from Italy (493 SSc patients and 509 controls) and Germany (466 SSc patients and 1,083 controls). RESULTS: An association between the IRAK1 haplotype and SSc was detected in the discovery set. In both the discovery and replication sets, the rs1059702 TT genotype was found to be associated with specific SSc subsets, highlighting a potential contribution to disease severity. A meta-analysis provided evidence of an association of both the T allele and TT genotype with the overall disease, with an odds ratio (OR) of 1.20 and 95% confidence interval (95% CI) of 1.06-1.35 for the T allele (P = 0.003) and an OR of 1.49 and 95% CI of 1.06-2.10 for the TT genotype (P = 0.023). However, the most notable associations were observed with the diffuse cutaneous, anti-topoisomerase I antibody positive, and SSc-related fibrosing alveolitis subsets (OR 2.35 [95% CI 1.51-3.66], P = 1.56 × 10(-4), OR 2.84 [95% CI 1.87-4.32], P = 1.07 × 10(-6), and OR 2.09 [95% CI 1.35-3.24], P = 9.05 × 10(-4), respectively). CONCLUSION: Our study provides the first evidence of an association between IRAK1 and SSc, demonstrating that a sex chromosome gene directly influences SSc susceptibility and its phenotypic heterogeneity.

Immunogenetics of systemic sclerosis.

In the field of genetics of SSc, we are currently reaching a period of rapid data production. Several themes are already rising from the first wave of results. First, some genetic variants clearly predispose to multiple autoimmune diseases, thus providing evidence for a shared autoimmune genetic background. Second, multiple genes are involved in the SSc predisposition and as expected the genetic associations are quite modest. Third, unless for a small number of exceptions, the causative genetic variations have not been definitively identified yet. Lastly, to date, the most convincing associations detected relate to genes playing a pivotal role in both innate and adaptative immunity. Indeed, additionally to the MHC, candidate gene studies have convincingly and reproducibly identified PTPN22, IRF5, STAT4, C8orf13-BLK, BANK1 and TNFSF4 as SSc susceptibility genes. Although these results have substantially advanced our understanding of the SSc pathogenesis, both gene-gene and gene-environment studies are now awaited in order to further improve our understanding of this multifacet disease. Finally, we should keep in mind that SSc is a very severe that is until now unfortunately free of effective therapy. Therefore, the identification of new susceptibility genes may offer a rich source of new hypotheses and experimental directions to follow that we should try to assembly in a near future to generate innovative therapies to fight this dramatic disease.

Association of the CD226 Ser(307) variant with systemic sclerosis: evidence of a contribution of costimulation pathways in systemic sclerosis pathogenesis.

OBJECTIVE: The nonsynonymous polymorphism rs763361 of the CD226 gene, which encodes DNAX accessory molecule 1, which is involved in T cell costimulation pathways, has recently been identified as a genetic risk factor for autoimmunity. The purpose of this study was to test for association of the CD226 rs763361 polymorphism with systemic sclerosis (SSc) in European Caucasian populations. METHODS: CD226 rs763361 was genotyped in 3,632 individuals, consisting of a discovery sample (991 SSc patients and 1,008 controls) and a replication sample (999 SSc patients and 634 controls). All study subjects were of European Caucasian origin. Expression of CD226 was assessed on peripheral blood mononuclear cells obtained from 21 healthy donors genotyped for CD226 rs763361. RESULTS: The CD226 rs763361 T allele was found to be associated with SSc in both the discovery and the replication samples, showing the following results in the combined populations: odds ratio (OR) 1.22 (95% confidence interval [95% CI] 1.10-1.34), P = 5.69 × 10(-5) . The CD226 T allele was also associated with various SSc subsets, highlighting a potential contribution to disease severity. The most remarkable associations of the CD226 TT risk genotype were observed with the diffuse cutaneous SSc subtype, the anti-topoisomerase I antibody-positive, and SSc-related fibrosing alveolitis subsets: OR 1.86 (95% CI 1.42-2.43), P = 5.15 × 10(-6) , OR 1.82 (95% CI 1.38-2.40), P = 2.16 × 10(-5) , and OR 1.61 (95% CI 1.25-2.08), P = 2.73 × 10(-4) , respectively. CD226 expression was not significantly influenced by CD226 rs763361 genotypes whatever the T cell subtype investigated. CONCLUSION: Our results establish CD226 as a new SSc genetic susceptibility factor underlying the contribution of costimulation pathways in the pathogenesis of SSc. Further work is nevertheless needed to define the causal variant at the CD226 locus as well as the functional consequences.

NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis.

BACKGROUND: Recent evidence has highlighted a potential role of interleukin 1ß (IL-1ß) in systemic sclerosis (SSc). NLRP1 provides a scaffold for the assembly of the inflammasome that promotes the processing and maturation of pro-IL-1ß. In addition, NLRP1 variants were found to confer susceptibility to autoimmune disorders. OBJECTIVE: /st> To study a possible association of the NLRP1 rs6502867, rs2670660 and rs8182352, rs12150220 and rs4790797 with SSc in the European Caucasian population. METHODS: NLRP1 single nucleotide polymorphisms were genotyped in 3227 individuals comprising a discovery set (870 SSc patients and 962 controls) and a replication set including individuals from Germany (532 SSc patients and 324 controls) and Italy (527 SSc patients and 301 controls), all individuals being of European Caucasian origin. RESULTS: Conditional analyses revealed a significant association for the NLRP1 rs8182352 variant with both anti-topoisomerase-positive and SSc-related fibrosing alveolitis (FA) subsets under an additive model: p=0.0042, OR 1.23 (95% CI 1.07 to 1.41) and p=0.0065 OR 1.19 (95% CI 1.05 to 1.36), respectively. Logistic regression analysis showed an additive effect of IRF5 rs2004640, STAT4 rs7574865 and NLRP1 rs8182352 risk alleles on SSc-related FA. CONCLUSIONS: Our results establish NLRP1 as a new genetic susceptibility factor for SSc-related pulmonary fibrosis and anti-topoisomerase-positive SSc phenotypes. This provides new insights into the pathogenesis of SSc, underlining the potential role of innate immunity in particular in the FA-positive SSc subphenotype, which represents a severe subset of the disease.

Association of a KCNA5 gene polymorphism with systemic sclerosis-associated pulmonary arterial hypertension in the European Caucasian population.

OBJECTIVE: Pulmonary arterial hypertension (PAH) has emerged as a leading cause of death in systemic sclerosis (SSc). The genetic basis of PAH has been unraveled in recent years, with a major role played by transforming growth factor ß receptors; however, some other candidate genes have also been advocated, including potassium voltage-gated channel, shaker-related subfamily, member 5 (KCNA5). We undertook this study to determine whether KCNA5 polymorphisms confer susceptibility to SSc and its vascular phenotype, including PAH. METHODS: Four KCNA5 single-nucleotide polymorphisms (SNPs), rs10744676, rs1860420, rs3741930, and rs2284136, were genotyped in a discovery set of 638 SSc patients and 469 controls. In addition, rs10744676 was genotyped in an independent replication sample (938 SSc patients and 564 controls) and in a cohort of 168 patients with different PAH subtypes. RESULTS: The KCNA5 rs10744676 variant was found to be associated with SSc in the discovery sample, with an odds ratio (OR) of 0.62 (95% confidence interval [95% CI] 0.48-0.79, adjusted P = 0.0003) in comparison with controls (C allele frequency 11.4% versus 17.2%). When subphenotypes were investigated, an association was found solely for PAH associated with SSc (OR 0.31 [95% CI 0.13-0.71], adjusted P = 0.04). The other KCNA5 SNPs tested were not associated with any SSc subset. The above association with PAH associated with SSc was replicated in the second set. In the combined population, rs10744676 was strongly associated with PAH associated with SSc in comparison with controls (OR 0.36 [95% CI 0.21-0.63], P = 0.0002). In the independent cohort of patients with PAH, after investigating PAH subtypes, only rs10744676 showed an association with PAH associated with SSc. CONCLUSION: Our results provide the first evidence for an association between the KCNA5 rs10744676 variant and PAH associated with SSc.

Association of the TNFAIP3 rs5029939 variant with systemic sclerosis in the European Caucasian population.

BACKGROUND: TNFAIP3 encodes the ubiquitin-modifying enzyme, a key regulator of inflammatory signalling pathways. Convincing associations between TNFAIP3 variants and autoimmune diseases have been reported. OBJECTIVE: To investigate the association of TNFAIP3 polymorphisms with systemic sclerosis (SSc). METHODS: Three single nucleotide polymorphisms (SNPs) in a set of 1018 patients with SSc and 1012 controls of French Caucasian origin were genotyped. Two intergenic SNPs, rs10499194 and rs6920220, and one located in TNFAIP3 intron 2, rs5029939, were selected. The TNFAIP3 rs5029939 found to be associated with SSc in this first set was then genotyped in a second set of 465 patients with SSc and 182 controls from Germany and 184 patients with SSc and 124 controls from Italy. Pooled odd ratios were calculated by Mantel-Haenszel meta-analysis. RESULTS: The rs5029939 G allele was found to be significantly associated with SSc susceptibility (pooled OR=2.08 (95% CI 1.59 to 2.72); p=1.16×10⁻7), whereas the rs10499194 and rs6920220 variants displayed no association. Only one of the predicted haplotypes investigated in the French sample was significantly associated with SSc (p=8.91×10⁻8), and this haplotype was discriminating only in the presence of the rs5029939 risk allele, suggesting that this SNP tags the association signal. The strongest associations of rs5029939 with subphenotypes, having large magnitudes for complex genetic disorders, were observed for diffuse cutaneous SSc (pooled OR=2.71 (1.94 to 3.79), p=5.2×10⁻9), fibrosing alveolitis (pooled OR=2.26 (1.61 to 3.17), p=2.5×10⁻6) and pulmonary arterial hypertension (pooled OR=3.11 (1.86 to 5.17), p=1.3×10⁻5). CONCLUSION: These results suggest that TNFAIP3 is a genetic susceptibility factor for SSc.