Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France

A national prospective study was designed to collect all cases of lymphoma appearing in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) throughout France over a period of 3 years. A total of 25 cases of lymphoma were recorded, 18 cases of non-Hodgkin lymphoma (NHL), 3 of which were associated with the presence of Epstein-Barr virus (EBV) in lymphoma cells, and 7 cases of Hodgkin disease (HD), 5 of them associated with EBV. Among the 8 patients who were treated by MTX withdrawal alone, 3 underwent remission, but 2 of them had a relapse, the third patient with clonal EBV-associated large granular lymphocytes T-cell NHL remaining alive in complete remission. The estimated annual incidence rate of NHL in RA patients treated with MTX was 33.3.10(-5) (0-80.5) among men and 16.7.10(-5) (0-33.3) among women. There was no significant excess with the French population as a comparison: the standardized mortality ratio (SMR) adjusted for age and sex was 1.07 (0.6-1.7). The estimated annual incidence rate of HD among men and women was, respectively, 27.8.10(-5) (0-70.1) and 2.8.10(-5) (0- 9.6). The incidence of HD was significantly increased compared with the French incidence, with an SMR adjusted for age and sex of 7.4 (3.0-15.3; P <.001). Thus, this 3-year prospective study indicated that, whereas the risk of NHL was not significantly increased in RA patients treated with MTX, the incidence of HD appeared to be higher in these patients compared to the French population.     

Characterization of SLC26A9 in Patients with CF‐Like Lung Disease

Diffuse bronchiectasis is a common problem in respiratory clinics. We hypothesized that mutations in the solute carrier 26A9 (SLC26A9) gene, encoding for a chloride (Cl^?) transporter mainly expressed in lungs, may lead to defects in mucociliary clearance. We describe two missense variants in the SLC26A9 gene in heterozygote patients presenting with diffuse idiopathic bronchiectasis : p.Arg575Trp, identified in a patient also heterozygote for p.Phe508del in the CFTR gene; and p.Val486Ile. Expression of both mutants in Xenopus laevis oocytes abolished SLC26A9‐mediated Cl^? conductance without decreasing protein membrane expression. Coexpression of CFTR with SLC26A9–p.Val486Ile resulted in a significant increase in the Cl^? current induced by PKA stimulation, similar to that obtained in oocytes expressing CFTR and SLC26A9–WT. In contrast, coexpression of CFTR with SLC26A9–p.Arg575Trp inhibited SLC26A9‐enhanced CFTR activation upon PKA. Further structure–function analyses led us to propose a site encompassing Arg575 in the SLC26A9–STAS domain for CFTR–SLC26A9 interaction. We hypothesize that SLC26A9–p.Arg575Trp prevented SLC26A9‐mediated functional activation of CFTR by altering SLC26A9–CFTR interaction. Although we cannot confirm that these mutations by themselves are deleterious, we propose that they trigger the pathogenic role of a single CFTR mutation and provide insight into a novel mechanism of Cl^? transport alteration across the respiratory mucosa, based on functional inhibition of CFTR.     

Pleural T-lymphocyte subsets in amiodarone-associated pleuropneumonitis

Two male patients presented with lung disorders with all the characteristics of amiodarone-related pneumonitis. Bilateral exudative pleural effusions were associated with pneumonitis. High lymphocytosis was present in the pleural fluid with a ratio of T-lymphocyte subsets close to that found in peripheral blood; in the blood T-lymphocyte subset ratio was nearly normal. By contrast, and as is usual in similar cases, lymphocytic alveolitis with T-lymphocyte subset imbalance was found in bronchoalveolar lavage fluid. These findings, never published so far to our knowledge, would favor a compartmentalization of the immune response inside the lung.     

Endobronchial metastases of cancer. Apropos of 29 cases

In a retrospective study covering a 3-year period, 29 cases were reviewed. All concerned patients with endoscopic abnormalities resembling those of a primary carcinoma and histologically of the same type as a previously known tumour affecting areas as diverse as the E.N.T. region (31%), the colorectal region (20.6%), the mammary gland (13.7%) or the bladder (10.3%). There was nothing particular in the clinical, radiological or endoscopic signs. In the vast majority of cases (27/29) the histological diagnosis was provided by bronchofibroscopy. Thus, not only does endoscopy frequently visualizes abnormalities in obviously secondary carcinomas, but it also diagnoses cancers with clinical, radiological and endoscopic features of primary cancers from which they are sometimes almost undistinguishable.     

Hormonal contraception and lupus]

The choice of an optimal contraceptive method (OC) therapy is a significant problem in female SLE patients. In view of the influence of sex hormones on the evolution of SLE, oral contraceptive (OC) therapy has to be efficient, reversible and safe, without aggravating disease activity and causing metabolic and vascular side effects. Ethinyl estradiol-containing preparations, even at 30 micrograms/day, have been shown to trigger a crisis or unmask SLE, and they exert adverse metabolic and vascular effects. Therefore, combination estrogen-progestogen compounds must be avoided in women with SLE. Pure progestogen OC preparations do not stimulate SLE activity, but norsteroids have harmful metabolic effects and microprogestogens are not sufficiently reliable. In light of the decreased level of plasma androgens in female SLE patients, an attempt to modulate the hormonal milieu by lowering the estrogen to androgen ratio, while ensuring contraception was attempted using cyproterone acetate. This agent markedly lowered plasma estrogens and was effective and well tolerated, but its long-term effect on bone mineralization remains to be evaluated. Chlormadinone acetate, a 17-OH progesterone derivative, was proven effective and devoid of any metabolic or vascular side effects, and should be recommended as the safest routine OC therapy in women with SLE.     

Organizing pneumonia related to common variable immunodeficiency. case report and literature review

A 68-year-old woman suffering from common variable immunodeficiency (CVI) developed a typical picture of organizing pneumonia. Causative factors other than CVI were eliminated. Several antibiotic regimens failed to improve the patient's condition, while the clinical manifestations rapidly disappeared under steroid therapy, with complete radiological recovery, but relapsed after steroid withdrawal. Finally, organizing pneumonia was definitely demonstrated by pathological findings obtained by open lung biopsy. Interestingly, pathological examination exhibited two other well-known CVI-associated lesions, i.e. benign lymphoid hyperplasia and noncaseating granuloma. In view of reports in the literature, we speculate that these different histological patterns could have resulted in a spectrum of symptomatic CVI-associated pulmonary disorders that improved under steroid therapy.     

Lack of evidence of a specific role for C4A gene deficiency in determining disease susceptibility among C4-deficient patients with systemic lupus erythematosus (SLE)

The aim of the present study was to investigate the prevalence of C4 and C2 deficiencies and to characterize genomic alterations in C4 genes in a large cohort of 125 unselected patients with SLE. We determined the protein concentration and functional activity of C2 and C4, as well as the C4 phenotype. C4 genotyping included Taq 1 restricted fragment lengh polymorphism (RFLP) analysis and polymerase chain reaction using sequence-specific primers (SSP-PCR). Type I C2 deficiency was diagnosed by PCR. Overall, 79.2% of the patients exhibited abnormalities of the C4 genes including deletion, non-expression, gene conversion and duplication. Among C4-deficient patients (n = 66, 52.8% prevalence), 41.0% of the patients exhibited a C4A deficiency and 59.0% a C4B deficiency. Half of the C4 deficiencies were due to a gene deletion. There was a strong association between C4A and C4B gene deletion and the presence of the DRB1*03 allele. Among the silent C4A genes, only two cases were related to a 2-bp insertion in exon 29 of the C4A gene. A gene conversion was demonstrated in eight patients (6.4%). One patient had a homozygous C4A deficiency. Three (2.4%) patients presented with a heterozygous type I C2 deficiency and none with homozygous deficiency. Our results argue against a specific role for C4A gene deficiency in determining disease susceptibility among patients with SLE that are C4-deficient.