Rheumatoid Arthritis: Pennec Y

Devauchelle-Pensec V, Pennec Y, Morvan J, Pers JO, Daridon C, Jousse-Joulin S, Roudaut A, Jamin C, Renaudineau Y, Roué IQ, Cochener B, Youinou P, Saraux A. · Hôpital de la Cavale Blanche, CHU Brest, France. · Arthritis Rheum. · Pubmed #17330280 links to  free full text

Abstract: OBJECTIVE: There is evidence to support a dominant role for B cells in the pathophysiology of primary Sjögren's syndrome (SS). Therefore, we evaluated the safety and efficacy of anti-CD20 monoclonal antibody. METHODS: Sixteen patients who met the new American-European Consensus Group criteria for primary SS and scored >50 on at least 2 of 4 visual analog scales (VAS; 100 mm) evaluating global disease, pain, fatigue, and global dryness received infusions of low-dose rituximab (375 mg/m(2)) at weeks 0 and 1 without steroid premedication. RESULTS: Slow rituximab infusions (100 mg/hour) were well tolerated, with only 1 patient experiencing serum sickness-like disease. There was a dramatic reduction in B cells of the blood and salivary gland (SG). At week 12, VAS scores with respect to fatigue and dryness (P < 0.05), tender point count (P < 0.035), and quality of life as evaluated by the Short Form 36 questionnaire (SF-36; P < 0.001) were significantly improved. At week 36, significant improvements were noted in the 4 VAS scores (P < 0.05), tender joint count (P = 0.017), tender point count (P = 0.027), and SF-36 (P < 0.03). Pulmonary manifestations were ameliorated in 1 patient. Patients with improvements on at least 3 of the 4 VAS scores at any visit (n = 11) had a shorter disease duration than the other patients (n = 5; mean +/- SD duration 3.8 +/- 5.4 versus 30.1 +/- 29.5 years; P = 0.02). CONCLUSION: Low-dose rituximab infusions were well tolerated without the benefit of steroids. Infusions induced a rapid depletion of B cells in the blood and SG and could improve primary SS. Controlled studies are needed.

Mariette X, Ravaud P, Steinfeld S, Baron G, Goetz J, Hachulla E, Combe B, Puéchal X, Pennec Y, Sauvezie B, Perdriger A, Hayem G, Janin A, Sibilia J. · Service de Rhumatologie, Hôpital de Bicêtre AP-HP, and Université Paris-Sud, Le Kremlin Bicêtre, France. · Arthritis Rheum. · Pubmed #15077311 links to  free full text

Abstract: OBJECTIVE: There is no effective treatment for patients with primary Sjögren's syndrome (SS). Since tumor necrosis factor alpha (TNF alpha) could be a key element in the pathogenesis of primary SS, we conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the effect of infliximab in primary SS. METHODS: A total of 103 patients with primary SS were randomly assigned to receive infliximab infusions (5 mg/kg) or placebo at weeks 0, 2, and 6 and were followed up for 22 weeks. All patients fulfilled the new American-European Consensus Group criteria for SS and had active disease as assessed by values >50 mm on 2 of 3 visual analog scales (VAS) (0-100 mm) that evaluated joint pain, fatigue, and buccal, ocular, skin, vaginal, or bronchial dryness. A favorable overall response was defined as the patient having > or =30% improvement between weeks 0 and 10 in the values on 2 of the 3 VAS. Secondary end points were values on each VAS separately, the number of tender and swollen joints, the basal salivary flow rate, results of the Schirmer test for lacrimal gland function, the focus score on labial salivary gland biopsy, the level of C-reactive protein, and the erythrocyte sedimentation rate evaluated at weeks 0, 10, and 22, as well as quality of life evaluated by use of the generic Short Form 36 questionnaire administered at weeks 0, 10, and 22. RESULTS: At week 10, 26.5% of patients receiving placebo and 27.8% of patients treated with infliximab had a favorable overall response (P = 0.89), and at week 22, 20.4% of the placebo group and 16.7% of the infliximab group had a favorable response (P = 0.62). In addition, the 2 groups did not differ in any of the secondary end points over the 22 weeks of the trial. Severe adverse events reported in the infliximab group did not differ from those observed in previous studies. CONCLUSION: This randomized, double-blind, placebo-controlled study of an anti-TNF agent did not show any evidence of efficacy of infliximab in primary SS.

d'Arbonneau F, Pers JO, Devauchelle V, Pennec Y, Saraux A, Youinou P. · Immunology Laboratory, Brest University Medical School, F-29609 Brest, France. · Arthritis Rheum. · Pubmed #16385503 links to  free full text

Abstract: OBJECTIVE: To determine the effect of excessive production of BAFF on the distribution and function of B cell subsets in patients with primary Sjögren's syndrome (SS). METHODS: The phenotype of B lymphocytes was analyzed by flow cytometry. Differences in the expression level of membrane IgD and CD38 were used to identify B lymphocyte subsets evolving from naive Bm1 through memory Bm5 cells. Based on our finding of a low expression of CD45RA, we sorted Bm2/Bm2' cells to determine the time course of translocation of the CD19 molecule and the B cell receptor into lipid rafts, by confocal microscopy. Serum levels of BAFF were measured by an enzyme-linked immunosorbent assay developed in-house. RESULTS: "Circulating" Bm2/Bm2' cells were expanded in patients with primary SS compared with rheumatic disease controls and with normal controls. In addition, these B cell subsets were functionally abnormal. Prolonged residency of the B cell receptor in lipid rafts in these cells was associated with elevated CD19 expression in B cells, most notably, Bm2 and Bm2' cells, obtained from the patients with primary SS. BAFF levels were higher in the patients than in the normal controls and correlated with the percentage of Bm2/Bm2' cells and their expression of CD19 in primary SS patients. These correlations were confirmed by placing sorted Bm1 or Bm2 cells from normal controls in culture in the presence or absence of BAFF. CONCLUSION: Bm2/Bm2' cells express more CD19 molecules in primary SS patients than in normal controls. BAFF might participate in this elevated expression of CD19. These patients might be suitable candidates for treatment with BAFF antagonists.

Saraux A, Berthelot JM, Chalès G, Le Henaff C, Thorel JB, Hoang S, Valls I, Devauchelle V, Martin A, Baron D, Pennec Y, Botton E, Mary JY, Le Goff P, Youinou P. · Rheumatology Unit, la Cavale Blanche Hospital, Brest Teaching Hospital, France. · Arthritis Rheum. · Pubmed #11710704 No free full text.

Abstract: OBJECTIVE: To determine how well the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) 1987 classification criteria for rheumatoid arthritis (RA), when used at study inclusion in a cohort of 270 patients with early (<1 year) arthritis, predicted a diagnosis of RA 2 years later and how well they classified these patients at the end of the 2 years. METHODS: Patients were evaluated during 1995-1997 at 7 hospitals in the Brittany region of France. Patients were evaluated at 6-month intervals until November 1999. The diagnosis made by a panel of 5 rheumatologists (P5R) after the last visit was used as the "gold standard." The ACR 1987 criteria for RA were applied prospectively, without taking into account the initial diagnosis. RESULTS: At the last visit (mean +/- SD followup 29.1 +/- 11.8 months; median 30 months), the P5R diagnosed RA in 98 patients. At the last visit, classification by the ACR criteria was satisfactory, and the combination of an office-based rheumatologist's (OBR's) diagnosis of RA and fulfillment of the ACR criteria was sensitive (87%; 85 of 98 RA patients had both) and highly specific (99%; 170 of 172 non-RA patients did not have both). Application of the criteria at the first visit was of limited value for predicting a diagnosis of RA 2 years later. CONCLUSION: After a 2-year followup, the ACR 1987 classification criteria used in combination with an OBR's diagnosis were effective in distinguishing patients with and without RA. The criteria were not useful for predicting RA in patients with arthritis onset within the previous year. Some patients who met the criteria at baseline and after 2 years did not have RA, suggesting that incorporating exclusion criteria may improve the performance of the ACR criteria when used without taking into account the diagnosis by a rheumatologist, particularly in early arthritis.

Basset C, Durand V, Jamin C, Clément J, Pennec Y, Youinou P, Dueymes M, Roitt IM. · Laboratory of Immunology, Institut de Synergie des Sciences et de la Santé (I3S), Brest, France. · Scand J Immunol. · Pubmed #10736100 No free full text.

Abstract: Increased serum immunoglobulin A (IgA) level is a common finding in primary Sjögren's syndrome (pSS). IgA might not be properly eliminated because of an abnormal glycosylation. We reported previously that IgA1 from patients with pSS was oversialylated. We extend this finding by showing that monomeric IgA1 contains more sialic acid (SA) in patients than in controls, as determined by enzyme-linked immunosorbent assay (ELISA) and Western blot with Sambucus nigra agglutinin (SNA), a lectin specific for SA. To localize this excess of SA on the N- and/or O-linked oligosaccharides, we analysed them separately, using N- and O-linked oligosaccharide profiling kits based on fluorophore-assisted carbohydrate electrophoresis. N-linked, but not O-linked, oligosaccharides of patients' IgA1 were oversialylated, and this seemed to be linked to an excess of SA on the same number of polysaccharides as normal IgA1. To localize the abnormality to the Fab and/or Fc fragments, monomeric IgA1 was digested with protease, separated and transferred to nitrocellulose, where SA was identified by SNA. Both Fab and Fc fragments appeared to be oversialylated. Oversialylation of N-linked oligosaccharides of IgA1 from patients with pSS might prevent the recognition of IgA by receptors that are responsible for their clearance, resulting in an excess of serum IgA and related immune complexes.