Abstract: OBJECTIVE: To evaluate the relevance of serum-free light chain (FLC) assessment in hepatitis C virus (HCV)-related lymphoproliferative disorders, including mixed cryoglobulinemia (MC) and B cell non-Hodgkin lymphoma (B-NHL). PATIENTS AND METHODS: A total of 59 patients infected with HCV were prospectively followed, including patients without MC (n = 17), with asymptomatic MC (n = 7) and with MC vasculitis (n = 35, 9 of whom had B-NHL). Clinical and biological data were recorded at the time of the initial evaluation and at the end of follow-up. Serum FLC quantitation was carried out using a serum FLC assay. RESULTS: The mean (SD) serum kappa FLC level was higher in patients with asymptomatic MC (27.9 (8.6) mg/litre), MC vasculitis (36.7 (46.2) mg/litre) and B-NHL (51.3 (78.3) mg/litre) than without MC (21.7 (17.6) mg/litre) (p = 0.047, 0.025 and 0.045, respectively). The mean serum FLC ratio was higher in patients with MC vasculitis (2.08 (2.33)) and B-NHL (3.14 (3.49)) than in patients without MC (1.03 (0.26)) (p = 0.008). The rate of abnormal serum FLC ratio (>1.65) correlated with the severity of HCV-related B cell disorder: 0/17 (0%) without MC, 0/7 (0%) asymptomatic MC, 6/26 (23%) MC vasculitis without B-NHL and 4/9 (44%) B-NHL (p = 0.002). Serum kappa FLC levels and the serum FLC ratio correlated with the cryoglobulin level (r = 0.32, p<0.001 and r = 0.25, p = 0.002, respectively) and the severity of the B cell disorder (r = 0.26, p = 0.045 and r = 0.41, p = 0.001, respectively). Among patients with an abnormal serum FLC ratio at baseline, the FLC ratio correlated with the virological response to HCV treatment. CONCLUSIONS: In patients infected with HCV, an abnormal serum FLC ratio appears to be a very interesting marker, as it is consistently associated with the presence of MC vasculitis and/or B-NHL. After antiviral therapy, the serum FLC ratio could be used as a surrogate marker of the control of the HCV-related lymphoproliferation.
Abstract: OBJECTIVE: To evaluate the relevance of monitoring anti-myeloperoxidase antibody (anti-MPO Ab) levels in the management of anti-MPO-associated vasculitides. METHODS: Thirty-eight patients with anti-MPO-associated vasculitides were included: microscopic polyangiitis (n=18), Wegener's granulomatosis (n=15) and Churg-Strauss syndrome (n=5). Baseline characteristics and outcomes were recorded. Serial measurements of anti-MPO Ab levels were performed (ELISA, positive>/=20 IU/mL). RESULTS: All patients achieved vasculitis remission after a mean time of 2.0+/-0.9 months, with a significant decrease in the mean anti-MPO Ab level at remission (478+/-598 vs. 41+/-100 IU/mL; P<0.001). Twenty-eight (74%) patients became anti-MPO Ab negative. After a mean follow-up of 54+/-38 months, 12 cases of clinical relapse occurred in 11/38 (29%) patients. Relapses were associated with an increase in anti-MPO Ab levels in 10/11 (91%) patients (34+/-88 vs. 199+/-314 IU/mL; P=0.002). The reappearance of anti-MPO Abs after achieving negative levels was significantly associated with relapse (OR 117; 95% CI 9.4-1450; P<0.001). Anti-MPO Abs showed a positive predictive value of 90% and a negative predictive value of 94% for relapse of vasculitis. Up to 60% of cases of relapse occurred less than 12 months after the reappearance of anti-MPO Abs. Relapse-free survival was significantly worse for patients who exhibited a reappearance of anti-MPO Abs than in those with persistent negative anti-MPO Abs (P<0.001). Anti-MPO Abs serum level was strongly correlated with the BVAS and the DEI (r = +0.49 ; P = 0.002). CONCLUSION: Through monitoring, anti-MPO Abs are a useful marker of disease activity and a good predictor of relapse in anti-MPO-associated vasculitides.
Abstract: BACKGROUND: Mixed cryoglobulin is usually associated with hepatitis C virus (HCV) infection and might cause systemic vasculitis. The presence and impact of cryofibrinogen, another cryoprotein, in the serum of HCV-infected patients have not yet been evaluated. The objective was to study the prevalence and the clinical and therapeutic impacts of cryofibrinogen in HCV-infected patients. METHODS: A total of 143 consecutive HCV-infected (RNA+) patients (including 57 patients with HCV-related vasculitis) were screened for cryofibrinogen and cryoglobulin (positive if >0.05 g/L). The main characteristics and outcome were evaluated according to the cryofibrinogen/cryoglobulin status at baseline. RESULTS: At baseline, 53 of 143 patients (37%) were cryofibrinogen positive, most of whom (47/53 [89%]) were also cryoglobulin positive. Only 37 of 90 cryofibrinogen-negative patients (41%) were cryoglobulin positive (P<.001). In patients with HCV-related vasculitis, 28 of 57 (49%) were cryofibrinogen positive compared with 25 of 86 patients (29%) without vasculitis (P=.03). There was a higher rate of renal involvement in cryofibrinogen-negative/cryoglobulin-positive patients than in cryofibrinogen-positive/cryoglobulin-positive patients (10/25 [40%] vs 3/27 [11%], respectively; P=.02). After a mean follow-up of 32.6 months, among patients who were cryofibrinogen positive at baseline, 12 of 26 (46%) of those who received an HCV treatment were cryofibrinogen negative at the end of follow-up compared with 4 of 16 (25%) of those who did not receive antiviral drugs. Most patients who became cryofibrinogen negative also became cryoglobulin negative (93%). CONCLUSION: Cryoproteins, including cryoglobulin and cryofibrinogen, are frequently found in the serum of HCV-infected patients. In such patients, a positive cryofibrinogen status is closely related to the presence of cryoglobulin at baseline and after antiviral therapy.
Abstract: OBJECTIVE: B lymphocyte stimulator (BLyS) is known to support B-cell proliferation (BCP) in B-cell haemopathies and autoimmune diseases. We assume that BLyS may play a role in the initiation and expression of hepatitis C virus (HCV)-associated BCP. We assessed BLyS serum levels in HCV-infected patients and in various forms of HCV-associated BCP [i.e. mixed cryoglobulin (MC), rheumatoid factor (RF) and systemic vasculitis]. METHODS: A total of 76 HCV-infected patients (HCV RNA+) were compared with 13 healthy volunteers. Epidemiological, clinical, immunochemical and virological data were prospectively collected. BLyS serum levels were assessed by an ELISA sandwich method. RESULTS: Of the 76 patients, 38 females, 38 males, mean age 53 +/- 15 yrs; 47 (62%) patients had type II (27 patients) or type III MC (20 patients); 27 (35.5%) patients had HCV-systemic vasculitis. BLyS serum levels tended to be higher in HCV-infected patients than in healthy controls (1.8 +/- 0.9 vs 1.5 +/- 0.2 ng/ml), were higher in patients with MC than without (2.03 +/- 1.02 vs 1.5 +/- 0.5 ng/ml; P = 0.008), and even higher in type II than type III MC (2.3 +/- 1.2 vs 1.7 +/- 0.6 ng/ml; P = 0.03). There was a correlation between BLyS and MC serum levels (R = 0.4; P = 0.004). BLyS serum levels were higher in patients with a positive RF than in those without (2.06 +/- 1.09 vs 1.6 +/- 0.56 ng/ml, P = 0.035), and with systemic vasculitis than in those without (2.24 +/- 1.16 vs 1.6 +/- 0.6 ng/ml; P = 0.006). CONCLUSION: BLyS serum levels are significantly correlated with B-cell proliferation during chronic HCV infection. These results strongly suggest a role for BLyS in the induction and expression of HCV-BCP.
Abstract: OBJECTIVE AND METHODS: We assessed the reliability of non-invasive biological scoring indexes (Fibrotest-Actitest [FT-AT], Forns, APRI, age-platelet, platelet, hyaluronic acid) as non-invasive alternatives to liver biopsy (LB) in 138 HCV-infected patients. RESULTS: Thirty-six of 138 (26%) patients had systemic vasculitis, 27% significant serum inflammation, 47% fibrosis (F2F3F4) on LB. The diagnostic value of FT (F2F3F4 vs. F0F1) was assessed by an AUC of 0.83, without difference regarding to systemic vasculitis or serum inflammation. A discordance between FT-AT and the Metavir scoring indexes, present in 29% of patients, was associated with serum hemolysis and male but not with systemic vasculitis or serum inflammation. The other non-invasive biological tests were not influenced by serum inflammation or systemic vasculitis but were less reliable than FT (P <or= 0.05). CONCLUSION: The FT-AT is a reliable non-invasive biochemical alternative to LB in HCV-infected patients with systemic vasculitis and is more reliable than other non-invasive biological indexes.
Abstract: OBJECTIVE: To investigate the diagnostic reliability of anti-CCP antibodies (anti-CCP Ab) in distinguishing hepatitis C virus (HCV) associated rheumatological manifestations and Sjögren's syndrome from rheumatoid arthritis. METHODS: 147 HCV infected patients (HCV RNA positive) were compared with 64 patients with definite rheumatoid arthritis in a retrospective study. Anti-CCP Ab were detected using the Immunoscan ELISA kit (second generation) and rheumatoid factor (RF) by the FIDIStrade mark Rheuma kit. RESULTS: Among the 147 HCV infected patients (77 women; mean (SD) age 58 (16) years), 77 (52%) had a mixed cryoglobulin (MC), 38 (26%) an MC associated systemic vasculitis, 35 (24%) arthralgia/arthritis, and seven (5%) definite Sjögren's syndrome. HCV infected patients with arthralgia were more often RF positive than those without arthralgia (54% v 27%; p = 0.003), but less often than patients with rheumatoid arthritis (54% v 81%; p = 0.009). Anti-CCP Ab were detected in only two HCV infected patients with arthralgia (5.7%), in none without arthralgia or with Sjögren's syndrome, and in 78% of patients with rheumatoid arthritis. With a specificity of 93.5% and a positive predictive value of 96% for rheumatoid arthritis, anti-CCP Ab were the most specific biological marker. CONCLUSIONS: Anti-CCP antibodies are very rarely found in HCV infected patients with rheumatological manifestations or Sjögren's syndrome. They are reliable serological markers to distinguish these from patients with rheumatoid arthritis.
Abstract: BACKGROUND: Data on essential mixed cryoglobulinemia (MC) are scarce, and most date back to studies before 1989 (ie, before the discovery of hepatitis C virus [HCV] infection). Our objective was to describe the spectrum of MC in the era of HCV infection. METHODS: Retrospective study from a single university hospital's database of 1434 patients who tested positive for MC between January 1989 and December 2003. RESULTS: One hundred thirty-three patients (9%) with persistent MC without HCV were included in the study. Sixty-five of 133 patients who fulfilled the criteria for MC vasculitis were compared with 118 patients with HCV-related MC vasculitis. The patients without HCV had increased frequencies of renal involvement and B-cell non-Hodgkin lymphoma (NHL), lower gammaglobulin levels, and higher death rates. Twenty-three of the patients had B-cell NHL (primarily of the lymphoplasmocytic and marginal zone types), and 8 patients had Sjögren syndrome. In multivariate analysis, a cryoglobulin level higher than 0.6 g/L (odds ratio [OR], 1.44) and the presence of MC vasculitis (OR, 4.3) and hypogammaglobulinemia (OR, 6.7) were independently associated with B-cell NHL. After a mean follow-up of 49.4 months, 18 (14%) of 133 patients had died, primarily of sepsis. In multivariate analysis, age at diagnosis older than 60 years (OR, 1.06) and renal involvement (OR, 5.20) were independently associated with death. CONCLUSION: Patients with non-HCV-related MC vasculitis have a poor outcome and have a 4-fold increased risk of developing B-cell NHL.
Abstract: Luminex technology allows simultaneous detection of several analytes in a single well. Applications have been recently developed for the detection of autoantibodies. PURPOSE: To evaluate the performances and convenience of the Fidis analytical system (BioMedical Diagnostics, Marnes-la-Vallee, France) for the detection of nine autoantibodies associated with connective diseases: SS-A, SS-B, Sm, RNP, Scl-70, Jo-1, CENP-B, P ribosomal and double stranded DNA antibodies. MATERIALS AND METHODS: Three hospital laboratories analysed 366 samples taken from their serum banks and corresponding to the main systemic autoimmune diseases. Control samples included 120 sera from blood donors and 42 sera from patients with dysglobulinemia. RESULTS: In each laboratory, handling of this new analytical system was easy. Results are readily obtained: nine autoantibodies are quantitated in fourty-four sera in less than two hours. A clear-cut discrimination between negative and positive results was observed, due to very low backgrounds. Intra-assay and inter-assay variations were low: coefficients of variation were under 10% in 80 and 64% of the cases, respectively. Results obtained with Fidis correlated satisfactorily with those obtained with the numerous routine techniques used in each laboratory. The overall concordance exceeded 93%. CONCLUSION: Fidis is a reliable and time-saving analytical system for the detection of autoantibodies associated with systemic autoimmune diseases.
Abstract: Arterial thrombotic events, thrombocytopenia, and hemolytic anemia with schistocytes may be encountered in the setting of both thrombotic thrombocytopenic purpura (TTP) and primary antiphospholipid syndrome (APS). We report 2 cases of TTP occurring in patients with definite primary APS. We also describe the results of tests for ADAMTS-13 activity in 20 consecutive patients with primary APS, as well as tests for antiphospholipid antibodies in 26 patients who had TTP, severe ADAMTS-13 deficiency, and ADAMTS-13-inhibiting antibodies. In both of the patients with primary APS and TTP, ADAMTS-13 activity was undetectable, and ADAMTS-13-inhibiting antibodies were present. None of the 26 patients with TTP and severe ADAMTS-13 deficiency was positive for the lupus anticoagulant. One of these patients had a low level of anticardiolipin antibodies (22 IgG phospholipid units). In the 20 patients with primary APS, mean ADAMTS-13 activity was 116% (range 44-250%), and no severe deficiency (< 5%) was observed. Our findings suggest that primary APS must be added to the list of autoimmune disorders that can be complicated by TTP.
Abstract: OBJECTIVE: To describe epidemiological, clinical, and immunological characteristics and the longterm course of persistent mixed cryoglobulinemia (MC) in patients infected with hepatitis C virus (HCV). METHODS: Retrospective study of HCV infected patients (HCV RNA positive) who had persistent positive MC, with 2 immunochemical typings of MC carried out after 24-month minimum interval. RESULTS: In total, 125 patients were studied, aged 52 +/- 13 years at diagnosis of MC, with duration of HCV infection of 18 +/- 10 years. At entry, 60 patients had type II MC, 53 patients had type III, and 12 patients had the oligoclonal type. At the second immunochemical typing, after a mean interval of 45 +/- 20 months, MC was type II in 72 patients, type III in 39 patients, and the oligoclonal type in 14 patients. The proportion of cases of MC with the same immunochemical type was higher among patients with type II (78%) than type III (59%) or oligoclonal MC (17%) (p < 0.01). The MC that changed turned more to type II (55.5%) than type III (29%) or the oligoclonal type (15.5%) (p = 0.0002). MC vasculitis (purpura, arthralgia, peripheral neuropathy, renal involvement) and other extrahepatic manifestations (polyarteritis nodosa, lymphoma) in 60/125 patients was associated with advanced age (p < 0.01), a longer duration of infection (p < 0.05), type II MC (odds ratio = 5, p < 0.01), and a higher MC serum level (p < 0.01). CONCLUSION: During chronic active HCV infection, type II MC is more stable over time than type III and oligoclonal MC. The oligoclonal type appears to be an intermediate stage in the course of type III changing to type II MC. Symptomatic persistent HCV MC was associated with advanced age, longer duration of HCV infection, type II MC, and a higher MC serum level.
Abstract: The objective was to report our experience of the detection of anti-nucleosome (anti-Nuc) antibodies (Ab) in a large series of consecutive patients, and to compare these results with those of anti-nuclear and anti-dsDNA Ab. In total, 1696 consecutive patients with suspected or confirmed autoimmune disease were tested over a two-year period. The biological investigation included detection of anti-nuclear, anti-dsDNA and anti-Nuc Ab. Among 1696 sera, 382 (23%) were negative for all Ab tested (anti-nuclear, anti-dsDNA and anti-Nuc) and 1314 (77%) were positive for at least one Ab. Anti-Nuc Ab were positive in 350/1314 patients. In this group, 249/350 (71%) also had positive anti-nuclear and anti-dsDNA, 97/350 (28%) had only positive anti-nuclear Ab without anti-dsDNA Ab and 4/350 (1%) had both anti-dsDNA and anti-Nuc Ab without anti-nuclear Ab. No patient had 'isolated' anti-Nuc Ab. Clinical data were available for 307/350 anti-Nuc positive patients. Systemic lupus erythematosus (SLE) was diagnosed in 240/307 (78%) patients, including 43 SLE patients with negative anti-dsDNA Ab. In conclusion, this study extends the relevance of anti-Nuc Ab to routine use for the diagnosis of connective tissue diseases, mainly anti-dsDNA Ab negative SLE.
