Low diagnostic and predictive value of anti-dsDNA antibodies in unselected patients with recent onset of rheumatic symptoms: results from a long-term follow-up Scandinavian multicentre study.

OBJECTIVES: To verify the diagnostic accuracy of anti-double-stranded DNA (anti-dsDNA) antibodies detected by the Crithidia luciliae immunofluorescence test (CLIFT) in a cohort of unselected patients, referred to a rheumatologist due to recent onset of rheumatic symptoms. METHOD: A total of 1073 consecutive patients were screened for anti-nuclear antibodies (ANAs). Serum samples from 292 ANA-positive and 292 matching ANA-negative patients were tested three times for anti-dsDNA antibodies, using two different CLIFT kits (ImmunoConcepts(®) and Euroimmun(®)). An initial clinical diagnosis was made by rheumatologists unaware of the results. The diagnoses were updated after a median follow-up of 4.8 years. RESULTS: CLIFT was positive at least once in 60 patients but only 23 patients were CLIFT positive in all of the assays. Diagnosis of systemic lupus erythematosus (SLE) was made initially in 65 patients, of whom 24 (37%) were CLIFT positive. Many other diagnoses were observed among the CLIFT-positive patients. Overall, 16 (5.5%) ANA-negative patients were CLIFT positive. After approximately 5 years, the diagnosis of SLE remained unchanged in 63 patients (23 CLIFT positive) and altered in only two (one CLIFT positive). Among the 36 CLIFT-positive patients who were not diagnosed with SLE at study entry, only one developed SLE during the follow-up period. CONCLUSIONS: CLIFT was not reliable as a diagnostic tool in unselected patients with rheumatic symptoms. ANAs were of little value as a screening test before the CLIFT analysis. CLIFT had surprisingly low positive predictive value (PPV) for the diagnosis of SLE despite its high specificity. For non-SLE patients, being CLIFT positive poses little risk of developing SLE within 5 years.

Telomere length identifies two different prognostic subgroups among VH-unmutated B-cell chronic lymphocytic leukemia patients.

Some evidences suggest that telomere restriction fragment length (TRF-L) is an effective indicator of histopathogenesis in B-cell tumors. As histopathogenesis is relevant for B-cell chronic lymphocytic leukemia (B-CLL) prognosis, TRF-L was assessed by Southern blot in 201 patients and compared to variable immunoglobulin heave chain gene mutational status (VH-MS) and to other known prognostic features. Overall survival (OS), time to first treatment (TTFT) and progression-free survival (PFS) were evaluated. Our results indicate the following: (1) TRF-L is heterogeneous among B-CLL patients (median 6014 bp, range 1465-16 762); (2) TRF-L correlates to VH-MS (r(2)=0.1994, P<0.0001) with VH-mutated patients showing long and VH-unmutated short telomeres; however, 41% of VH-unmutated and 5% of VH-mutated patients did not show this correlation and were thus defined as 'discordant'; (3) TRF-L effectively predicts outcome in terms of TTFT, PFS and OS; (4) VH-unmutated discordant patients have a better clinical outcome than VH-unmutated concordant patients (OS P<0.01, PFS P<0.05) and similar to that of VH-mutated patients (OS, PFS P=NS). Compared to VH-unmutated concordant patients, VH-unmutated discordant patients showed no peculiarity in their immunoglobulin rearrangement nor in their flow cytometry or fluorescence in situ hybridization profile. In conclusion, TRF-L can be helpful to refine prognostication of B-CLL patients, particularly those with a VH-unmutated immunoglobulin sequence.

Marked telomere shortening in mobilized peripheral blood progenitor cells (PBPC) following two tightly spaced high-dose chemotherapy courses with G-CSF.

The purpose of the study was to compare telomere length (TL) in peripheral blood progenitor cells (PBPC) collected after two tightly spaced high-dose (hd) chemotherapy courses. We assessed 37 previously untreated lymphoma patients undergoing a hd-chemotherapy program with autografting. They sequentially received hd-cyclophosphamide (CY) and hd-Ara-C, both followed by PBPC harvesting. Both post-CY and post-Ara-C harvests were assessed for TL by Southern blot analysis. In 12 patients, the assay was also performed on purified CD34+ cells. All patients displayed high PBPC mobilization following both hd-CY and hd-Ara-C. In all but one patient, TL was shorter in PBPC collected after Ara-C compared to CY: 7226bp (range: 4135-9852) vs 8282 bp (range 4895-14860) (P < 0.0001). This result was confirmed on CD34+ cells. Platelet recovery in patients receiving post-Ara-C PBPC was significantly slower compared to those receiving post-CY PBPC. In conclusion, (i) administration of tightly spaced hd-chemotherapy courses induces marked telomere shortening on harvested PBPC; (ii) engraftment kinetics seem slower, with delayed platelet recovery, in patients autografted with PBPC suffering marked TL erosion; (iii) long-term follow-up is required to verify whether PBPC with shortened telomeres display defective engraftment stability and/or risk of secondary leukemia; (iv) TL evaluation is advisable whenever new mobilization procedures are developed.

[Indication for a modern therapy of rheumatoid arthritis]. / Il razionale per una moderna terapia dell'artrite reumatoide.

The treatment of rheumatoid arthritis is currently based on pathogenesis and pathophysiology, being the etiology still unknown. At cognition and activation phase of rheumatoid arthritis, there is a number of potential therapeutic approaches, still in development and in early trials. At inflammation and even more at invasive phase of rheumatoid arthritis, the treatment should take into consideration the parallel activation of several different processes, sustained by the heterogeneity of cells in the inflamed synovium. The early detection of potential severe rheumatoid arthritis patients is crucial, in order to be able to adjust the treatment according to the severity of disease in each patient. Evaluation of genetic and clinical markers for severe disease within the sixth month and in any case no later than the third year of disease is recommended. As far as pharmacotherapy is concerned, it is useful to distinguish anti-rheumatic agents in symptom-modifying drugs (SM-ARDs) and disease-controlling therapy (DC-ART). Discovering the causal agent of rheumatoid arthritis could dramatically change the treatment of rheumatoid arthritis. In the meantime, one can envisage a further development of immuno-pharmacotherapy and the introduction in the clinical practice of specific or selective immunotherapy.

[Efficacy and tolerability of methotrexate in the treatment of rheumatoid arthritis]. / Efficacia e tollerabilità del methotrexate nel trattamento dell'artrite reumatoide.

OBJECTIVE: To verify, in an open study, the efficacy and safety of long-term administration of low weekly doses (5 mg) of methotrexate (MTX) i.m. in different stage rheumatoid arthritis patients. PATIENTS AND METHODS: The study has been performed for 24 months in 42 patients (37 females and 5 males), fulfilling the ARA criteria for rheumatoid arthritis. Main functional parameters, main serological data and some immunology indexes were periodically monitored (after 1, 3, 6, 12 and 24 months of therapy); moreover, some instrumental exams (X-ray of involved joints, liver ultrasound, respiratory function tests) have been performed. RESULTS: Thirty of 42 enrolled patients completed the whole 24 month therapy, and 22 are still using methotrexate. Results were as follows: therapeutic remission in one patient, marked improvement in 12 cases, moderate improvement in 16 and worsening in 1. Among the 12 remaining patients, 2 refused further treatment; 6 and 4 patients were withdrawn from the study because of inefficacy and toxicity, respectively. A significant improvement was observed in all of the main efficacy parameters taken into consideration. Moderate and reversible side effects were registered in 23 patients. CONCLUSIONS: Our results confirm the value of MTX in the treatment of rheumatoid arthritis. In our opinion this drug is very effective even in a relatively early stage of the disease, mainly in patients whose genetic and clinical markers may predict a more aggressive and severe outcome.

[Exfoliative conjunctival cytology in Sjögren's syndrome]. / La citologia esfoliativa congiuntivale nella sindrome di Sjögren.

The study has been performed in order to give a contribution to the knowledge of the conjunctival cytology in Sjögren's syndrome. Exfoliated cells were obtained by a tampon from the inferior conjunctival sac of 11 patients affected by primary or secondary Sjögren's syndrome; the material was placed onto a microscope slide and it was stained with May-Grumwald-Giemsa, after the ferning test had been performed. Tear production had been previously assessed in all patients by Schirmer's I test and basic secretion test that showed an evident tear fluid hyposecretion. Cytoanalysis of tear fluid showed, in all patients, a marked lymphocytosis, presence of epithelial cells (sometimes cell-adhesion) and a number of "snake-cells", with a nucleus-cytoplasm ratio in favour of cytoplasm. Some of those cells have a thicker cytoplasmic membrane and/or a spindle-shaped peripheral nucleus, characteristic finding of keratoconjunctivitis sicca. In all cases we found mucus and fibrin (sometimes with included cells), organic debris and big crystals, some of which aggregated.