Phenotypic analysis of IL-10-treated, monocyte-derived dendritic cells in patients with systemic lupus erythematosus.

Dendritic cells (DC) play a dual role in the immune response, participating in its induction, and the maintenance of immune tolerance. The aim of this work was to perform a quantitative and phenotypic analysis of DC generated in vitro in the presence of IL-10 in patients with systemic lupus erythematosus (SLE). Blood samples were obtained from 10 active and untreated patients with SLE and six controls. Monocyte-derived DC were generated in vitro in the presence or absence of IL-10, and a quantitative and phenotypic analysis was performed. We found that freshly isolated monocytes from SLE patients had an increased expression of CD11b. On the other hand, the efficiency of in vitro DC generation was diminished in blood samples from SLE patients for conventional DC, but not for IL-10-treated DC. A diminished expression of HLA-DR, CD9 and CD86 was observed in conventional DC from SLE patients compared with controls. In contrast, enhanced levels of HLA-DR, CD80, CD9 and CD151 tetraspanins, FN1 (a class II MHC-tetraspanin epitope), CD85j/ILT2 and CD69 were detected in IL-10-treated DC from SLE patients. Accordingly, the phenotypic profile of IL-10-treated DC was very different in SLE and controls. However, the synthesis of IL-10 and IL-12 was similar in IL-10-treated and conventional cells in both SLE patients and controls. Our findings on the aberrant phenotype of IL-10-treated DC in SLE and their normal efficiency of in vitro generation may be important for the design of future therapies of this condition based on the administration of DC to induce immune tolerance.

Allogeneic peripheral blood stem cell transplantation using reduced intensity versus myeloablative conditioning regimens for the treatment of leukemia.

Reduced intensity conditioning (RIC) have allowed the application of transplantation to older patients and to patients with underlying medical problems. Between October, 1999, and June, 2003, 61 patients with acute leukemia or chronic myeloid leukemia received allogeneic peripheral blood hematopoietic stem cell transplantation (HSCT) from HLA-identical siblings. Thirty-four were conditioned with myeloablative protocols and twenty-seven with RIC regimens. The patients in the myeloablative group were younger (29 vs. 37 years; p < 0.0003), most of them were transplanted in complete remission (74% vs. 59%; p < 0.03), had a shorter interval between diagnosis and HSCT (12 vs. 21 months; p < 0.02) and a greater proportion belonged to standard-risk prognosis (68% vs. 48%; p < 0.1). The median times to neutrophil, platelet and red blood cell engraftment for the myeloablative and RIC groups were 14 versus 11 days (p < 0.009), 17 versus 9 days (p < 0.0001), and 19 versus 12 days (p < 0.007), respectively. Transfusion requirements were lower in the RIC group. Severe mucositis was present in 32% and 7%, respectively (p < 0.01). The proportion of patients having acute graft versus-disease (GVHD), chronic GVHD, and infections was the same, as well as early and late mortality, disease-free survival, and overall survival. Analyzing all the patients together, three factors significantly influenced overall survival: standard risk patients, complete remission at transplant, and the absence of severe acute GVHD. In conclusion, our data suggest that even in high-risk patients, RIC transplantation seems to be as useful as ablative HSCT.

Donor lymphocyte infusions for relapse of chronic myeloid leukemia after allogeneic stem cell transplantation: prognostic significance of the dose of CD3(+) and CD4(+) lymphocytes.

Between December 1993 and November 2001, 30 patients with chronic myeloid leukemia who relapsed after stem cell transplantation were studied. Seventeen patients were not treated before donor lymphocyte infusion (DLI), eight patients received interferon-alpha (IFN-alpha), and five underwent chemotherapy. The method of DLI was the bulk dose regimen. The median time between DLIs was 6 weeks. The median number of infusions was three; the median time from transplant to relapse was 17 months and from relapse to DLI 2 months. Eleven patients (37%) were in molecular/cytogenetic relapse, 14 (47%) in chronic phase, and five (16%) in accelerated or blastic phase. Seventeen patients (57%) developed acute graft-versus-host disease (GVHD). Chronic GVHD was observed in 15 of 24 (62%) patients. Four (13%) patients developed cytopenia after a median of 30 days. Nineteen (63%) patients achieved response, 15 of them developed GVHD. The response rate according to the disease phase was molecular or cytogenetic relapse: 91%, chronic phase: 57%, and accelerated or blastic phase: 20%. The median time to response was 6 months. Patients treated with IFN-alpha or no treatment as well as those who were in molecular/cytogenetic relapse and those who received a CD3(+) cell dose <1 x 10(8)/kg and CD4(+) <8 x 10(7)/kg had better survival. We conclude that patients who receive lower doses of lymphocytes have better survival. In some patients IFN-alpha seems to be a good choice to potentiate the graft-versus-leukemia (GVL) effect.

Long-term effectiveness of danazol corticosteroids and cytotoxic drugs in the treatment of hematologic manifestations of systemic lupus erythematosus.

The purpose of this study was to compare the long-term effectiveness among danazol, corticosteroids, cytotoxics, and dapsone in the treatment of hematological manifestations of systemic lupus erythematosus (SLE). Medical charts of all patients seen at the Rheumatic Disease Unit from January to December of 1998 were reviewed. Patient characteristics, disease and treatment information were collected. The main outcome measures were the cause of and time to discontinuation of drugs used to treat hematological manifestations of SLE resulting from all causes, mainly toxicity and inefficacy or both. Bivariate analysis including one-way ANOVA and chi2 tests were used to compare differences between means and proportions, respectively. Survival curves among the different drugs were evaluated using the Kaplan-Meier method. Multivariate analysis (Cox-regression) was used to adjust for potential confounders. After all medical records were reviewed 41 cases were eligible. Two cases had hemolytic anemia, 34 had thrombocytopenia, and five had both. These cases had received a total of 121 cycles of treatment at different times and they represent the study population (corticosteroids n = 37, danazol n = 51, citotoxic drugs n = 29, and dapsone n = 4). Crude rates of discontinuations due to any cause, toxicity and inefficacy werenot statistically significant among the drugs. However, the Kaplan-Meier curves showed statistically significant difference for discontinuations due to all causes as well as inefficacy. Prednisone and cytotoxic drugs had the lowest probability of continuation. In contrast, there were not statistically significant differences among the drugs with respect to first relapse. This is the first study examining the long-term termination rates of several drugs used to treat hematological manifestations of SLE. Using rates of discontinuation adjusted for time there were statistically significant differences among the drugs. Danazol had the highest probability of continuation.

Disappointing longterm results with disease modifying antirheumatic drugs. A practice based study.

OBJECTIVE: To evaluate the longterm effectiveness of disease modifying antirheumatic drugs (DMARD) in an inception cohort of patients with rheumatoid arthritis (RA) seen by rheumatologists. METHODS: We performed a retrospective audit of the records of patients with onset of RA between January 1985 and June 1994. Charts were reviewed from the time of diagnosis to the last consult. Survival analysis was performed using Kaplan-Meier and Cox proportional hazard regression to adjust for potential confounders. RESULTS: A total of 2296 DMARD therapies were analyzed. Roughly half were started within 2 years of disease onset. By 16 months, 50% of the DMARD therapy courses had been discontinued, and after 4.5 years 75% had been discontinued. Over all, methotrexate (MTX) had the highest probability of continuation. After roughly 3 years 50% of patients were still receiving MTX, compared to one-third of patients who received antimalarials or intramuscular gold, 30% D-penicillamine, 25% sulfasalazine, and 18% oral gold. After 6 years, when considering all DMARD together, only 20% of the therapies had not been discontinued, with no substantial differences between drugs. Toxicity from gold compounds occurred within the first 18 months of therapy and stabilized thereafter. For MTX, withdrawals due to toxicity continued throughout therapy. CONCLUSION: This is the largest observational study examining the longterm termination rates of DMARD in patients followed from the time of their initial consult. Our results confirm previous reports of short therapeutic times, even for patients treated early in the course of their disease. MTX appears to be the best drug within the first 5 years of disease. These differences, however, decrease in the longer term. It is unclear whether the results observed for MTX within the first years of therapy translate to better health status in the longer term when compared to other DMARD.

Cyclophosphamide pulse therapy in optic neuritis due to systemic lupus erythematosus: an open trial.

OBJECTIVE: To evaluate the efficacy of intravenous cyclophosphamide pulse therapy in patients with optic neuritis associated with systemic lupus erythematosus (SLE). PATIENTS AND METHODS: Ten consecutive patients with optic neuritis due to SLE whose condition was refractory to corticosteroids and oral immunosuppressants were treated with intravenous cyclophosphamide (0.5 to 1.0 g/m2) monthly for 6 months. RESULTS: All patients had bilateral eye involvement. One eye was legally blind, and 13 eyes could see only hand movements or count fingers. Six patients had evidence of the secondary antiphospholipid antibody syndrome. Complete recovery in visual acuity occurred in 10 eyes (50%), and a partial response occurred in six eyes (30%); four eyes (20%) had no response. Complete response in the field tests occurred in eight eyes (40%), with a partial response in nine eyes (45%); no improvement occurred in three eyes (15%). CONCLUSIONS: Intravenous cyclophosphamide pulse therapy seems to be an effective treatment for optic neuritis refractory to corticosteroids, oral immunosuppressants, or both. A randomized controlled trial will be necessary to confirm our results.

Rheumatic manifestations of hematologic disorders.

A review of the literature during the past year on rheumatic manifestations in hematologic diseases supports the idea that 80% of the hemorrhage in hemophilia occurs within the joints, with knees, elbows, and ankles being the most affected joints in adults. In contrast, the ankle is the target joint in children. Septic arthritis in hemophilic patients is becoming more important due to the advent of HIV infection. Radioactive synoviorthesis in hemarthrosis has the same rate of success as surgical synovectomy, but with far lower costs. A new study documents the association of arthritis and vasculitis in patients with myelodysplasic syndromes and lymphoproliferative disorders. An increased incidence of scoliosis in patients with beta-thalassemia has been noted. Finally, the effects of bone marrow transplantation in patients with previous autoimmune diseases is reviewed. Progression of rheumatoid arthritis after bone marrow transplantation is documented in a patient with 13 years of follow-up. Hematologic disorders in rheumatic diseases are not the topic of this review.

Long-term effectiveness of antimalarial drugs in rheumatic diseases.

OBJECTIVE: The purpose of this study was to compare the long-term effectiveness between chloroquine (CQ) and hydroxychloroquine (HCQ). METHODS: Medical charts of all patients seen by eight rheumatologists practising in two tertiary care centres and starting antimalarial treatment between January 1985 and December 1993 were reviewed. Patient characteristics, disease, and treatment information were collected. The main outcome measures were the cause of and the time to the discontinuation of antimalarial drugs resulting from all causes, principally toxicity or inefficacy, or both. Bivariate analysis including t tests and chi 2 tests were used to assess differences between means and proportions respectively. Survival curves were evaluated using the Kaplan-Meier method. Multivariate analysis (Cox regression) was used to adjust for potential confounders. RESULTS: After all medical records were reviewed, 1042 eligible cases were identified. From these, 940 (90%) had usable information and they represent the cohort. Five hundred and fifty eight had rheumatoid arthritis, 178 had systemic lupus erythematosus, 127 had palindromic arthritis, and 77 had other diagnoses. Fifty seven per cent of the patients received CQ and 43% HCQ. The proportion of patients with side effects taking HCQ and CQ was 15% and 28% respectively (p = 0.001). Using Cox regression model to adjust for age at the onset of antimalarial treatment, physician differences, sex, disease type, disease duration before treatment, and rank selection, there were no differences in the hazard ratio (HR) for overall discontinuations between CQ and HCQ. While the HR for discontinuations because of toxicity was lower for HCQ (HR = 0.6, 95% CI 0.4, 0.9), the HR for discontinuations because of inefficacy was significantly higher for HCQ (HR = 1.4, 95% CI 1.1, 1.9). CONCLUSIONS: After adjusting for time and several confounders HCQ was less toxic but less effective than CQ. Only one case of probable/possible retinopathy was found. Therefore, we propose a careful baseline ophthalmological evaluation by an expert and then one or every two years if proper doses are used.

Variations and trends in the prescription of initial second line therapy for patients with rheumatoid arthritis.

OBJECTIVE: To evaluate practice variation and time trends in the initial prescription of second line drugs for the treatment of rheumatoid arthritis (RA) by a group of selected rheumatologists. METHODS: We retrospectively reviewed medical charts of all patients with a diagnosis of RA, initially seen between January 1, 1985, and June 30, 1994, by rheumatologists from a tertiary center and a rheumatology referral clinic in Edmonton. RESULTS: 1427 patients initially seen between 1985 and 1994 were included in the study. Of these, 1244 (87%) received a second line drug, 71% within 1.5 years after the disease onset. Overall, antimalarials and parenteral gold were the most frequently prescribed. Statistically significant trends were observed for the years under study. From 1985 to 1987, the most frequently prescribed initial second line drug was parenteral gold, between 1988 to 1990, sulfasalazine, and after 1991, antimalarials. Methotrexate was rarely used as a first choice. Marked variability was observed among rheumatologists in the use of initial second line drugs. In general, year of prescription and prescribing rheumatologist were significantly associated with the selection of all second line drugs but methotrexate. In addition, disease duration and residence (urban or rural) were associated with the selection of antimalarials and parenteral gold. CONCLUSION: Most patients were treated early with second line drugs. Initial prescription patterns varied among rheumatologists. These patterns have changed over the last 10 years. An increasing trend in the use of antimalarials was noted, and unlike prescription patterns in the US, methotrexate was rarely used as the first second line drug.

Rheumatic manifestations of neurologic and psychiatric diseases.

Rheumatic diseases have not proved to be more prevalent among neurologic or psychiatric patients than in the general population, except for osteoarthritis in some chronic disabling neurologic conditions (poliomyelitis, spinal cord injury). Some neurologic entities with relevant musculoskeletal manifestations are described here. The lower prevalence of rheumatoid arthritis in schizophrenia patients is mentioned, and a brief description is presented of somatoform disorders that may confound diagnosis with rheumatic diseases. Factitious disorders and malingering are frequently presented with rheumatic complaints such as low back pain and may have an important impact on the costs associated with the disease. Finally, some of the immune system abnormalities described in major depression and schizophrenia are mentioned with a clear reference to the growing field of psychoneuroimmunology. This paper will not address the issue of neurologic or psychiatric manifestations of rheumatic diseases.

Rheumatic manifestations of malignancy.

Rheumatic manifestations of malignancy include a wide spectrum of osteoarticular, muscular, glandular, endocrinologic, and systemic features, posing a therapeutic challenge. The clinician should be aware that Sjögren's syndrome, polymyositisdermatomyositis, rheumatoid and rheumatoid-like arthritis, polymyalgia rheumatica and temporal arteritis, and diverse osteomuscular conditions may be the immunopathogenic features of a neoplasm, the direct consequence of osteomuscular tumors, the effect of tumor-associated hormones, or the consequence of cancer therapy. The principal articles that have appeared in the past year on these associations are discussed. We also review the association of x-ray irradiation and cancer in patients with ankylosing spondylitis.

[Chronic rhinosinusitis: predominant symptoms in children under 14 years of age who were seen at the Regional Center for the Prevention and Treatment of Allergic Diseases]. / Rinosinusitis crónica, síntomas predominantes en menores de 14 años que acudieron al Centro Regional para la Prevención y el Tratamiento de las Enfermedades Alérgicas.

Chronic rhinosinusitis occurs to 5% of the population with upper respiratory infections. The objective of this study is to know the main symptoms in a pediatric population younger than 14 years with the diagnosis of chronic rhinosinusitis, to know age and sex distribution and evolution. We did a medical history, physical examination, nasal cytology, skin tests and sinus X rays in each of 100 patients. Results the main symptoms were: cough, halitosis, postnasal discharge, fever, headache, sore throat, facial sensitivity and periorbital edema. This findings predominated in males and the average evolution time was 1-2 years.

Clinical evaluation of various selected ELISA kits for the detection of anti-DNA antibodies.

Fifty four coded sera, 38 from eight patients with systemic lupus erythematosus (SLE), four from one patient with systemic vasculitis, one from one patient with polyarthritis and 11 normal controls were tested for anti-dsDNA antibodies using seven commercial enzyme linked immunosorbent assays (ELISA) and the radioimmunoassay method (RIA) routinely used in our unit. Sensitivity, specificity and predictive values were tested for both SLE diagnosis and disease activity. Using anti-dsDNA antibodies as a diagnostic test for SLE there were differences in sensitivity (from 66% to 95%), specificity (from 75% to 100%), predictive positive values (from 89% to 100%) and predictive negative values (from 50% to 87%) among ELISA kits. The RIA method was either more specific or equal to ELISA kits. Using 'equivocal' values as positive values an increase in sensitivity was observed but at the expense of specificity. Similar differences and trends were observed when the results were used as a measure for disease activity. This suggests that there are differences in sensitivity, specificity and predictive values among ELISA kits both in the diagnosis of SLE as well as in the determination of disease activity.