DNA methylation modulates HRES1/p28 expression in B cells from patients with Lupus.

Systemic lupus erythematosus (SLE) disease is an autoimmune disease of unknown aetiology that affects predominantly women of child bearing age. Since previous studies, including ours, have demonstrated that CD4+ T cells and B cells from SLE patients are defective in their ability to methylate their DNA upon antigen stimulation, the aim of this study was to investigate whether DNA demethylation affects the transcription of HRES-1 in B cells. HRES-1 is the prototype of Human Endogenous Retrovirus (HERV) overexpressed in SLE. We have observed that SLE B cells were characterized by their incapacity to methylate the HRES-1 promoter, both in unstimulated and in anti-IgM stimulated B cells. In turn, HRES-1/p28 expression was increased in SLE B cells after B cell receptor engagement, but not in controls. In SLE B cells the Erk/DNMT1 pathway was defective. In addition, blocking the autocrine-loop of IL-6 in SLE B cells with an anti-IL-6 receptor monoclonal antibody restores DNA methylation and control of HRES-1/p28 expression became effective. As a consequence, a better understanding of HERV dysregulation in SLE reinforces our comprehension of the disease and opens new therapeutic perspectives.

Epidemiology, imaging, and treatment of giant cell arteritis.

Giant cell arteritis (GCA) is the most common vasculitis, and epidemiological data indicate a further increase in incidence over the last two decades. The disease predominates in individuals from Scandinavia and other Northern European countries. The impact of GCA on mortality remains unclear, although an increased risk of cardiovascular events has been reported. Most of the complications are related to the use of glucocorticoids to treat the disease. Recently introduced tools for diagnosing GCA include high-resolution Doppler ultrasonography and magnetic resonance imaging (MRI), whose performance remains to be determined. Glucocorticoids constitute the mainstay of the treatment of GCA. Other drugs have been evaluated, including dapsone, hydroxychloroquine, methylprednisolone pulse therapy, azathioprine, cyclosporine, cyclophosphamide, and methotrexate; however, the studies were methodologically flawed and produced conflicting results. No drug has been found effective in reducing glucocorticoid requirements. The role for biotherapies remains unclear, as the promising results obtained in open-label studies were not borne out by controlled trials.

Maintenance of infliximab treatment in ankylosing spondylitis: results of a one-year randomized controlled trial comparing systematic versus on-demand treatment.

OBJECTIVE: Continuous treatment with the anti-tumor necrosis factor alpha (anti-TNFalpha) antibody infliximab is efficacious in ankylosing spondylitis (AS), whereas treatment discontinuation results in disease relapse, with variable delay. This study was undertaken to compare the efficacy of continuous treatment with infliximab with that of a treatment regimen adapted to symptom recurrence. Methotrexate (MTX) in combination with infliximab was also tested. METHODS: Patients with active AS were randomly assigned at week 0 to receive infliximab every 6 weeks (continuous treatment) or upon symptom recurrence (on-demand treatment), following infusions at weeks 4, 6, and 10. Patients in the on-demand group were randomly assigned to receive either MTX in combination with infliximab or infliximab alone. Patients were monitored for 1 year. The primary end point was the proportion of patients who met the ASsessment in AS International Working Group criteria for 20% improvement (ASAS20) at week 58. RESULTS: Of 247 patients, 124 were assigned to receive infliximab every 6 weeks and 123 to receive on-demand treatment. Among the latter, 62 received MTX, and 61 received infliximab alone. A greater proportion of patients receiving infliximab every 6 weeks fulfilled ASAS20 response criteria at week 58 than did patients receiving on-demand treatment (75% versus 46%; P<0.0001). Patients in the continuous treatment group received more infliximab infusions after week 10 than did those in the on-demand group (mean+/-SD 5.8+/-2.2 versus 3.5+/-2; P<0.0001). Addition of MTX did not significantly affect the proportion of patients with an ASAS20 response at week 58, nor the number of infliximab infusions administered. CONCLUSION: These findings indicate that continuous treatment of AS with infliximab is more efficacious than on-demand treatment, and that the addition of MTX to infliximab provides no significant benefit.

Anti-alpha-actinin antibodies: a new marker of lupus nephritis.

The exact role of anti-ds (double stranded) DNA antibodies in the pathogenesis of kidney injury in lupus nephritis remains a focus of continuing investigation. One theory explaining the pathogenicity of anti-dsDNA antibodies in lupus nephritis is direct cross-reactivity with renal antigens. Several years ago, alpha-actinin was identified as a major cross-reactive target for pathogenic anti-dsDNA antibodies in murine SLE. Indeed, binding of a nephritogenic murine anti-dsDNA antibody was stronger to the alpha-actinin derived from a lupus prone mouse mesangial cell line as compared to alpha-actinin in a non-autoimmune mouse mesangial cell line. Furthermore, we recently showed that immunization of non-autoimmune mice with alpha-actinin induces anti-chromatin antibodies, glomerular IgG deposition and proteinuria. In humans, anti-alpha-actinin autoantibodies (Ab) were associated with anti-dsDNA Ab in SLE. In those patients, anti-alpha-actinin rather than anti-dsDNA Ab were significantly associated with glomerulonephritis and disease activity. The anti-alpha-actinin reactivity was associated with high avidity anti-dsDNA Ab. Moreover, the anti-alpha-actinin response was related to the actin-binding site of alpha-actinin. Taken together, these studies indicate that detection of anti-alpha-actinin Ab, in association with anti-dsDNA Ab, may constitute a new marker in lupus nephritis.

Association of alpha-actinin-binding anti-double-stranded DNA antibodies with lupus nephritis.

OBJECTIVE: Anti-double-stranded DNA (anti-dsDNA) antibodies may contribute to the pathogenesis of glomerulonephritis (GN) by cross-reacting with alpha-actinin in murine models and in some patients with systemic lupus erythematosus (SLE). We therefore sought to determine possible disease associations with serologic and clinical features and to characterize this new autoantibody specificity. METHODS: One hundred patients with SLE were recruited into this multicenter study, as well as 100 rheumatic disease controls and 2,100 healthy blood donors. Clinical disease was evaluated by the SLE Disease Activity Index (SLEDAI; excluding the anti-DNA component). Anti-dsDNA antibodies were detected by conventional enzyme-linked immunosorbent assay (ELISA) and by a commercial enzyme immunoassay (EIA). Anti-alpha-actinin antibodies were detected by ELISA, and their specificity was confirmed by Western blotting and by indirect immunofluorescence using rat kidney sections and mesangial cells as substrates. Highly positive sera were selected for absorption experiments and were affinity-purified for cross-reactivity studies and measurement of antibody avidity. RESULTS: Sera from 62 of the SLE patients had anti-dsDNA antibodies; 21 of these sera also had anti-alpha-actinin antibodies, as compared with 1 of the 38 sera without anti-dsDNA antibodies. Of the 22 patients with anti-alpha-actinin antibodies, 10 had GN, as compared with 14 of the 78 without anti-alpha-actinin antibodies (P < 0.01). In patients with GN, anti-alpha-actinin, but not anti-dsDNA, antibodies correlated with the SLEDAI score (minus the anti-DNA component) and with treatment. The fraction of serum anti-dsDNA antibodies that cross-reacted with alpha-actinin exhibited high avidity for dsDNA, as determined using a commercial EIA for high-avidity anti-dsDNA antibodies and an in-house conventional ELISA. CONCLUSION: The alpha-actinin-binding antibodies are significantly associated with GN in SLE. Whether such autoantibodies may anticipate the development of this complication of SLE remains to be verified.

Group B streptococcal arthritis.

Recent data suggest that group B streptococcal arthritis is being increasingly diagnosed. We retrospectively reviewed the records of patients admitted to our Teaching Hospital Rheumatology Department for septic arthritis between May 2000 and May 2004 and we reviewed the relevant literature to determine the characteristics of group B streptococcal arthritis. We compared age, hospital stay duration, and number of joints involved in the patients with group B streptococcal arthritis and in those with septic arthritis due to other organisms. Of 48 consecutive patients with septic arthritis, five (10.4%) had arthritis due to group B streptococci. Mean age of these five patients was 51.6+/-18.3 years and mean hospital stay duration was 13.2+/-9.23 days. Arthritis distribution was oligoarticular in three patients, polyarticular in one patient, and monoarticular in one patient. The mean number of involved joints was significantly (P=0.005) higher in the patients with group B streptococcal arthritis than in the other patients (2.6+/-1.5 vs 1.1+/-0.4 joints). Age and hospital stay duration were not significantly different. The frequently oligoarticular or polyarticular distribution of group B streptococcal arthritis, together with the sometimes limited symptoms, may lead to diagnostic wanderings or delays.

Performance of hand radiographs in predicting the diagnosis in patients with early arthritis.

OBJECTIVE: To evaluate the ability of baseline hand radiographs to predict the diagnosis 2 years later in a cohort of patients with early arthritis. METHODS: A total of 258 patients with arthritis onset within the previous year were evaluated. At baseline, all patients underwent a standardized evaluation including laboratory tests and radiographs. Hand radiographs were read by a blinded observer who used a standardized procedure for detecting features of crystal deposition diseases and rheumatoid arthritis (RA). After 30 +/- 11.3 months, the final diagnosis was established by a panel of rheumatologists. All radiographs were evaluated. RESULTS: Significant associations were found between radiographic features and a clinical diagnosis of RA, calcium pyrophosphate dihydrate (CPPD) arthritis, and hydroxyapatite arthritis. No radiographic abnormalities suggesting psoriatic arthritis or gout were seen. The sensitivities of hand radiographs for diagnosing CPPD or hydroxyapatite arthritis ranged from 80% to 100%. Baseline hand radiographs suggested the final diagnosis in 31/258 patients, including 21 (22.5%) of the 93 patients with RA, 10 of the 11 (91%) patients with CPPD or hydroxyapatite deposition disease, and none of the patients with other disorders. Sensitivity was 29%, specificity 86.5%, positive predictive value 61%, and negative predictive value 63%. CONCLUSION: In our cohort of patients with recent arthritis, the overall performance of hand radiographs in predicting a diagnosis 2 years later was modest. However, they had an excellent diagnostic value for calcium deposition diseases.

Incidence and nature of karate injuries.

OBJECTIVES: To determine the incidence and nature of karate injuries sustained in karate clubs and to identify risk factors for injuries. METHODS: One hundred eighty-six individuals from three karate clubs in Brest, France, were entered in a retrospective study extending from September 2002 to June 2003. Each athlete was asked to complete a questionnaire on karate injuries sustained during the previous year (type, location, mechanism, exercise during which the injury occurred, number of days off training and work, and medical care). Injury types were described by number of injuries and risk factors per number of injured athletes. RESULTS: Forty-eight (28.8%) of the 186 athletes sustained 83 injuries (63 while training and 20 while competing). The annual injury rate was 44.6 per 100 athletes. Incidence rates were similar in males and females and across the three clubs but increased with age, time spent training (3.6+/-1.7 vs. 2.9+/-1.5 h/week; P=0.001), rank (lower ranks vs. brown and black belts, P=0.015), and years of practice (7.3+/-5.5 years in athletes with injuries vs. 5.1+/-4.8 in those without injuries; P=0.03). Injuries consisted of 43 (53%) hematomas, 16 (19%) sprains, seven (7%) muscle lesions, six (7%) fractures, four (5%) malaise episodes, and seven (7%) miscellaneous lesions. Time off training occurred for 26 (31.3%) injuries and ranged from 8 to >30 days. The body region involved was the head in 22 (26.5%) injuries, the torso in eight injuries (9.6%), the upper limb in 24 (28.9%) injuries, and the lower limb in 29 (35%) injuries. CONCLUSION: Karate injuries are fairly common but usually minor. They are more likely to occur during competitions than while training. The head and limbs are the main regions involved. Longer training times per week and higher rank are associated with an increased risk of injury. Prevention seems crucial.

Induction of endothelial cell apoptosis by the binding of anti-endothelial cell antibodies to Hsp60 in vasculitis-associated systemic autoimmune diseases.

OBJECTIVE: Anti-endothelial cell antibodies (AECAs), which recognize a number of endothelial antigens, are seen in patients with systemic autoimmune diseases, more often in the presence of vasculitis than in its absence. Some AECAs induce apoptosis of endothelial cells (ECs), but their target antigens remain unknown. The aim of this study was to determine whether Hsp60 is a target antigen and whether AECAs induce apoptosis in ECs. METHODS: Two-dimensional electrophoresis and conventional Western blotting techniques were used to characterize AECA targets. Hsp60 reactivity was determined by enzyme-linked immunosorbent assay. RESULTS: Hsp60 was shown to be targeted by a proportion of AECAs. The level of reactivity was higher in patients with systemic autoimmune disease and vasculitis than in those without vasculitis and in patients with systemic lupus erythematosus than in patients with other systemic autoimmune diseases. Hsp60 was expressed on the plasma membrane of heat-stressed ECs, and this followed Hsp60 messenger RNA transcription, confinement of the protein to the cytoplasm, and translocation of the protein to the surface. Shedding of Hsp60 from ECs was induced by stress and resulted in the binding of soluble Hsp60 to the surface of ECs, particularly stressed ECs. Apoptosis of ECs was triggered by anti-Hsp60-containing AECA-positive sera and was inhibited by preincubation of the ECs with recombinant Hsp60. CONCLUSION: Our data support the notion that Hsp60 is an important target for AECAs and that such an interaction contributes to pathogenic effects, especially in vasculitis-associated systemic autoimmune disease.

BAFF overexpression is associated with autoantibody production in autoimmune diseases.

The B-cell activity factor (BAFF) acts as a positive regulator of B-cell function. To gain further insight into the understanding of B-cell hyperactivity in autoimmune diseases, the serum level of BAFF was determined in 43 systemic lupus erythematosus (SLE) patients, 58 primary Sjögren's syndrome (pSS) patients, 28 rheumatoid arthritis (RA) patients, and 68 normal control subjects using an in-house sandwich ELISA. A commercial kit was used to detect soluble CD23 (sCD23) reflecting B-cell activation. In-house assays for the detection of autoantibodies also were used. We found an increased level of BAFF in SLE, pSS, and RA sera compared with normal subjects (respectively, 10.6 +/- 8.5, 15.8 +/- 12.9, 9.7 +/- 1.5 ng/mL vs. 4.6 +/- 2.9 ng/mL, P < .001). sCD23 released on B-cell activation also was found to be elevated in SLE, pSS, and RA compared with normal sera. However, no correlation was found between the circulating BAFF and the level of sCD23. By contrast, we observed that high levels of BAFF were associated with the presence of autoantibodies (anti-double-stranded DNA antibodies in SLE, anti-SSA antibodies in pSS, and rheumatoid factors in RA). Our data suggest that BAFF is influential in driving antibody production rather than activation of the B lymphocytes in autoimmune diseases.

Post-fracture osteolysis of the pubic bone simulating a malignancy: report of a case.

Post-fracture osteolysis of the pubic bone is rare. We report a case of a 70-year-old woman with osteoporosis and a history of radiation therapy 2 years earlier. At presentation, she was found to have a bilateral sacral fracture and fractures of both pubic rami on one side. The pain persisted, and follow-up radiographs showed osteolysis of the pubic rami suggestive of metastatic disease. The development of a bony callus within 8 months established the diagnosis of benign osteolysis. About 50 cases of osteolysis at fracture sites have been reported to date, of which about a dozen occurred after radiation therapy. All the patients were elderly women with post-menopausal osteoporosis. Radiation therapy probably further increases the risk in this setting. The possibility of osteolysis at fracture sites in patients with osteoporosis should be borne in mind to avoid unnecessary and burdensome investigations that are costly and cause undue anxiety to the patients. Rest is the only effective treatment.

Ability of foot radiographs to predict rheumatoid arthritis in patients with early arthritis.

OBJECTIVE: In a cohort of patients with early arthritis, to evaluate how well foot radiographs at study inclusion predicted a diagnosis of rheumatoid arthritis (RA) 2 years later. METHODS: A cohort of patients with arthritis of less than one year duration was evaluated in a multicenter study and followed for 30 +/- 11 months. An observer blinded to patient data read all 149 hand and foot radiographs done at study inclusion, using item 7 of the 1987 American College of Rheumatology (ACR) criteria for RA and Sharp's method to score erosions and joint space narrowing. RESULTS: The kappa coefficient for the 1987 ACR item 7 was 0.52 for bony decalcification and 0.87 for erosions. Intra and interobserver correlation coefficients for Sharp's scores ranged from 0.90 to 0.98. Erosions at the feet were significantly associated with RA. The item 7 erosion component at the feet was more specific than the full item 7 (97.5% vs 94%; p = 0.01). Sharp's erosion score at the feet was not better than the erosion component of item 7 (sensitivity 18%; specificity 97.5%). Combined use of radiographs of the hands and feet improved the diagnostic performance of the item 7 erosion component; (sensitivity and specificity of item 7 erosions at the hands combined with the feet were 32.5% and 94.5%, respectively). CONCLUSION: The "erosion" criterion at the feet had the best diagnostic performance and was significantly associated with a diagnosis of RA. Combining hand and foot radiographs improved diagnostic performance.

Musculoskeletal manifestations in cystic fibrosis.

Although bone and joint manifestations are common in children with cystic fibrosis (CF), they have received little attention in adults. As compared to healthy individuals, bone mineral density is low, even with calcium intakes greater than 1500 mg/d. Nevertheless, calcium and phosphate levels in blood and urine are often normal, and vitamin D levels vary. Short stature with a low body mass index and central hypogonadism are the rule in these patients. Fractures and kyphosis are often reported. CF arthropathy occurs in 2-8.5% of patients. Arthritis develops, and there may be skin eruptions. Non-steroidal antiinflammatory drug therapy is effective. Hypertrophic osteoarthropathy associated with respiratory failure is present in 2-7% of patients. Rheumatoid arthritis, spondyloarthropathies, sarcoidosis, and amyloidosis have been reported in association with CF. Knee pain due to patellofemoral syndrome, quinolone-induced arthropathy, and mechanical back pain have been described. Rheumatoid factor titers are higher than in healthy controls, particularly in patients with episodic arthritis. No data are available on antiperinuclear factor or antikeratin antibody titers. Tests for antinuclear antibody are usually negative. Circulating immune complex levels and antibodies to heat shock proteins may be elevated. Antineutrophil cytoplasmic antibody of the bactericidal/permeability-increasing protein (BPI) or azurocidin (AZ) type has been reported, often in high titers (up to 40%).

Value of antibodies to citrulline-containing peptides for diagnosing early rheumatoid arthritis.

OBJECTIVE: To compare the diagnostic values of antiperinuclear factor (APF), antikeratin antibody (AKA), and anti-cyclic citrullinated peptides (anti-CCP) to discriminate between patients with and without rheumatoid arthritis (RA) and to determine the diagnostic value of anti-CCP used alone or with other tests. METHODS: Two hundred and seventy patients with early arthritis underwent standardized investigations in 1995-1997. The clinical utility of APF, AKA, and anti-CCP in first-visit sera was evaluated using receiver-operating characteristic curves. Combinations of anti-CCP with other laboratory tests were assessed by multiple logistic regression. RESULTS: Anti-CCP, APF, and AKA were not perfectly correlated with one another. Anti-CCP with 53 UI as the cutoff was 47% sensitive and 93% specific, versus 52% and 79%, and 47% and 94%, for APF and AKA, respectively. Multiple logistic regression selected anti-CCP, AKA, IgM-rheumatoid factor (RF) ELISA, and the latex test. CONCLUSION: Rheumatologists can routinely use 2 or 3 tests for diagnosing RA (latex and/or IgM RF ELISA, and either AKA or anti-CCP ELISA) and can add a third or fourth test when the diagnosis remains in doubt.