Elisabeth Palazzo

Anti-heat shock protein 70 kDa and 90 kDa antibodies in serum of patients with rheumatoid arthritis

OBJECTIVES Stress proteins (HSPs) are highly conserved immunodominant antigens found in various species. The purpose of this study was to assess the prevalence and prognostic significance of antibodies to HSC 70 kDa and HSP 90 kDa in three groups of patients with longstanding rheumatoid arthritis (RA) defined based on the severity of articular erosions. METHODS 73 patients with longstanding (> 6 years) RA whose HLA-DR genotype was known were divided in three groups according to Larsen’s score and compared with 47 recent onset (<1 year) RA patients and with control groups composed of patients with other inflammatory diseases (n=137) or of normal controls (n=48). IgGs and IgMs to HSC 70 kDa and HSP 90 kDa were determined using an ELISA with purified bovine HSC 70kDa or HSP 90 kDa. RESULTS Concentrations of IgGs and IgMs to HSC 70 were significantly increased in 41.1% and 42.5% of longstanding RA patients, respectively. Corresponding figures for IgGs and IgMs to HSP 90 were 39.7% and 56%. IgMs to HSC 70 and HSP 90 were less frequent in recent onset RA (19% and 13% respectively). Among the groups with other inflammatory diseases, only the MCTD group exhibited high frequencies of IgGs to HSC 70 (80%) and HSP 90 (85%). DRB1*0401 positive RA patients (n=23) were not more likely to have increased concentrations of antibodies to HSC 70 kDa or HSP 90 kDa than other RA patients (DR4 positive but DRB1*0401 negative, or DR1 positive, n=31; or negative for both DR4 and DR1, n=14). IgGs to HSP 90 kDa were significantly more frequent (p<0.05) in longstanding RA patients whose Larsen’s score was 4 or more (57%) than in those whose Larsen’s score was 2 or 3 (39.4%) or less than 2 (16%). No associations were found between Larsen’s score and IgGs or IgMs to HSC 70 kDa or IgMs to HSP 90 kDa. A significant correlation was demonstrated between IgGs to HSP 90 kDa and two other serological markers for RA, rheumatoid factor, and anti-Sa antibody; there were no correlations with antikeratin antibody, antiperinuclear factor, or anti-RA 33. CONCLUSION IgGs to HSP 90 kDa are most common in longstanding RA patients with articular erosions, suggesting that they may be related to the articular prognosis in RA

Antibodies to mutated citrullinated vimentin for diagnosing rheumatoid arthritis in anti-CCP-negative patients and for monitoring infliximab therapy

IntroductionAntibodies against cyclic citrullinated peptides (CCPs) are useful for diagnosing rheumatoid arthritis (RA). Antibodies to mutated citrullinated vimentin (MCV) were described recently in RA. The aims of this study were to evaluate the usefulness of anti-MCV for diagnosing RA in anti-CCP-negative patients and to monitor anti-MCV titres during infliximab therapy for RA.MethodsWe studied two groups of RA patients, one with (n = 80) and one without (n = 76) anti-CCP antibodies. The specificity of anti-MCV was evaluated by investigating 50 healthy controls and 158 patients with other rheumatic diseases (51 psoriatic rheumatism, 58 primary Sjögren syndrome, and 49 ankylosis spondylitis). Serum anti-MCV and anti-CCP titres were measured in 23 patients after 6, 12, 18, and 24 months of infliximab treatment. Anti-CCP2 and anti-MCV levels were assayed using a commercial enzyme-linked immunosorbent assay. IgM rheumatoid factor was determined by nephelometry.ResultsIn accordance with the cutoff values recommended by the manufacturer, the specificity of anti-MCV antibodies was 90.9%. We adjusted the cutoff values to obtain the same specificity as that of anti-CCP antibodies (94.2%). With this optimal cutoff, anti-MCV antibodies were found in 11.8% (9/76) of RA patients without anti-CCP, and similarly, anti-CCP antibodies were found in 11.2% (9/80) of RA patients without anti-MCV. Anti-MCV antibodies were positive in 6 patients who tested negative for both anti-CCP and rheumatoid factor. Anti-MCV titres were significantly decreased after 18 and 24 months of infliximab therapy compared with baseline (P < 0.01) as a significant decrease of anti-CCP levels occurred only at 24 months (P < 0.04). Moreover, an anti-MCV decrease was significantly associated with DAS28 (disease activity score using 28 joint counts) improvements 12 months into therapy.ConclusionsOur results suggest that anti-MCV antibodies may be valuable for diagnosing RA in anti-CCP-negative patients without replacing them as an equivalent number of anti-CCP-positive RA patients test negative for anti-MCV. Moreover, anti-MCV antibodies could be useful for monitoring the effects of infliximab therapy.

High Levels of Anti-Cyclic Citrullinated Peptide Autoantibodies Are Associated with Co-occurrence of Pulmonary Diseases with Rheumatoid Arthritis

Objective. To investigate whether levels of anti-cyclic citrullinated peptide antibodies (anti-CCP2) in patients with rheumatoid arthritis (RA) are associated with the co-occurrence of lung diseases. Methods. A total of 252 RA patients were included in a cross-sectional study. Pulmonary disease was confirmed by high-resolution chest computed tomography scan. Circulating anti-CCP2 were quantified using ELISA. Multivariate logistic regression was conducted to identify independent risk factors for lung disease. Results. Male sex (OR 3.29, 95% CI 1.59–6.80) and high anti-CCP2 levels (OR 1.49, 95% CI 1.25–1.78) were identified as independent risk factors for lung disease in the RA population. Conclusion. High anti-CCP2 levels are associated with lung disease in the RA population.

Anti-oxidized low-density-lipoprotein (OxLDL) antibodies in systemic lupus erythematosus with and without antiphospholipid syndrome.

The aim of this study was to examine potential links between antiOxLDL antibodies and the clinical and biological features of secondary antiphospholipid syndrome (II APLS) associated with systemic lupus erythematosus (SLE). A cohort study was done of 98 SLE patients followed-up for 1 y, including 18 with definite II APLS and 13 patients with definite primary APLS (I APLS). IgG anticardiolipin, IgG antib2 GPI, lupus anticoagulant, VDRL and IgG antiOxLDL were measured in all 98 study subjects. High antiOxLDL titers were found in seven (39%) of the 18 patients with II APLS vs 10 (12.5%) of the 80 patients without APLS (P < 0.01; OR ‘ 4.45; 95% CI = 1.4–14.1) and none of the 13 patients with I APLS (P < 0.02). The mean antiOxLDL titer was not significantly higher in the SLE patients with than without II APLS (P > 0.05). A high antiOxLDL titer was correlated with deep venous thrombosis (P < 0.01; OR = 5.77; 95% CI = 0.54–61) but not with arterial thrombosis (P > 0.05; OR = 1; 95% CI = 0.29–3.09), thrombocytopenia, central nervous system involvement, livedo reticularis, or a positive Coombs test. The antiOxLDL antibody titer was correlated with the IgG anticardiolipin antibody titer (r = 0.235; P = 0.02) and with the IgG anti-b2 GPI antibody titer (r = 0.224; P = 0.026). AntiOxLDL elevation was found in 17% of SLE patients and was significantly associated with II APLS and venous thrombosis. We found no evidence suggesting that antiOxLDL may be associated with atherosclerosis.

Body mass index influences the response to infliximab in ankylosing spondylitis

IntroductionThe excess of adipose tissue in obese individuals may have immunomodulating properties and pharmacokinetic consequences. The aim of this study was to determine whether body mass index (BMI) affects response to infliximab (IFX) in ankylosing spondylitis (AS) patients.MethodsIn 155 patients retrospectively included with active AS, the BMI was calculated before initiation of IFX treatment (5 mg/kg intravenously). After 6 months of treatment, changes from baseline in BASDAI, Visual Analogue Scale (VAS) pain, C-reactive protein (CRP) level, and total dose of nonsteroidal antiinflammatory drug (NSAID) were dichotomized with a threshold corresponding to a decrease of 50% of initial level of the measure, into binary variables assessing response to IFX (BASDAI50, VAS50, CRP50, NSAID50). Whether the BMI was predictive of the response to IFX therapy according to these definitions was assessed with logistic regression.ResultsMultivariate analysis found that a higher BMI was associated with a lower response for BASDAI50 (P = 0.0003; OR, 0.87; 95% CI (0.81 to 0.94)), VAS50 (P < 0.0001; OR, 0.87; 95% CI (0.80 to 0.93)); CRP50 (P = 0.0279; OR, 0.93; 95% CI (0.88 to 0.99)), and NSAID50 (P = 0.0077; OR, 0.91; 95% CI (0.85 to 0.97)), criteria. According to the three WHO BMI categories, similar results were found for BASDAI50 (77.6%, 48.9%, and 26.5%; P < 0.0001), VAS50 (72.6%, 40.4%, and 16.7%; P < 0.0001); CRP50 (87.5%, 65.7%, and 38.5%; P = 0.0001), and NSAID50 (63.2%, 51.5%, and 34.6%; P = 0.06).ConclusionsThis study provides the first evidence that a high BMI negatively influences the response to IFX in AS. Further prospective studies, including assessment of the fat mass, pharmacokinetics, and adipokines dosages are mandatory to elucidate the role of obesity in AS IFX response.

Anti-RNA Polymerase III Antibody Prevalence and Associated Clinical Manifestations in a Large Series of French Patients with Systemic Sclerosis: A Cross-sectional Study

Objective. To determine the prevalence of anti-RNA polymerase III autoantibodies in French patients with systemic sclerosis (SSc) and to identify the associated clinical manifestations. Methods. Consecutive patients with SSc seen in 3 tertiary centers in Paris were included. Sera samples were collected together with the relevant clinical and immunological data. Anti-RNA polymerase III antibodies were detected by ELISA at a central laboratory. Data on other antibodies were abstracted from the medical records. Results. We included 319 patients: 84% women, 36% with a diffuse cutaneous subtype, 44% with pulmonary fibrosis, 5% with pulmonary hypertension, 4% with renal crisis, among whom 29 (9.4%) had anti-RNA polymerase III antibodies. These antibodies were more prevalent in patients with diffuse than with limited cutaneous disease (14.3% vs 6.0%; OR 2.6, 95% CI 1.2–5.48, p = 0.016). Renal crisis was more prevalent in patients with than in those without anti-RNA polymerase III antibodies (14% vs 3%; OR 5.0, 95% CI 1.4–17.3, p = 0.012). Renal crisis occurred in 2.2% of patients with anti-topoisomerase I and 3.9% of patients with anticentromere antibodies. Of the patients with anti-RNA polymerase III antibodies, 24 (83%) had no other systemic sclerosis-specific autoantibodies. Conclusion. The prevalence of anti-RNA polymerase III antibodies in French patients appeared to be lower than in the United States and similar to that in continental Europe. These antibodies were consistently associated with diffuse cutaneous disease and were the most common immunological marker for renal crisis. Anti-RNA polymerase III determination can help to risk-stratify SSc patients at high risk for this severe manifestation.

Angiotropic large cell lymphoma with mononeuritis multiplex mimicking systemic vasculitis.

Angiotropic large cell lymphoma (ALCL), the so-called malignant angioendotheliomatosis, is characterised by proliferation of tumorous cells within small vessels. Manifestations in the CNS and cutaneous lesions prevail in the clinical presentation, although any organ can be involved. The recent classification of this lymphoma as part of the large cell lymphomas has modified the therapeutic approaches employed. This should improve the prognosis of this usually fatal disease. An unusual case presenting with fever, mononeuritis multiplex, and cutaneous lesions is reported. Peripheral neuropathy without other neurological symptoms is uncommon, and, to our knowledge, such isolated mononeuritis multiplex with nerve lesions has not been previously reported in ALCL. The clinical diagnosis was a systemic necrotising vasculitis and it is considered that its differential diagnosis must include angiotropic large cell lymphoma.

Prospective cohort study of effects of infliximab on rheumatoid factor, anti-cyclic citrullinated peptide antibodies and antinuclear antibodies in patients with long-standing rheumatoid arthritis.

BACKGROUND Antibodies to cyclic citrullinated peptide (anti-CCP) and IgM rheumatoid factor (IgM-RF) are well-established serological markers for rheumatoid arthritis (RA). Lupus-like disease with antinuclear antibodies (ANA) has been reported during TNFalpha antagonist therapy. Our objectives were to investigate the effect of infliximab therapy on these three autoantibodies in patients with established RA and to look for correlations linking IgM-RF and anti-CCP titres to a treatment response (defined as a good or moderate EULAR response) after 48 weeks of infliximab therapy. METHODS Thirty-six patients with long-standing RA not responding to disease-modifying anti-rheumatic drugs (DMARDs) received intravenous infliximab (starting dose: 3mg/kg) at 0, 2, and 6 weeks then at 8-week intervals, in combination with a DMARD. At baseline, week 24, and week 48, C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) were determined and the disease activity score (DAS28) was calculated. Serum samples collected at the same time points were used to measure anti-CCP (commercial second-generation ELISA), IgM-RF (quantitative nephelometric assay), and ANA (indirect immunofluorescence in HEp2 cells). Correlations linking baseline autoantibody titres to changes in autoantibody levels were examined. RESULTS At baseline, tests were positive for anti-CCP in 31/36 (94.6%) patients, IgM-RF in 29/36 (80.5%) patients, and ANA in 16/36 (44%) patients. IgM-RF titres decreased significantly (p<0.001), whereas anti-CCP showed little change (p=0.053). ANA titres increased significantly (p<0.001). The treatment response was not associated with changes in anti-CCP or IgM-RF titres during infliximab therapy (OR for a response in patients with a 50% anti-CCP decrease, 0.77 [95%CI, 0.16-3.58]; OR for a response in patients with a 50% IgM-RF decrease, 0.82 [95%CI, 0.16-4.13]). CONCLUSIONS During infliximab therapy used to treat established RA, IgM-RF titres showed larger decreases than anti-CCP titres. Changes in IgM-RF and anti-CCP failed to correlate with the 48-week treatment response.

Lumboradiculopathy due to epidural varices: two case reports and a review of the literature

Lumbar radicular pain caused by epidural varices is rare. Its incidence is evaluated at 4.5% of operations for disc herniation. We report 2 cases which were only diagnosed during surgery for a herniated disk as is usually observed in the literature. The mechanism behind radicular pain is not fully understood. It may be compression by the varix itself but it may also be secondary to diffculty in venous return. Several anatomical types are described: thrombosed varix (type 1), non thrombosed varix (type 2), localized hematoma (type 3). Our 2 cases corresponded to type 2. The diagnosis can established by MRI at the pre-operative stage. The images vary according to the anatomical type and the age of the lesions. Treatment is by surgery.

Prevalence of Autoantibodies in SAPHO Syndrome: A Single-center Study of 90 Patients

Objective. To determine the prevalence of the most often tested autoantibodies in synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. Methods. We identified 90 patients seen in our unit between June 2002 and June 2009, and diagnosed according to the proposed criteria for SAPHO syndrome. Demographic and clinical data were collected as well as immunological results, including antinuclear, antithyroid peroxydase (TPO), antithyroid globulin (Tg), antigastric parietal cell, antismooth muscle, antimitochondria, and anti-liver-kidney microsome (LKM) antibodies. Anticyclic citrullinated peptide (CCP) antibodies were analyzed in 69 patients, antibodies to soluble extractable nuclear antigens in 43, anti-double-stranded DNA (dsDNA) antibodies in 22 [depending on the type of fluorescence of antinuclear antibody (ANA)], and antiendomysium antibodies in 55. Results Autoantibodies were found in 20 patients (22.2%): 14 patients (15.5%) had positive ANA (titer ≥ 1/160); among them, 10 (11%) patients never took a lupus-inducing drug. Antithyroid antibodies (anti-TPO and/or anti-Tg antibodies) were found in only 3 patients (3.3%). Three patients (3.3%) were positive for antigastric parietal cell antibodies and 4 (4.4%) were weakly positive for antismooth muscle antibodies. Antimitochondria and LKM antibodies were negative in all 90 patients. Anti-CCP and anti-dsDNA antibodies were negative in the 69 and 22 patients tested, respectively. One out of 43 patients (2.3%) had anti-SSA antibodies. Antiendomysium antibodies were negative in the 55 patients tested. Conclusion. Our study indicates an increased prevalence of autoantibodies in SAPHO syndrome, with no specific profile. We failed to confirm the reports of an increased prevalence of antithyroid antibodies. These results tend to support a link between autoimmunity and SAPHO syndrome.