Sule Yavuz

Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group

Objectives To assess the effects of Rituximab (RTX) on skin and lung fibrosis in patients with systemic sclerosis (SSc) belonging to the European Scleroderma Trial and Research (EUSTAR) cohort and using a nested case-control design. Methods Inclusion criteria were fulfilment of American College of Rheumatology classification criteria for SSc, treatment with RTX and availability of follow-up data. RTX-treated patients were matched with control patients from the EUSTAR database not treated with RTX. Matching parameters for skin/lung fibrosis were the modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), follow-up duration, scleroderma subtype, disease duration and immunosuppressive co-treatment. The primary analysis was mRSS change from baseline to follow-up in the RTX group compared with the control group. Secondary analyses included change of FVC and safety measures. Results 63 patients treated with RTX were included in the analysis. The case-control analysis in patients with severe diffuse SSc showed that mRSS changes were larger in the RTX group versus matched controls (N=25; −24.0±5.2% vs −7.7±4.3%; p=0.03). Moreover, in RTX-treated patients, the mean mRSS was significantly reduced at follow-up compared with baseline (26.6±1.4 vs 20.3±1.8; p=0.0001). In addition, in patients with interstitial lung disease, RTX prevented significantly the further decline of FVC compared with matched controls (N=9; 0.4±4.4% vs −7.7±3.6%; p=0.02). Safety measures showed a good profile consistent with previous studies in autoimmune rheumatic diseases. Conclusions The comparison of RTX treated versus untreated matched-control SSc patients from the EUSTAR cohort demonstrated improvement of skin fibrosis and prevention of worsening lung fibrosis, supporting the therapeutic concept of B cell inhibition in SSc.

Long-term Efficacy and Safety of Low-Dose and Dose-Escalating Interferon Alfa-2a Therapy in Refractory Behcet Uveitis

OBJECTIVE To investigate the long-term efficacy and safety of low-dose and dose-escalating therapy of interferon alfa-2a in the treatment of Behçet uveitis. METHODS This study included 37 patients with refractory Behçet panuveitis unresponsive to conventional immunosuppressive therapy. Induction interferon alfa-2a therapy was given as a daily dose of 3.0 million IU (MIU) subcutaneously for 14 days. Maintenance dose was achieved with 3.0 MIU 3 times per week given subcutaneously. The dosage was increased sequentially to 4.5, 6.0, and 9.0 MIU 3 times per week if uveitis relapses occurred. Total therapy duration was 24 months. Primary outcome measure was control of uveitis with quiescence during maintenance therapy. Ocular relapses per patient-year before and after initiation of interferon alfa-2a therapy and a corticosteroid-sparing effect were secondary outcomes. We also estimated the rate of remission after discontinuing interferon alfa-2a therapy. RESULTS During maintenance therapy, interferon alfa-2a controlled uveitis in 35 patients (95%). In 15 patients (41%), a maintenance dosage of 3.0 MIU 3 times per week controlled uveitis without any relapse. The rate of uveitis relapses decreased from 3.52 per patient-year before to 0.75 per patient-year after initiating interferon alfa-2a therapy. Seventeen patients were receiving systemic corticosteroids at the time of initiation of interferon therapy. During the maintenance stage, 9 patients were able to discontinue and 8 to taper systemic corticosteroid therapy. Survival analysis estimated that the rate of remission after discontinuation of interferon alfa-2a therapy was 76% by 3 months. The rate of remission remained stable thereafter. CONCLUSION A treatment protocol using a low-dose and dose-escalating therapy with interferon alfa-2a was able to control and achieve remission of uveitis in most patients with refractory ocular Behçet disease.

Comparative Performance Analysis of 4 Different Anti-Citrullinated Protein Assays in the Diagnosis of Rheumatoid Arthritis

Objective. To evaluate the diagnostic performances of 2 recently developed assays, third-generation anti-cyclic citrullinated peptide (anti-CCP3) and anti-mutated citrullinated vimentin (anti-MCV), in comparison to conventional second-generation anti-cyclic citrullinated peptide (anti-CCP2) assay; and to assess a novel fully automated, random-access AxSYM anti-CCP assay for early diagnosis of rheumatoid arthritis (RA). Methods. A cohort of 176 patients was enrolled in our study; 93 were diagnosed as having RA. The non-RA group consisted of 83 patients including 38 with systemic lupus erythematosus, 17 with primary Sjögren’s syndrome, 11 with osteoarthritis, and 17 healthy controls. All were tested for presence of anti-CCP2, anti-CCP3, AxSYM anti-CCP, anti-MCV, and rheumatoid factor (RF)-IgM according to the manufacturers’ instructions. Results. Diagnostic performance of the assays revealed the highest area under the curve for the novel AxSYM anti-CCP [89.1; 95% confidence interval (CI) 84.3–93.8], followed by anti-CCP3 (86.7; 95% CI 81.6–91.9), anti-CCP2 (82; 95% CI 75.8–88.3), and anti-MCV (71.9; 95% CI 64.4–79.5). The sensitivities and specificities were 60.2% and 98.8% for anti-CCP2, 61.3% and 97.6% for anti-CCP3, 80.6% and 84.3% for AxSYM anti-CCP, 49.8% and 91.6% for anti-MCV, and 67.8% and 91.6% for RF-IgM, respectively. Conclusion. At cutoff of 5 U/ml, AxSYM anti-CCP emerged as a highly sensitive first-line early diagnostic tool for RA, with the greatest discrimination power, above 16 U/ml, in case of positive result. Using a single easily performed automated assay at 2 determined decision limits we were able to diagnose 81% of cases of RA and missing only 1.2%.

Exposure to ACE inhibitors prior to the onset of scleroderma renal crisis-results from the international scleroderma renal crisis survey

OBJECTIVE To determine whether exposure to angiotensin-converting enzyme (ACE) inhibitors prior to the onset of scleroderma renal crisis (SRC) leads to worse outcomes of SRC. METHODS Prospective cohort study of incident SRC subjects. The exposure of interest was ACE inhibitors prior to the onset of SRC. The outcomes of interest were death or dialysis during the first year after the onset of SRC. RESULTS A total of 87 subjects with incident SRC were identified and 1-year follow-up data were obtained in 75 (86%) subjects. Overall, 27 (36%) subjects died within the first year and an additional 19 (25%) remained on dialysis 1 year after the onset of SRC. In adjusted analyses, exposure to ACE inhibitors prior to the onset of SRC was associated with an increased risk of death (hazard ratio 2.42, 95% CI 1.02, 5.75, p < 0.05 in the primary analysis and 2.17, 95% CI 0.88, 5.33, p = 0.09 after post-hoc adjustment for pre-existing hypertension). CONCLUSION Overall, the 1-year outcomes of SRC were poor. Prior exposure to ACE inhibitors was associated with an increased risk of death after the onset of SRC, although there was uncertainty around the magnitude of the risk and the possibility of residual confounding could not be ruled out. Further studies will be needed to confirm these findings.

Rituximab for Remission Induction in a Patient with Relapsing Necrotizing Scleritis Associated with Limited Wegener's Granulomatosis

Purpose: The authors report a case of necrotizing scleritis associated with Wegeners granulomatosis (WG), which was treated with rituximab for relapsing disease. Method: Observational case report. Results: A 32-year-old male patient presented with necrotizing scleritis in his left eye. The patient was diagnosed as having limited WG. Cyclophosphamide was begun. Under maintenance treatment with azathioprine two relapses of scleritis occurred. Since a high cumulative dose of cyclophosphamide (22.5 g) was utilized initially, two intravenous infusions of rituximab 1 g was given. Complete resolution of scleritis occurred. Conclusions: Rituximab may be effective to induce remission in patients with scleritis due to WG.

TRAF1/C5, eNOS, C1q, but not STAT4 and PTPN22 gene polymorphisms are associated with genetic susceptibility to systemic lupus erythematosus in Turkey

A significant source of variability in the literature on systemic lupus erythematosus (SLE) susceptibility genes has been the inability to replicate genetic findings across different racial or ethnic groups. We investigated whether a single nucleotide polymorphism (SNP) of the STAT4 (rs7574865), PTPN22 (rs2476601), TRAF1/C5 (rs10818488), and C1q (rs292001) genes as well as the 27-bp VNTR polymorphism on intron 4 of eNOS, previously associated with SLE in other populations, are also associated with SLE risk in Turkey. A group of 158 SLE patients and 155 healthy controls were included in this study. A genetic association of the TRAF1/C5, C1q, and eNOS gene polymorphism, but not of STAT4 and PTPN22, was found to confer a degree of risk for SLE. These data highlight the importance of comparative studies in different populations to confirm the previously detected genetic associations.

Agreement Between Quantiferon-TB Gold Test and Tuberculin Skin Test in the Identification of Latent Tuberculosis Infection in Patients with Rheumatoid Arthritis and Ankylosing Spondylitis

Objective. To compare the Quantiferon-TB Gold test (QTF-G) with the tuberculin skin test (TST) for the detection of latent tuberculosis infection (LTBI) among patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS), with reevaluation of the patients treated with tumor necrosis factor-α (TNF-α) antagonists in the followup. Methods. The study involved 140 consecutive patients, 82 with RA and 58 with AS. Thirty patients were evaluated with QTF-G for detection of LTBI before and after 6 months of TNF-α antagonist treatment. QTF-G was also performed on 49 healthy controls. QTF-G results were recorded as positive, negative, or indeterminate. A positive TST was defined as ≥ 5 mm for RA and AS. Results. The percentages of positive QTF-G were comparable in RA and AS (37% vs 32%). The rate of positive QTF-G in healthy controls (29%) was also similar to RA and AS. In contrast to QTF-G results, a high rate of TST positivity was observed in AS compared to RA (82% vs 55%; p = 0.02). The total agreement between QTF-G and TST was observed to be 61% (κ = 0.29) in the whole group, 70% (κ = 0.42) in RA, and 49% (κ = 0.14) in AS. After 6 months of treatment with TNF-α antagonists, a high rate of QTF-G change was observed in patients with indeterminate results (23% vs 3%; p = 0.03). Conclusion. The comparable prevalence of LTBI among the study groups according to QTF-G supports the view that QTF-G is less susceptible to external factors than TST. Sequential testing for QTF-G in patients with indeterminate or negative results may also be helpful in discriminating LTBI better.

A common SNP in the CD40 region is associated with systemic lupus erythematosus and correlates with altered CD40 expression: implications for the pathogenesis

Background In systemic lupus erythematosus (SLE) sustained CD40L expression by T cells and platelets activates a variety of cells via its receptor CD40 contributing to disease pathogenesis. Although CD40 has recently been identified in genome-wide association study as a novel rheumatoid arthritis susceptibility gene such an association has not been documented for SLE. Objective To investigate whether the rs4810485 CD40 single nucleotide polymorphism (SNP) is associated with increased risk for SLE and its impact on CD40 expression. Materials and methods The primary sample set consisted of 351 patients with SLE and 670 matched healthy controls of Greek origin. 158 patients with SLE and 155 controls from Turkey were used as a replication sample. Genotyping of rs4810485 was performed by restriction fragment length polymorphism and the Sequenom MassArray technology. The expression of CD40 mRNA and protein was assessed in unstimulated and lipopolysaccharide-stimulated peripheral blood mononuclear cells by quantitative real time PCR and flow cytometry, respectively. Results The minor allele T of CD40 rs4810485 SNP was significantly under-represented in Greek patients with SLE compared with healthy controls (OR=0.65, 95% CI 0.54 to 0.79). The association was replicated in the Turkish cohort (OR=0.57, 95% CI 0.41 to 0.80; meta-analysis of 509 patients with SLE and 825 healthy controls: OR=0.63, 95% CI 0.53 to 0.74, p = 2×10−8). In both cases and controls, the rs4810485 G/T and T/T genotypes were associated with significantly reduced CD40 mRNA and protein expression in peripheral blood CD14+ monocytes and CD19+ B cells compared with G/G genotype, both under basal conditions and following stimulation. Conclusions CD40 has been identified as a new susceptibility locus in Greek and Turkish patients with SLE. The rs4810485 minor allele T is under-represented in SLE and correlates with reduced CD40 expression in peripheral blood monocytes and B cells, with potential implications for the regulation of aberrant immune responses in the disease.

Mapping and predicting mortality from systemic sclerosis

Objectives To determine the causes of death and risk factors in systemic sclerosis (SSc). Methods Between 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation. Results We identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile. Conclusion Combining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients’ survival.

Comparison of QuantiFERON-TB Gold test and tuberculin skin test for the identification of latent Mycobacterium tuberculosis infection in lupus patients

The tuberculin skin test (TST) has low sensitivity for the diagnosis of tuberculosis (TB). QuantiFERON-TB Gold (QFT-G) is an IFN-gamma-release assay that measures the release of interferon-gamma after stimulation in vitro by Mycobacterium tuberculosis antigens using ELISA. The main advantage of this assay compared with TST is the lack of cross-reaction with Bacillus Calmette-Guérin (BCG) as well as most of non-tuberculous mycobacteria. The aim of our study is to compare QFT-G with TST for the detection of latent tuberculosis infection (LTBI) among patients with systemic lupus erythematosus (SLE). Methods: Seventy-eight patients with SLE and 49 healthy subjects (HCs) participated in the study. All patients and controls were interviewed for a history of TB then BCG vaccinations were recorded and chest X-rays were examined for a sign of TB infection. QTF-G and TST were performed on both patients and controls. QTF-G results were recorded as positive, negative or indeterminate. A positive TST for SLE was defined as ≥5 mm. Results: Seventy-six SLE patients (97.4%) had been BCG vaccinated. Similar to the HC (28.5%), 19 of 78 (24.3%) SLE patients had positive QTF-G. Two patients had an indeterminate result. The agreement between QTF-G and TST was 49/76 (64.4%) (κ = 0.33). There were fewer positive QFT-G test results than positive TST results (24.3% vs. 50%; p < 0.01). Twenty-two (28.9%) patients were TST(+)/QTF-G(−) while only 3(3.9%) patients were TST(−)/QTF-G(+). When the positive TST was defined as ≥10 mm indurations, which is the cut-off in screening for LTBI in Turkey, the agreement between two tests increased up to 58/76 (76.3%) with a κ value of 0.47. The mean TST measurements was higher in QTF-G positive patients (13.4 ± 8.8 mm) than the QTF-G negative patients (4 ± 5.3 mm) (p < 0.001). Discussion: In a TB-endemic and BCG vaccinated population, the QuantiFERON-TB Gold assay seemed to be a more accurate test for the detection of LTBI in SLE patients. Although 5 mm is usually accepted to be the standard cut-off for TST in immunocompromised patients such as SLE, the level of agreement between QTF-G and TST was better with a 10 mm cut-off in our population.