Micro- and macrovascular treatment targets in scleroderma heart disease.

Cardiac involvement in systemic sclerosis (SSc) is a frequent visceral complication that considerably affects the prognosis of the disease. The pathophysiologic hallmark is myocardial fibrosis which can progress leading to arrhythmia, right and/or left heart dysfunction and failure. Symptoms range from unusual to prominent and from mild to dramatic, but clinically overt disease is a poor prognostic factor. Primary myocardial involvement is related to focal ischemia due to transient coronary spasm, and the available data support that microvascular functional and structural abnormalities rather than macrovascular coronary involvement represent the main underlying mechanism of the disease. However, the existence and prevalence of atherosclerotic coronary artery disease in SSc remain to be determined, as several studies have generated conflicting reports. Despite the lack of effective targeted therapy for SSc itself, sensitive and quantitative techniques have demonstrated the ability of vasodilators to improve myocardial function and perfusion and to prevent the evolution of subclinical heart involvement to decompensated heart failure. Further research will provide a better understanding of the disease by detecting the potent contribution of coronary artery involvement, explaining differences in accelerated atherosclerosis between SSc and other autoimmune disorders, and opening directions for the development of novel treatment strategies for this life-threatening complication of SSc.

Scleroderma renal crisis accompanied by new-onset pulmonary arterial hypertension: an acute systemic endothelial injury? Case report and literature.

Systemic Sclerosis (SSc) is a multisystem connective tissue disease characterized by fibrosis of the skin and internal organs and extensive vasculopathy. We report a case of a 41 year-old white woman with a 10 year-history of limited scleroderma, who developed the rare combination of Scleroderma Renal Crisis (SRC) and Systemic Sclerosis related Pulmonary Arterial Hypertension (SScPAH) in the same time. Although the patient received the proposed antihypertensive treatment, the renal function did not recover, and she initiated on renal replacement therapy. SRC and SScPAH are two aspects of SSc vasculopathy characterized by endothelial dysfunction mediated by endothelin-1 and other vasoactive hormones. Further new studies with therapies directed towards the underlying mechanisms of SRC (i.e. endothelin-receptor antagonists), which are proven helpful in SScPAH, should take place to establish new therapeutic options and improve prognosis of these patients, for which our therapeutic armamentarium is currently poor.

Determination of two COX-2 inhibitors in serum and synovial fluid of patients with inflammatory arthritis by ultra performance liquid chromatography-inductively coupled plasma mass spectroscopy and quadrupole time-of-flight mass spectrometry.

The determination of two sulphur-containing drugs, the COX-2 inhibitors celecoxib and etoricoxib, in the serum and synovial fluid of inflammatory arthritis patients, is described using a sensitive ultra performance liquid chromatography-inductively coupled plasma mass spectroscopy (UPLC/ICPMS) method. Confirmation of the identity of the analytes in the samples was also performed by electrospray quadruple time-of-flight mass spectrometry in positive electrospray ionisation mode. The two COX-2 inhibitors were extracted from serum and synovial fluid following dilution with acetate buffer (pH 5) and liquid-liquid extraction (LLE) into ethyl acetate. Extracted samples were then analysed using UPLC/ICPMS with sulphur-specific detection. The limit of detection by UPLC/ICPMS was 0.45 ng/ml of sulphur in both serum and synovial fluid. The UPLC/ICPMS method was applied to the analysis of samples from patients receiving either 200 mg/day of celecoxib (2x 100 mg), 90 mg/day etoricoxib or placebo. The range of concentrations detected in the samples for the two drugs was from 0.3 to 3.3 microg/ml.

Reactivation of pulmonary tuberculosis in a patient with rheumatoid arthritis during treatment with IL-1 receptor antagonists (anakinra).

This single case report describes reactivation of previous pulmonary tuberculosis (TBC) after 23 months of treatment with the IL-1 receptor antagonist anakinra. This patient had severe acute rheumatoid arthritis (Disease Activity Score >6). Initially, he received treatment with 10 mg prednisolone daily along with oral methotrexate 15 mg weekly. Methotrexate was discontinued after 3 months because of repeated liver enzyme elevation. After the disease became more active, he was treated with the IL-1 receptor antagonist along with 10 mg prednisolone daily. One month later, the patient improved significantly, and prednisolone was decreased to 5 mg on alternate days and discontinued after another 3 months. After 23 months of anakinra monotherapy, the patient developed pulmonary TBC and was put on quadruple anti-TBC treatment, which resulted in excellent recovery. Six years before, the patient had pulmonary TBC and received triple anti-TBC treatment for 9 months with complete clinical and radiologic remission. We believe this is the first reported case of TBC reactivation during anakinra treatment.

Presentation and analysis of data on radiographic outcome in clinical trials: experience from the TEMPO study.

OBJECTIVE: To evaluate different methods of presentation and analysis of radiographic data in a rheumatoid arthritis (RA) randomized controlled trial. METHODS: A double-blind randomized controlled trial including 682 patients with active RA who were treated with methotrexate, etanercept, or a combination of the 2 drugs was used for this study. Probability plots of the change from baseline to year 1 were produced to visualize progression, and were compared with usual descriptive statistics. The primary analysis of the trial (based on annualized actual mean change from baseline in total Sharp score at 1 year, using linear imputation) was challenged using various ways of handling missing information with alternative imputation methods, and by various statistical analyses including analysis of covariance (ANCOVA) and mixed model analysis on both raw and log-transformed data. RESULTS: Probability plots provided detailed insight into the differentiated treatment effects between the 3 arms of this study. As adjuncts to formal hypothesis testing, these plots were more useful for presenting data than were summary descriptive statistics or use of preset cutoff points to define lack of progression. Additional analyses presented here support the results obtained with the per-protocol analysis that showed an advantage of the combination treatment compared with the monotherapy arms and for etanercept versus methotrexate alone. Various ways of handling missing information confirmed the robustness of the results. In addition, both ANCOVA and mixed model analyses on raw and on log-transformed data produced similar results. CONCLUSION: We suggest a panel of alternative analysis methods and alternative ways of handling missing information to verify that the radiographic results reported in an randomized controlled trial are not influenced by technical factors, such as interpolation, handling of missing data, and choice of statistical tests.

Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial.

BACKGROUND: Etanercept and methotrexate are effective in the treatment of rheumatoid arthritis but no data exist on concurrent initiation or use of the combination compared with either drug alone. We aimed to assess combination treatment with etanercept and methotrexate versus the monotherapies in patients with rheumatoid arthritis. METHODS: In a double-blind, randomised, clinical efficacy, safety, and radiographic study, 686 patients with active rheumatoid arthritis were randomly allocated to treatment with etanercept 25 mg (subcutaneously twice a week), oral methotrexate (up to 20 mg every week), or the combination. Clinical response was assessed by criteria of the American College of Rheumatology (ACR). The primary efficacy endpoint was the numeric index of the ACR response (ACR-N) area under the curve (AUC) over the first 24 weeks. The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score. Analysis was by intention to treat. FINDINGS: Four patients did not receive any drug; thus 682 were studied. ACR-N AUC at 24 weeks was greater for the combination group compared with etanercept alone and methotrexate alone (18.3%-years [95% CI 17.1-19.6] vs 14.7%-years [13.5-16.0], p<0.0001, and 12.2%-years [11.0-13.4], p<0.0001; respectively). The mean difference in ACR-N AUC between combination and methotrexate alone was 6.1 (95% CI 4.5-7.8, p<0.0001) and between etanercept and methotrexate was 2.5 (0.8-4.2, p=0.0034). The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage (mean total Sharp score -0.54 [95% CI -1.00 to -0.07] vs 2.80 [1.08 to 4.51], p<0.0001, and 0.52 [-0.10 to 1.15], p=0.0006; respectively). The mean difference in total Sharp score between combination and methotrexate alone was -3.34 (95% CI -4.86 to -1.81, p<0.0001) and between etanercept and methotrexate was -27 (-3.81 to -0.74, p=0.0469). The number of patients reporting infections or adverse events was similar in all groups. INTERPRETATION: The combination of etanercept and methotrexate was significantly better in reduction of disease activity, improvement of functional disability, and retardation of radiographic progression compared with methotrexate or etanercept alone. These findings bring us closer to achievement of remission and repair of structural damage in rheumatoid arthritis.