A single high-affinity binding site for von Willebrand factor in collagen III, identified using synthetic triple-helical peptides

The essential event in platelet adhesion to the injured blood vessel wall is the binding to subendothelial collagen of plasma von Willebrand factor (VWF), a protein that interacts transiently with platelet glycoprotein Ibalpha (GPIbalpha), slowing circulating platelets to facilitate firm adhesion through collagen receptors, including integrin alpha2beta1 and GpVI. To locate the site in collagen that binds VWF, we synthesized 57 overlapping triple-helical peptides comprising the whole triple-helical domain of collagen III. Peptide no. 23 alone bound VWF, with similar affinity to that of native collagen III. Immobilized peptide no. 23 supported platelet adhesion under static and flow conditions, processes blocked by an antibody that prevents collagen from binding the VWF A3 domain. Truncated and alanine-substituted peptides derived from no. 23 either strongly interacted with both VWF and platelets or lacked both VWF and platelet binding. Thus, we identified the sequence RGQOGVMGF (O is hydroxyproline) as the minimal VWF-binding sequence in collagen III.     

A Ras-induced conformational switch in the Ras activator Son of sevenless

The Ras-specific guanine nucleotide-exchange factors Son of sevenless (Sos) and Ras guanine nucleotide-releasing factor 1 (RasGRF1) transduce extracellular stimuli into Ras activation by catalyzing the exchange of Ras-bound GDP for GTP. A truncated form of RasGRF1 containing only the core catalytic Cdc25 domain is sufficient for stimulating Ras nucleotide exchange, whereas the isolated Cdc25 domain of Sos is inactive. At a site distal to the catalytic site, nucleotide-bound Ras binds to Sos, making contacts with the Cdc25 domain and with a Ras exchanger motif (Rem) domain. This allosteric Ras binding stimulates nucleotide exchange by Sos, but the mechanism by which this stimulation occurs has not been defined. We present a crystal structure of the Rem and Cdc25 domains of Sos determined at 2.0-A resolution in the absence of Ras. Differences between this structure and that of Sos bound to two Ras molecules show that allosteric activation of Sos by Ras occurs through a rotation of the Rem domain that is coupled to a rotation of a helical hairpin at the Sos catalytic site. This motion relieves steric occlusion of the catalytic site, allowing substrate Ras binding and nucleotide exchange. A structure of the isolated RasGRF1 Cdc25 domain determined at 2.2-A resolution, combined with computational analyses, suggests that the Cdc25 domain of RasGRF1 is able to maintain an active conformation in isolation because the helical hairpin has strengthened interactions with the Cdc25 domain core. These results indicate that RasGRF1 lacks the allosteric activation switch that is crucial for Sos activity.     

Do current arterial hypertension treatment guidelines apply to systemic lupus erythematosus patients? A critical appraisal

Objective

Arterial hypertension (HTN) is reported to burden up to 74% of systemic lupus erythematosus (SLE) patients and contributes significantly to accelerated atherosclerosis and increased cardiovascular (CV) risk. Current HTN treatment guidelines have not incorporated lupus patients in their recommendations; whether these guidelines can be fully implemented in SLE is doubtful.

Methods

A critical appraisal of the existing HTN guidelines in regard to SLE is presented in this review, based upon clinical and experimental data. Particular issues addressed are the time of antihypertensive therapy initiation, the optimal blood pressure level, the antihypertensive agent of first-choice and the need for reduction of the total cardiovascular risk in SLE.

Results

Antihypertensive therapy should be recommended at levels of 140/90 mmHg (systolic and diastolic BP, respectively) in newly diagnosed lupus patients without overt target organ involvement. In the case of lupus nephritis (LN) or diabetes mellitus (DM), therapy should be implemented at lower levels, such as 130/80 mmHg. Hypertensive lupus patients should be considered at high or very high CV risk and, consequently, the optimal BP level should be less than 130/80 mmHg. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) seem to be a safe and efficacious first-choice antihypertensive treatment in lupus patients. Total CV risk should be considered and co-morbidities (dyslipidemia, antiphospholipid syndrome, etc.) should be managed promptly.

Conclusions

Current HTN therapeutic guidelines, lacking data from large-scale clinical trials, may not adequately apply to SLE patients. The assessment of the aforementioned recommendations in randomized clinical trials is expected to confirm their value in reducing CV risk in SLE.     

The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus

Objective

The antimalarial medication hydroxychloroquine has been proposed as a thromboprotective agent in systemic lupus erythematosus (SLE), but studies thus far have been limited by the possibility of confounding by indication. This study was conducted to assess whether exposure to antimalarial drugs is associated with a decrease in thrombovascular events (TEs) in patients with SLE.

Methods

The study was designed as a nested case–control study embedded in an inception cohort of patients with SLE, which allowed adjustments for possible confounding by calendar year, duration of disease, duration of observation, and severity of lupus. After controlling for the possible confounding variables in conditional logistic regression models, the use of antimalarial drugs was assessed for its effects on the development of TEs in lupus patients.

Results

Fifty‐four cases of TE were identified, and these were matched with 108 control subjects (lupus patients without TEs). Univariate analyses identified older age (odds ratio [OR] 1.04, 95% confidence interval [95%CI] 1.01–1.07) or being older than age 50 years (OR 3.5, 95% CI 1.4–8.6) and ever having hypertension (OR 2.5, 95% CI 1.0–5.8) as being associated with an increased risk of TEs, whereas use of antimalarial drugs (OR 0.31, 95% CI 0.13–0.71) was associated with a decreased risk of TEs. Separate analyses were done for arterial and venous TEs, which yielded similar results. In multivariate analyses, use of antimalarial drugs (OR 0.32, 95% CI 0.14–0.74) and older age (OR 1.04, 95% CI 1.01–1.07) were the only 2 variables that remained significant.

Conclusion

The results from this nested case–control study demonstrate that, after accounting for the effects of disease severity, disease duration, and calendar year, antimalarial drugs were found to be thromboprotective, being associated with a 68% reduction in the risk of all TEs, with a range of risk reduction of at least 26% up to as high as 86%.

     

Update on Biomarkers in Psoriatic Arthritis

Biomarkers in psoriatic arthritis (PsA) may serve as surrogate end points for disease outcome and can provide insights into disease susceptibility and natural history. Biomarkers could relate to diagnosis, pathogenesis, prognosis, therapeutic response, and comorbidities. The “felt need” is, however, in the development of biomarkers for the presence of PsA in patients with psoriasis, as well as that for joint damage. During the past few years, many studies related to PsA biomarkers have been conducted. These studies are reviewed here. C-reactive protein, matrix metalloproteinase-3, and circulating osteoclast precursors show promise. An international goal-directed study to determine biomarkers for joint damage in PsA is now under way through a collaborative effort of GRAPPA (the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis) and OMERACT (Outcome Measures for Rheumatology Clinical Trials).     

Cardiovascular comorbidities in psoriasis and psoriatic arthritis: pathogenesis, consequences for patient management, and future research agenda: a report from the GRAPPA 2009 annual meeting

Psoriasis is often associated with other diseases, substantially adding to the patient's burden of disease. Recent epidemiologic studies have demonstrated an increased cardiovascular morbidity among patients with psoriasis and psoriatic arthritis (PsA), which contributes to their reduced life expectancy. At the meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) adjacent to the International Federation of Psoriasis Associations (IFPA) congress, members discussed the pathogenetic aspects of this association and resulting consequences for the management of patients with psoriasis and PsA. A future research agenda was considered.     

The SLICC inception cohort for atherosclerosis

The Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) is a group of rheumatologists and methodologists from 27 international centers who have a particular interest and expertise in systemic lupus erythematosus. Initially, its efforts focused on development and validation of disease activity and damage indices. In 2000, the SLICC Registry for Atherosclerosis was established to determine the incidence, prevalence, nature, and risk factors of atherosclerotic coronary artery disease in systemic lupus erythematosus. Risk factors for coronary artery disease at presentation to the cohort were reported, as well as their accumulation over the first few years. Development of the metabolic syndrome was also described. Among the first 1078 patients who entered the cohort, 61 vascular events have occurred in 47 patients who were older at diagnosis and more likely male and hypertensive than were the patients without vascular events. Additional studies using this cohort are ongoing.     

Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial

OBJECTIVE: Adalimumab, a fully human, anti-tumor necrosis factor monoclonal antibody, was evaluated for its safety and efficacy compared with placebo in the treatment of active psoriatic arthritis (PsA). METHODS: Patients with moderately to severely active PsA and a history of inadequate response to nonsteroidal antiinflammatory drugs were randomized to receive 40 mg adalimumab or placebo subcutaneously every other week for 24 weeks. Study visits were at baseline, weeks 2 and 4, and every 4 weeks thereafter. The primary efficacy end points were the American College of Rheumatology 20% improvement (ACR20) response at week 12 and the change in the modified total Sharp score of structural damage at week 24. Secondary end points were measures of joint disease, disability, and quality of life in all patients, as well as the severity of skin disease in those patients with psoriasis involving at least 3% of body surface area. RESULTS: At week 12, 58% of the adalimumab-treated patients (87 of 151) achieved an ACR20 response, compared with 14% of the placebo-treated patients (23 of 162) (P < 0.001). At week 24, similar ACR20 response rates were maintained and the mean change in the modified total Sharp score was -0.2 in patients receiving adalimumab and 1.0 in those receiving placebo (P < 0.001). Among the 69 adalimumab-treated patients evaluated with the Psoriasis Area and Severity Index (PASI), 59% achieved a 75% PASI improvement response at 24 weeks, compared with 1% of the 69 placebo-treated patients evaluated (P < 0.001). Disability and quality of life measures were also significantly improved with adalimumab treatment compared with placebo. Adalimumab was generally safe and well-tolerated. CONCLUSION: Adalimumab significantly improved joint and skin manifestations, inhibited structural changes on radiographs, lessened disability due to joint damage, and improved quality of life in patients with moderately to severely active PsA.     

Frequency and determinants of flare and persistently active disease in systemic lupus erythematosus

Objective

Selection of flare as the primary outcome variable in systemic lupus erythematosus (SLE) clinical trials fails to capture patients with persistently active disease (PAD). We sought to elucidate the frequency and determinants of flare and PAD.

Methods

Prospectively collected data from the Toronto Lupus Cohort were used to determine the incidence of flare and PAD in 2004 and 2005. Flare was defined as an increase in SLE Disease Activity Index 2000 update (SLEDAI‐2K) score of ≥4 from the previous visit. PAD was defined as a SLEDAI‐2K score of ≥4, excluding serology alone, on ≥2 consecutive visits. Data from 1, 2, and 3 years prior were used to model flare and PAD in 2004. Model properties were tested for prediction of flare and PAD in 2005.

Results

One‐third of the patients had ≥1 flare, whereas nearly half experienced PAD in a given year. Nearly 60% of the patients had episodes of flare or PAD per year. At least 25% of patients had PAD without achieving the definition of flare. In the best‐fitting model, predictors of PAD in 2004 were SLEDAI‐2K score at the start of the outcome interval and prior cutaneous or musculoskeletal disease activity. This model gave 79% correct prediction of PAD in 2005. In contrast, flare prediction models performed poorly.

Conclusion

Persistent activity is a common disease state in SLE and should be an outcome variable in SLE clinical trials. Our PAD prediction model may aid prognostication and selection of patients for inclusion in clinical trials.