Rachel Murphy

Pilot study of vardenafil for the treatment of Raynaud's disease

marker for disease activity): ‘easy-to-treat RA’ and ‘difficult-to-treat RA’. Proinflammatory and anti-inflammatory cytokine levels changed after mirthful laughter in easy-to-treat and difficult-to-treat patients, compared with no change in healthy participants; the extent of immunomodulation was dependent on disease activity. Since this study found favorable effects of mirthful laughter on the immune response, the authors suggest that psychological support should be offered as an adjunct to treatment for patients with RA. Rachel Murphy

620W polymorphism in PTPN22 is a risk factor for Wegener's granulomatosis

implicated in other rheumatic diseases, has previously been detected in the skin and muscle of patients with juvenile dermatomyositis. Researchers at the NIH conducted a case–control study of 62 patients with juvenile dermato myositis to investigate a possible link between parvovirus B19 and the disease. Plasma samples were collected from the patients and from 62 healthy controls, matched for age, sex and ethnicity. IgG antibodies to parvo virus B19 were detected in the plasma of 25 patients (40.3%) and in 36 (58.1%) control individuals, while IgM anti bodies to parvovirus B19 were detected only in one control individual. All samples were negative for parvovirus B19 DNA by dot–blot hybridization, but two individuals in each group were positive for parvo virus B19 DNA detected by PCR. No link was found between juvenile dermatomyositis and parvovirus B19 infection: the rate of seropositivity to the organism in patients with juvenile dermatomyositis was similar to that previously published for healthy children. While the juvenile dermatomyositis patients were from locations across the US, the controls were residents of the Washington, DC area. This geographic difference might explain the different rates of seropositivity to parvo virus B19 found between the groups, but would not implicate parvovirus B19 in the etiology of this autoimmune disease. Jim Casey

B-cell depletion as a treatment for refractory SLE

disease than untreated mice. Deposition of IgG and complement 3 was significantly less in the TwHF groups, although levels of auto antibodies to double-stranded DNA increased during treatment for all three groups. Splenomegaly and normalization of splenic architecture occurred only in TwHF-treated mice. The authors conclude that an ethyl acetate extract of TwHF could provide a novel therapeutic approach in SLE patients. Rachel Murphy

Mirthful laughter affects cytokine levels in patients with rheumatoid arthritis

compared with usual care (nonsteroidal antiinflammatory drugs, physiotherapy, or both) in AS. All patients had a Bath Ankylosing Spondylitis Disease Activity Index score of ≥4. Probabilities of toxicity of TNF inhibitors, efficacy and relapse were derived from two European randomized trials. Benefits and costs used in the analysis were derived from a 2-year observational Dutch cohort. The quality-adjusted life years (QALYs) gained by treatment were 2.89, 3.16 and 3.11 for usual care, etanercept and infliximab, respectively. The estimated incremental costs of TNF inhibitors per QALY compared with standard care were €42,914–123,761 for etanercept, and €67,207–237,010 for infliximab. Data showed that the cost per QALY of etanercept and infliximab are greater than the implicit thresholds of cost per QALY that are applied in the US, the UK and the Netherlands; however, this study was hampered by limited data on the natural progression of AS and the long-term effects of TNF inhibitors. Future investigations to improve cost–benefit analyses, and to identify subgroups of patients for whom anti-TNF treatment is cost-effective, are warranted. Rachel Murphy

Pulmonary arterial hypertension predicts death in diffuse cutaneous systemic sclerosis

and saline placebo, in patients with stable hip OA. Small injection volumes of 2 ml were used to avoid joint-lavage effects. Although in all 101 treated patients (placebo, n = 36; hyaluronic acid, n = 33; corticosteroids, n = 32) the injections were well tolerated and there were no serious adverse effects, only those who received corticosteroids showed a moderate (but transient) improvement in pain scores. Corticosteroid injection might, therefore, have a role in acute pain relief for patients with hip OA. None of the groups showed an improvement in any of the outcome measures by the 3-month follow-up. This duration should have been sufficient to show an effect, according to the literature on intra-articular injection therapies, and, therefore, these treatments cannot be recommended as standard therapy for hip OA. These results rule out a moderate-to-large clinical effect of hyaluronic-acid injection in hip OA, say the authors, although future studies with 100 patients in each treatment group could reveal a small effect size. They speculate that high-molecular-weight hyaluronic acid might have a greater effect than was seen in this study. Caroline Barranco

Exercise in water is beneficial for patients with fibromyalgia

Two separate studies published in the journal Arthritis & Rheumatism (Arthritis Care & Research) have shown that patients with fibromyalgia could benefit from exercise in water. Regular physical exercise has proven to be beneficial in patients with fibromyalgia, but little is known about the specific effects of hydrotherapy. The two studies—one performed in Brazil and the other in Spain—aimed to evaluate the effect of water therapy on clinical aspects of fibromyalgia. In the Brazilian study, the authors evaluated the efficacy of deep-water running (DWR) compared with that of land-based exercises (LBE) in 60 sedentary women, aged 18–60 years, with fibromyalgia. In the DWR group (n = 30), patients performed a running movement while immersed in warm water (28–31 oC) up to shoulder level. In the LBE group (n = 30), patients walked or jogged around the local park. Both groups exercised for 1 h, three times a week, for 15 weeks. The study showed that the clinical endpoints of pain, mood, function, and quality of life improved in both the DWR and LBE groups to a similar degree. There was more improvement in the emotional aspects of fibro myalgia in the DWR group compared with the LBE group, although the authors caution that this study was not designed to assess this outcome. Four patients dropped out of the study, but not because of adverse events. There were no serious side effects in either group, confirming that patients with fibromyalgia can undergo physical training without worsening of symptoms. In the Spanish study, the investigators evaluated the efficacy of exercise in waist-high, warm water (33 oC) in 34 women, aged 35– 73 years, who had severe fibromyalgia. The 17 women assigned to the exercise group trained in water for 1 h, three times a week for 12 weeks. At the end of the 12 weeks, the exercise group was instructed to avoid physical exercise for a further 12 weeks. A control group of 17 women followed their normal daily activities for 24 weeks. In the exercise group, there were marked and clinically relevant gains in muscle strength of the knee extensors at low velo cities, which is a major predictor of daily living dependency; however, there was no improvement at medium velocities, which is asso ciated with gait speed. Improvements in muscle strength were maintained after the 12-week rest period. Pain, self care and depression improved after the 12 weeks of exercise, and most of these improvements were maintained; however, pain levels returned to baseline after 12 weeks of rest. These two studies show that exercise in warm water is safe and effective, and is a viable form of low-impact exercise for patients with fibromyalgia. Since fibromyalgia is a chronic disease, studies to evaluate the long-term efficacy of exercise in water are warranted. Rachel Murphy

Tumor necrosis factor antagonists do not increase cancer risk in patients with RA

The double-blind, randomized, controlled trial included 33 patients with systemic lupus erythematosus (SLE) and cutaneous lesions. Over a 6-month period, 16 patients received 100 mg clofazimine and 17 patients received 250 mg chloroquine, both once daily. A stable prednisone dose was administered throughout, as was twice-daily broad-spectrum sunscreen. Two independent, blinded observers assessed the lesions on a scale of 1–6, and SLE disease activity was assessed using the Mexican SLE Disease Activity Index. Patients whose prednisone needed to be increased or who received immunosuppressive drugs were withdrawn from the trial, and the scores obtained at last evaluation were analyzed. The trial found that 75% of clofazimine patients and 82.4% of chloroquine patients responded to treatment, and in both groups improvement was greatest towards the end of the trial. SLE flare caused five clofaziminetreated patients to withdraw from the trial and one patient died; in the chloroquine group, one patient withdrew. Because of a lack of a placebo group and a small number of patients, the possibility that clofazimine caused the SLE flares cannot be ruled out. Long-term efficacy and safety studies are required for clofazimine, but this agent could be an option for treatment of cutaneous lesions in chloroquine-refractory patients with SLE. Rachel Murphy

Cost–benefit analysis of tumor necrosis factor inhibitors in ankylosing spondylitis

Nonsteroidal anti-inflammatory drugs are the preferred agents for treating chronic pain in knee osteoarthritis (OA), although they have known side effects of gastric irritation, renal impairment and reduced platelet aggregation. Selective cyclo-oxygenase 2 inhibitors (coxibs) might offer equivalent analgesia with a favorable safety profile. The novel coxib LUMIRA COXIB reaches higher concentrations in synovial fluid than in plasma; researchers, therefore, compared its short-term analgesic effects in patients with knee OA with those of placebo and celecoxib (the latter has known analgesic efficacy in knee OA). Participants from 32 German centers were enrolled in this randomized, controlled trial. After an analgesic-free washout period, patients were given celecoxib (200 mg twice daily, n = 145), lumiracoxib (400 mg once daily, n = 144) or placebo (n = 75). Pain scores were assessed at baseline and after 7 days of treatment. Despite a large placebo effect, as is typical of studies that assess pain scores, lumiracoxib provided superior analgesic efficacy to placebo. Lumiracoxib provided rapid and effective analgesia, comparable with that of celecoxib. Pain relief was evident as early as 3 h after the first dose. The efficacy of analgesia was maintained between doses throughout the study, supporting the once-daily regimen of lumiracoxib used. The authors suggest that the rapid onset of analgesia seen with lumiracoxib is likely to benefit patients with knee OA, who tend to need intermittent, rather than continuous, pain relief. Caroline Barranco

Molecular mechanisms underlying gouty inflammation

INTRODUCTION The objective of this study was to determine whether serum biomarkers for degradation and synthesis of the extracellular matrix of cartilage are associated with, and can predict, radiographic damage in patients with rheumatoid arthritis (RA). METHODS Clinical and radiographic data of 87 RA patients were recorded 1 year after disease onset and then annually up to four years. Serum concentrations of four cartilage biomarkers were determined at these time points: a neoepitope formed by collagenase cleavage of type II collagen (C2C), a neoepitope formed by collagenase cleavage of type II collagen as well as type I collagen (C1,2C), a carboxy propeptide of type II procollagen formed during synthesis (CPII), and a cartilage proteoglycan aggrecan turnover epitope (CS846-epitope). Biomarker concentrations between patients with rapid radiographic progression (>7.3 Sharp/van der Heijde units per year) and those with slow radiographic progression (<2.3 units per year) were compared. In addition, we evaluated the long-term and short-term predictive value of each biomarker for progression of radiographic damage. RESULTS Patients with rapid radiographic progression had higher C2C, higher C1,2C, and higher CS846-epitope levels than slow progressors. CPII levels showed no differences. Most importantly, the long-term radiographic progression for C2C, for C1,2C, and for CS846-epitope can be predicted by the biomarker value at year 1 after disease onset. C2C was also a predictor for joint space narrowing and annual radiographic damage during the subsequent year. CONCLUSION This study shows that the concentration of serum biomarkers of cartilage collagen breakdown and proteoglycan turnover, but not of collagen synthesis, are related to joint destruction in RA. The use of these biomarkers may be of value when studying progression of joint damage in patients with RA.

A new model for rheumatoid arthritis etiology in a subgroup of patients

Elevated serum prolactin levels are common in patients with systemic lupus erythematosus (SLE). In mouse models, elevated prolactin is associated with high disease activity, but clinical reports have been inconclusive. Serum prolactin normally circulates predominantly as monomeric prolactin (23 kDa), with lesser amounts of ‘big’ prolactin (dimeric/trimeric, 45–50 kDa) and macroprolactin (>100 kDa). Researchers in Mexico investigated the relationship between SLE activity and serum levels of the different prolactin isoforms. Total serum prolactin levels were not associated with disease activity. Patients with active SLE had higher levels of monomeric prolactin than those with inactive disease, and there was a negative correlation between disease activity and serum levels of ‘big’ prolactin and macroprolactin. The results indicate that hyperprolactinemia per se does not predict greater SLE disease activity, but that greater severity of disease correlates with higher serum levels of monomeric prolactin. Macroprolactin has been shown to have biological activity in vitro, but the authors suggest that the high molecular weight of the protein impedes its ability to cross capillary walls in vivo and, therefore, limits its effect on disease activity. Patients with prolactinmodulated SLE could benefit from drugs that reduce prolactin levels; bromocriptine, which inhibits prolactin secretion from the anterior pituitary gland, has been shown to have bene ficial effects on SLE disease activity in clinical trials. Jim Casey