Kamran Naraghi

Autologous Hematopoietic Stem Cell Transplantation vs Intravenous Pulse Cyclophosphamide in Diffuse Cutaneous Systemic Sclerosis: A Randomized Clinical Trial

IMPORTANCE High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials. OBJECTIVE To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide. DESIGN, SETTING, AND PARTICIPANTS The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation-registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013. INTERVENTIONS HSCT vs intravenous pulse cyclophosphamide. MAIN OUTCOMES AND MEASURES The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure. RESULTS A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years. CONCLUSIONS AND RELEVANCE Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN54371254.

Autologous HSCT for systemic sclerosis.

www.thelancet.com Vol 381 June 15, 2013 2079 ER-positive disease should eventually be considered together with fi ndings for all patients in all such trials (13 000 in ATLAS, 7000 in aTTom, 2000 in smaller trials). The ATLAS report chiefl y emphasises fi ndings in ER-positive disease, but it also provides analyses (appendix p 16) that, much as Litton and col leagues suggest, use the fi ndings in ER-untested disease to improve the estimated eff ect in ER-positive disease, still yielding an RR of 0·83 (but with 95% CI 0·73–0·94 and χ2 8·1, p=0·004). This χ2 of 8·1 is large enough to demonstrate an overall eff ect, but not to support the subgroup analyses by age suggested by Patrick Neven and colleagues. The conclusion that longer is better than shorter treatment in both premenopausal and postmenopausal women should be based not on unreliable subgroup analyses of individual trials of 10 years versus 5 years of tamoxifen, but on reliable analyses of their overall results plus reliable evidence of substantial effi cacy in both premenopausal and postmenopausal women from the trials of 5 years of tamoxifen versus none (which have an overall χ2 of 81, ten times that in ATLAS). Trials with a highly signifi cant overall result often yield unreliable subgroup analyses. Even if there is little real heterogeneity between the RRs in diff erent subgroups, a false negative in some subgroup or other is likely, unless the overall χ2 is very large—far larger than is needed just to test signifi cance (because the overall χ2 value is approximately shared between the subgroup χ2 values). As the overall χ2 in the trials of tamoxifen versus none was so large (81), it could be shared between two subgroups and still yield reliable evidence of benefi t in each of them. If it had been only 8·1 (p=0·004) instead of 81, however, a dangerously false negative result in the smaller subgroup would be likely, even if the real RRs are similar in both subgroups.

Changes in bone density and bone turnover in patients with rheumatoid arthritis treated with rituximab, a B cell depleting monoclonal antibody (HORUS TRIAL)

Background The mechanism of osteoporosis in rheumatoid arthritis (RA) is multifactorial. However, inflammation and autoimmunity are key players in its pathogenesis. Treatment with tumour necrosis factor alpha (TNFa) blockers has been shown to be beneficial for bone metabolism and they were able to prevent bone deformities in RA. Moreover, they improved the bone mineral density (BMD) [1]. However, the role of B lymphocytes in bone turnover is still controversial. Mice models showed that B cell deficiency resulted in marked osteopenia [2]. This was explained by the marked decrease in bone marrow levels of osteoprotegerin (OPG) produced by B cells. However, treatment of 46 RA patients with rituximab revealed a marked reduction of the bone resorption marker beta-crosslaps (bCTX) after 6 months [3].

Changes in bone density and bone turnover in patients with rheumatoid arthritis treated with rituximab, results from an exploratory, prospective study

Data describing the effect of in vivo B cell depletion on general bone loss in patients with rheumatoid arthritis (RA) are limited. Given the pathogenetic role of B cells in RA, it is tempting to speculate that B cell depletion might have a beneficial effect on bone loss. We prospectively investigated the changes in bone mineral density (BMD), bone turnover, inflammation and disease activity before and after rituximab in 45 RA patients over a 12 month period, 36 patients of whom completed the study and were included in the analysis. There was no significant change in our primary endpoint; lumbar spine BMD after 12 months. However, we found a significant decrease in neck of femur (mean -0.017 g/cm2, 95% CI -0.030, -0.004 p = 0.011) and total femur BMD (mean -0.016 g/cm2, 95% CI -0.025, -0.007 p = 0.001). Additionally, there was a significant increase in procollagen type 1 amino-terminal propeptide (P1NP) and bone specific alkaline phosphatase (BAP); biomarkers of bone formation (median change from baseline to 12 months; P1NP 11.3 μg/L, 95% CI -1.1, 24.8 p = 0.025; BAP 2.5 μg/L, 95% CI 1.2, 3.6 p = 0.002), but no significant change in bone resorption or osteocyte markers. The fall in BMD occurred despite improvement in disease control. Post-menopausal women had the lowest mean lumbar spine, femoral and forearm BMD at baseline and after 12 months, additionally they had a higher level of bone turnover throughout the study. In conclusion, BMD was maintained at the lumbar spine and forearm, but fell at the femur sites. A high prevalence of vitamin D deficiency was observed and these patients had lower BMD and evidence of higher bone turnover.

Determination of smoking status of rheumatoid arthritis patients by means of a self-reported questionnaire and serum cotinine assay: a cross-sectional study

Rheumatoid arthritis (RA) is characterised by a chronic, destructive and debilitating arthritis.1 Smoking may adversely influence the severity of RA as well as its response to treatment in a dose-dependent manner.1,–,4 Furthermore, the link between passive smoking and RA has been suggested by some researchers.5 Self-reporting is commonly used to identify the smoking status of RA patients. In the general population, self-reporting underestimates the true rate of smoking.6 7 To what extent this issue affects RA patients in particular is unreported. Unless we correctly ascertain RA patients in terms of smoking status, it will remain difficult to investigate the true impact of smoking, or smoking cessation, on signs and symptoms associated with the disease. To address this issue, we recently determined the smoking status of RA patients attending the Rheumatology Department of a large university …