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Objective: To assess patients with SSc who present without circulating antinuclear antibodies (ANA) or Raynaud’s phenomenon (RP).Methods: 5390 patients who fulfilled the ACR criteria for SSc and were enrolled in the EULAR Scleroderma Trials And Research (EUSTAR) database were screened for the absence of both RP and circulating ANA. To differentiate SSc from its mimics, additional information was gathered using a standardized questionnaire. Results: 5378 (99.8%) of the 5390 SSc patients in the EUSTAR database had either detectable ANA or a history of RP. Twelve patients (0.2%) lacked both circulating ANA and RP. Details of the medical history could be obtained for six patients. Three cases were compatible with ANA-negative and RP-negative SSc and were not typical of any known SSc mimic. Four patients had a malignancy: two had breast cancer, one had multiple myeloma with possible scleromyxoedema, and one had bladder carcinoma. There was no temporal relationship between the onset of skin fibrosis and that of the tumor. Although no patient with confirmed nephrogenic systemic fibrosis (NSF) was identified among the cases of ANA-negative and RP-negative SSc, the presentation of one patient could be compatible with that of NSF other than for the absence of chronic kidney disease or of known prior gadolinium exposure. Conclusion: We have identified a very small subgroup of SSc patients who lack both circulating ANA-and RP, none of whom fulfils the diagnostic criteria for any known SSc mimic. Prospective studies are needed to elucidate the clinical presentation, evolution, and outcome of such patients. Objective. To assess patients with SSC who present without circulating ANAs or RP. Methods: Five thousand three hundred and ninety patients who fulfilled the ACR criteria for SSc and were enrolled in the EULAR Scleroderma Trials and Research (EUSTAR) database were screened for the absence of both RP and circulating ANA. To differentiate SSc from its mimics, additional information was gathered using a standardized questionnaire. Results: Five thousand three hundred and seventy-eight (99.8%) of the 5390 SSc patients in the EUSTAR database had either detectable ANA or a history of RP. Twelve (0.2%) patients lacked both circulating ANA and RP. Details of the medical history could be obtained for seven patients. Three cases were compatible with ANA-negative and RP-negative SSc and were not typical of any known SSc mimic. Four patients had a malignancy: two had breast cancer, one had multiple myeloma with possible scleromyxoedema and one had bladder carcinoma. Therewas no temporal relationship between the onset of skin fibrosis and that of the tumour. Although no patient with confirmed nephrogenic systemic fibrosis was identified among the cases of ANA-negative and RP-negative SSc, the presentation of one patient could be compatible with that of nephrogenic systemic fibrosis other than for the absence of chronic kidney disease or of known prior gadolinium exposure. Conclusion: We have identified a very small subgroup of SSc patients who lack both circulating ANA and RP, none of whom fulfils the diagnostic criteria for any known SSc mimic. Prospective studies are needed to elucidate the clinical presentation, evolution and outcome of such patients.

Objective. The aim of the present study was to explore the long-term outcome and clinical characteristics of adult patients with juvenile onset in the EULAR Scleroderma Trials and Research (EUSTAR) cohort and compare them with adult patients with onset between 20 and 40 years of age. Methods. From the EUSTAR SSc cohort two patient groups were analysed: patients with juvenile SSc (jSSc) who are adults at present, and patients diagnosed between the age of 20 and 40 years (aSSc). Demographic data of the patients, organ involvement and outcome of the disease were examined using the Minimal Essential Data Set database system. Results. From 5000 patients in the EUSTAR cohort, 60 patients (1.2%) with jSSc and 910 patients (18%) with aSSc were selected according the inclusion criteria. In the jSSc group, the mean age of disease onset was 12.4 years (range 2-15.9 years), and in the aSSc group, the mean age was 32 years (range 20-40 years). Disease subsets were similar. The antibody profile was also comparable except for ACAs, which were positive in 5% of the jSSc group and 26.9% of the aSSc group (P

Background: We have previously compared outcome in two groups of systemic sclerosis (SSc) patients with disease onset a decade apart and we reported data on 5 year survival and cumulative incidence of organ disease in a contemporary SSc cohort. The present study examines longer term outcome in an additional cohort of SSc followed for 10 years.Methods: We have examined patients with disease onset between years 1995 and 1999 allowing for at least 10 years of follow-up in a group that has characteristics representative for the patients we see in contemporary clinical practice.Results: Of the 398 patients included in the study, 252 (63.3%) had limited cutaneous (lc) SSc and 146 (36.7%) had diffuse cutaneous (dc) SSc. The proportion of male patients was higher among the dcSSc group (17.1% v 9.9%, p = 0.037) while the mean age of onset was significantly higher among lcSSc patients (50 ± 13 v 46 ± 13 years ± SD, p = 0.003).During a 10 year follow-up from disease onset, 45% of the dcSSc and 21% of the lcSSc subjects developed clinically significant pulmonary fibrosis, p < 0.001. Among them approximately half reached the endpoint within the first 3 years (23% of dcSSc and 10% of lcSSc) and over three quarters within the first 5 years (34% and 16% respectively). There was a similar incidence of pulmonary hypertension (PH) in the two subsets with a steady rate of increase over time. At 10 years 13% of dcSSc and 15% of lcSSc subjects had developed PH (p=0.558), with the earliest cases observed within the first 2 years of disease. Comparison between subjects who developed PH in the first and second 5 years from disease onset demonstrated no difference in demographic or clinical characteristics, but 5-year survival from PH onset was better among those who developed this complication later in their disease (49% v 24%), with a strong trend towards statistical significance (p = 0.058). Incidence of SSc renal crisis (SRC) was significantly higher among the dcSSc patients (12% v 4% in lcSSc, p = 0.002). As previously observed, the rate of development of SRC was highest in the first 3 years of disease- 10% in dcSSc and 3% in lcSSc. All incidences of clinically important cardiac disease developed in the first 5 years from disease onset (7% in dcSSc v 1% in lcSSc, p < 0.001) and remained unchanged at 10 years. As expected, 10-year survival among lcSSc subjects was significantly higher (81%) compared to that of dcSSc patients (70%, p = 0.006). Interestingly, although over the first 5 years the death rate was much higher in the dcSSc cohort (16% v 6% in lcSSc), over the following years it became very similar for both subsets (14% and 13% between years 5 and 10, and 18% and 17% between years 10 and 15 for dcSSc and lcSSc respectively).Conclusions: Even though dcSSc patients have higher incidence for most organ complications compared to lcSSc subjects, the worse survival among them is mainly due to higher early mortality rate. Mortality rate after first 5 years of disease becomes comparable in the two disease subsets.Disclosure statement: The authors have declared no conflicts of interest.

Objective. With rising numbers of anti-tumour necrosis factor a (TNF-a) treatments for rheumatoid arthritis (RA), Crohn’s disease and other conditions, physicians unaware of potential pitfalls are increasingly likely to encounter associated severe infections. Our purpose was to assess the incidence and nature of severe infections in our RA patients under anti-TNF-a therapy. Methods. We reviewed patient charts and records of the Infectious Disease Unit for serious infections in patients with RA in the 2 yr preceding anti-TNF-a therapy and during therapy. Results. Serious infections affected 18.3% of patients treated with infliximab or etanercept. The incidence was 0.181 per anti-TNF-a treatment year vs 0.008 in the 2 yr preceding anti-TNF-a therapy. In several cases, only a few signs or symptoms indicated the severity of developing infections, including sepsis. Conclusions. A high level of suspicion of infection is necessary in patients under anti-TNF-a therapy. We suggest additional strategies for the prevention, rapid identification and pre-emptive therapy of such infections. The efficacy of the anti-tumour necrosis factor a (TNFa) agents infliximab and etanercept in the treatment of rheumatoid arthritis (RA) has been demonstrated in large-scale trials w1‐4x. Their results indicate a superior effect of these agents compared with conventional disease-modifying anti-rheumatic drugs (DMARDs). Among the undesired effects of anti-TNF-a agents, infections have been a primary concern. Under study conditions, 53% of patients in the group treated with 3m gukg infliximab together with methotrexate had an infection compared with 40% in the placebo group w1x. For any given infection, the difference between the groups was statistically significant. However, the incidence of serious infections, defined as life-threatening or requiring hospitalization, was not statistically different over the dose ranges studied (6% for placebo vs 1% for 3m gukg every 8 weeks to 6% for 10 mg every 4 weeks). With etanercept, infections occurred in 51% of the patients in the active treatment group compared with 63% in the placebo group w3x. On the basis of these data, it was assumed that the incidence and severity of infections were not markedly increased under treatment with these agents when compared with other data on infections in RA w5‐7x. Recently, anti-TNF-a therapy has been associated with the reactivation of tuberculosis, again raising concerns that infections may pose a significant threat w8x. In addition to the existing warnings of potential infections under etanercept and infliximab contained in the package insert, in the case of the latter the FDA (Food and Drug Administration, USA) requested the addition of a ‘black box’ with recommendations concerning tuberculosis. So far, postmarketing surveys have not revealed significant problems with serious infections under anti-TNF-a therapy. However, because the nature and course of infectious disease may be altered by anti-TNF-a therapy, it is of critical importance to consider this aspect in the care of patients. We evaluated a series of serious infections from our institution which highlight the potential pitfalls and difficulties with infections under infliximab and etanercept.

The benefit:risk ratio of HSCT in autoimmune disease appears to justify the initiation of prospective controlled comparative studies. The comparator arm is open, one possibility being mobilized (Cy 2 or 4 g/m2 + G-CSF), but not transplanted. Inclusion and exclusion criteria for different disease categories need to be standardized, as do outcome measurements. In Europe, the EBMT has established a new working party for autoimmune disease with representatives from all involved groups, including the USA. A similar parallel group is being established in North America. The aim will be consensus and standardization of disease-specific aspects. Standardization of immune reconstitution parameters could prove critical in the understanding of autoimmune mechanisms, with early guidelines being developed and available to interested groups. Data collection is critical, with advanced discussions on common registration forms between the EBMT and the American Bone Marrow Transplantation Registry (ABMTR) already taking place. Common detailed disease-specific clinical data forms are now a top priority, so that data from the two major databases may be compared. All patients fulfilling entry criteria should be registered and followed long term, including those not able to be treated for non-medical reasons, such as insurance. This will provide a prospective 'conventional treatment' control group. Regular and flexible liaison between the data managers of both groups will be encouraged, as with regulatory authorities such as the Food and Drug Administration. The following such meeting was in Basel, 8-10 October 1998.

Osteoporosis is prevalent among postmenopausal women and presents a major health problem in terms of cost and loss of mobility. Low bone mass is by far the most important risk factor for the development of osteoporotic fractures. Bone mass is largely determined by genetic factors governing peak bone mass, which occurs during the third decade of life. Screening for the risk of osteoporosis at the time of menopause involves assessment of bone mass. Several techniques for determining bone density are discussed as well as the applicability of biochemical markers of bone turnover. Clinical decisions concerning pharmacological intervention depend not only on the level of bone mass, but also on age, associated risk factors, the existence of previous fractures and the risk/benefit ratio of particular therapeutic regimens.

Scleroderma is clinically heterogeneous and a variety of plausible mechanisms of disease have been hypothesized. Recent years have witnessed a significant improvement in overall survival although all of the gains in management have been therapies for specific organ involvement, e.g. renal crisis and pulmonary arterial hypertension. Future studies will rely on improved clinical science, which involves structured validation of proposed measures of outcome; development of a combined response index; and further refinement of specific subsets of disease expression. Immunoablation with stem cell reconstitution is an example of aggressive therapy chosen as appropriate for a particularly severe disease subset and in whom the pilot data are encouraging. Good science and clinical ethics force continued consideration of equipoise between risk and benefit.

Classification criteria for SSc are being updated as previous ACR preliminary classification criteria did not include some lcSSc patients and early SSc.Objectives. Items from two large European and NA surveys were reduced by experts using Delphi and nominal group techniques that resulted in 23 items. The face, discriminant and construct validity were studied using many databases in Europe and NA. Further item reduction occurred ranking 20 cases of SSc and mimickers by experts with variable probabilities of having SSc and weighing items relative to each other after agreeing on further item reduction using the 1000 minds exercise.Results. In the Delphi exercise, skin thickening, SSc-specific autoantibodies, abnormal nailfold capillary pattern, RP and some organ involvement ranked highest. Compared with diseases that mimic SSc in multiple databases, SSc patients are more likely to have skin thickening (OR = 427), telangiectasias (OR = 91), RNA polymerase III (OR = 75), puffy fingers (OR = 35), finger flexion contractures (OR = 29), tendon/bursal friction rubs (OR = 27), topo I (OR = 25), RP (OR = 24), finger tip ulcers/pitting scars (OR = 19), anti-centromere (OR = 14), abnormal nailfold capillaries (OR = 10), GERD (OR = 8) and ANA, calcinosis, dysphagia, oesophageal dilation (all OR = 6), ILD/pulmonary fibrosis (OR = 5) and PM-Scl antibody (OR = 2). Low DL CO and FVC and PAH had OR