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High dose immunosuppressive therapy with subsequent autologous stem cell transplantation (ASCT) has proved effective for treatment resistant autoimmune diseases.1 However, in a number of patients, relapses of autoimmune disease after initial improvement or even remission occur. Until recently, it was impossible to differentiate recent thymic emigrants from residual or peripherally expanded T cells. Douek and coworkers2 and later our group3 described a method for detection of T cell receptor excision circles, stable DNA episomes which are formed during T cell receptor rearrangement in the thymus which are not replicated during mitosis, but are diluted during cell divisions.4 This study aimed at investigating whether these flares are associated with de novo T cell development. Peripheral blood mononuclear cells were collected from six patients, mean age 32.5 years, range 24–42 (four with systemic sclerosis (SSc), one with Wegener’s granulomatosis …

IgG4-assoziierte Erkrankungen werden immer haufiger diagnostiziert. Bei unklaren Raumforderungen resp. inflammatorischen Organlasionen sollte an eine solche Erkrankung gedacht werden.

Des maladies a IgG4 sont de plus en plus souvent diagnostiquees. Il faut y penser en presence de processus expansifs de nature indeterminee ou de lesions organiques inflammatoires.

Objectives Autoantibodies are useful biomarkers for diagnosing and monitoring treatment in some autoimmune diseases. Antibodies against isoforms of 14-3-3 protein have been proposed as biomarkers for the presence of aortic aneurysm in large-vessel vasculitis (LVV). Here, we aimed to evaluate the diagnostic role and potential immunopathological involvement of anti-14-3-3 antibodies in newly diagnosed LVV patients. Methods Antibodies against three isoforms of 14-3-3 (γ, ɛ and ζ) were measured in 90 subjects: 48 GCA and 3 Takayasu's arteritis (TA) patients, and 39 controls (non-inflammatory and inflammatory diseases), using a multiplexed bead-based immunoassay and immunoprecipitation studies. The positive cut-off value was defined based on young healthy controls. Anti-14-3-3 IgG antibodies in LVV patients were compared with those in controls in order to assess their diagnostic performance, and the relationship of anti-14-3-3 IgG antibodies to the immunohistopathology of artery explants was assessed. Results Antibodies against all three 14-3-3 isoforms were detected in LVV patients as well as in age-matched inflammatory and non-inflammatory controls. Among LVV patients, detection of antibodies targeting 14-3-3 ɛ and ζ was associated with more severe disease. Detection of antibodies against 14-3-3 γ was linked to latent Toxoplasma gondii infection, a parasite that secrets a 14-3-3 homologue, suggesting potential cross-reactivity. Conclusion Detection of antibodies against 14-3-3 proteins at the time of LVV diagnosis is not disease-specific. Their presence at high levels in LVV patients with stroke, aortitis and-in a previous study-aneurysm formation may indicate an association with extensive tissue destruction. The relevance of 14-3-3 antibodies in non-LVV patients needs to be investigated in larger cohorts.

The objective of this prospective cross-sectional case-control study was to examine the prevalence of dryness symptoms and its impact on quality of life (QoL) among very long-term survivors after hematopoietic SCT (HSCT) in comparison with their respective sibling donors. Forty-four allogeneic HSCT recipients with a long-term survival (median: 17.5; range: 11-26 years) were included. Their respective, HLA-identical sibling donors served as controls. Clinical examinations included saliva flow rates (SFR) and the Schirmer's test. The presence of sicca symptoms of mouth, eyes and skin were inquired. The social functioning (SF)-36 questionnaire was applied. Recipients had lower (P

Purpose: In patients with suspected giant cell arteritis (GCA), a search for the perivascular halo sign, a sophisticated color duplex ultrasound (CDU) finding, at experienced centers reliably identifies inflamed temporal arteries (TA). We tested whether TA compression in patients with GCA, a simple, largely operator-independent maneuver, elicits contrasting echogenicity between the diseased artery wall and the surrounding tissue (compression sign). Materials and Methods: 80 individuals with suspected GCA were prospectively enrolled in this single-center study. In all study participants, bilateral ultrasound examination of the TA established the presence/absence of the halo and compression sign. A positive compression sign was defined as visibility of the TA upon transducer-imposed compression of the artery. Based on ACR criteria, a team of specialized physicians independently grouped patients as GCA versus non-GCA. Results: 43/80 study participants were grouped as GCA. Both the halo sign and the compression sign were positive in 34/43 patients in the GCA group, and negative in all 37/37 of the non-GCA group, resulting in a sensitivity of 79 % and a specificity of 100 % for both the halo and the compression sign. Conclusion: In this cohort of individuals with suspected GCA, the halo sign and the compression sign were equal in their diagnostic performance. The simplicity of the compression sign suggests a level of reliability warranting further evaluation.

Autologous hematopoietic stem cell transplantation (HSCT) has been used to treat severe and refractory autoimmune diseases (ADs) in children and adults for more than 15 years. The aim of this treatment is to restore tolerance through an intense lymphodepleting conditioning, and many patients have achieved lasting remissions. However, HSCT is associated with significant morbidity and mortality and is therefore not yet standard of care. Pre-existing reduced organ function of patients with ADs may increase the organ toxicity of conditioning. In the early post-HSCT phase, bacterial or fungal infections occur and therapy-associated lymphopenia sets patients at risk for reactivation of endogenous viruses and other opportunistic infections. During re-emerging of lymphopoiesis after HSCT, de novo autoimmunity may develop through loss of central or peripheral control mechanisms. Late effects of autologous HSCT (e.g., on the endocrine system) and a potentially increased frequency of secondary malignancies are of concern. The steadily increasing knowledge about specific complications occurring in patients with ADs after HSCT has led to the adaption of treatment protocols and has already reduced toxicity. Further prospective long-term follow-up studies are needed to identify patients at risk for developing serious complications after HSCT.

International audience; To describe the incidence, risk factors, and treatment of autoimmune diseases (ADs) occurring after cord blood transplantation (CBT), we analyzed both CBT recipients reported to EUROCORD who had developed at least 1 new AD and those who had not. Fifty-two of 726 reported patients developed at least 1 AD within 212 days (range, 27-4267) after CBT. Cumulative incidence of ADs after CBT was 5.0% +/- 1% at 1 year and 6.6% +/- 1% at 5 years. Patients developing ADs were younger and had more nonmalignant diseases (P \textless .001). ADs target hematopoietic (autoimmune hemolytic anemia, n = 20; Evans syndrome, n = 9; autoimmune thrombocytopenia, n = 11; and immune neutropenia, n = 1) and other tissues (thyroiditis, n = 3; psoriasis, n = 2; Graves disease, n 1; membranous glomerulonephritis, n = 2; rheumatoid arthritis, n = 1; ulcerative colitis, n = 1; and systemic lupus erythematosus, n = 1). Four patients developed 2 ADs (3 cases of immune thrombocytopenia followed by autoimmune hemolytic anemia and 1 Evans syndrome with rheumatoid arthritis). By multivariate analysis, the main risk factor for developing an AD was nonmalignant disease as an indication for CBT (P = .0001). Hematologic ADs were most often treated with steroids, rituximab, and cyclosporine. With a median follow-up of 26 months (range, 2-91), 6 of 52 patients died as a consequence of ADs. We conclude that CBT may be followed by potentially life-threatening, mainly hematologic ADs.

Whereas systemic vasculitis is the most common form of vasculitis, vasculitis restricted to a single organ system is rare. Primary vasculitis restricted to striated skeletal muscle has been described in few case reports for polyarteritis nodosa and leucocytoclastic vasculitis, but not for small vessel vasculitis, type microscopic polyangiitis. The authors describe three patients with primary small vessel vasculitis of the skeletal muscle without evidence of other major organ involvement. All three patients presented with myalgias and highly elevated acute phase reactants while muscle weakness and elevated creatine kinase levels were not consistently present. Diagnoses were established by muscle biopsy and extensive search for potential causes of secondary vasculitis. Complete remission could be accomplished by steroids alone in only one case, while additional immunosuppressants were needed in the other two cases. Primary small vessel vasculitis of the skeletal muscle should be considered in patients presenting with myalgia and signs of systemic inflammation in the absence of other organ manifestations. Once diagnosed, aggressive systemic immunosuppression is appropriate.

Giant cell arteritis (GCA) is the most common of the vasculitis syndromes and, being a disease of the elderly, its incidence is increasing with the general ageing of the population. GCA is most feared for its early complications, namely blindness and stroke, resulting from inflammation and subsequent occlusion of ocular and extra cranial arteries, respectively. More recently, however, GCA has been recognised to also affect limb arteries and the aorta with a high prevalence. These newly recognised features of GCA pose diagnostic, therapeutic and prognostic challenges to treating physicians. Here, recent developments in the field of GCA are summarised and discussed.

Currently there are no reliable biomarkers in the synovial fluid available to differentiate between septic and non-septic arthritis or to predict the prognosis of osteoarthritis, respectively. Nuclear magnetic resonance (NMR) spectroscopy is an analytical technique that allows a rapid, high throughput metabolic profiling of biological fluids or tissues.Proton (1H)-nuclear magnetic resonance (NMR) spectroscopy was performed in synovial fluid samples from patients with septic arthritis, crystal arthropathy, different forms of inflammatory arthritis or osteoarthritis (OA). The metabolic environment based on the low molecular weight components was compared in disease subsets and principal component analysis (PCA) was performed.Fifty-nine samples from patients with OA, gout, calcium pyrophosphate disease, spondylarthritis, septic arthritis and rheumatoid arthritis (RA) were analysed. NMR yielded stable and reproducible metabolites over time. Thirty-five different metabolites as well as paracetamol and ibuprofen were identified in synovial fluid. The metabolic profile of septic arthritis assessed by PCA was distinguishable from the other samples whereas no differences were seen in OA compared to crystal-associated arthritis, RA or spondylarthritis.1H-NMR is a fast analytic tool with possible implications in synovial fluid diagnostics. A distinctive metabolism is observed in septic arthritis whereas metabolites in OA are similar to those in inflammatory arthritis.

Background Hematopoietic stem cell transplantation has become an established procedure worldwide. Severe early and late complications are well described. Little is known about more subtle changes in general health status of very long-term survivors. The study objective was to assess health status of very long-term survivors in comparison with their respective human leukocyte antigen-identical sibling donors. Design and Methods Case matched comparison in a cross-sectional cohort was performed in a tertiary university hospital and referral center for hematopoietic stem cell transplantation. Forty-four pairs of recipients and their respective donors with a very long-term (17.5 years median; 11–26 years range) follow up after allogeneic hematopoietic stem cell transplantation were included. A comparative clinical evaluation and examination of routine clinical chemistry tests was carried out. Results Recipients more frequently had a lower Karnofsky score ( P =0.05), hypertension ( P =0.015) and dyslipidemia ( P =0.002) but were less likely to be smokers ( P =0.016). Recipients showed systematically lower glomerular filtration rates ( P

Abstract 2322 New onset of AD have been reported after autologous and allogeneic HSCT and AD patients (pt) treated by HSCT may be at higher risk for developing a secondary AD. A single US centre study showed that more profound T cell depleting conditioning with antithymocyte globulin (ATG) or alemtuzumab enhanced the risk of secondary AD after HSCT for primary AD. We therefore aimed at specifying the incidence, nature and risk factors for secondary AD after autologous or allogeneic HSCT for a primary AD. Methods: Retrospective analysis of AD pts treated by HSCT as reported to the EBMT data management system ProMISe until November 2009. Each EBMT participating centre was asked to identify all pts having developed at least one AD and those not having developed AD after HSCT as controls with complete detailed information on HSCT and outcome of original disease and treatment and outcome of secondary AD for cases. Cumulative incidence curves were used to estimate incidence of AD considering death as a competing event. Associations of patients and graft characteristics with secondary AD were evaluated by multivariate analyses, using Cox proportional hazards. All tests were two-sided. The type I error rate was fixed at 0.05 to determinate factors associated with time to event outcomes. Results (median, extremes): Out of 338 patients from 26 centres in 12 European countries, 33 developed at least one secondary AD within 569 (19-1489) days after HSCT, 305 pts without secondary AD served as controls. Characteristics of both groups are in table 1. The cumulative incidence of secondary AD after HSCT for primary AD was 6.5 (±1) % after 3 years and 11.1 (±2) % after 5 years. Diagnoses of secondary AD were thyroiditis (n=13), autoimmune hemolytic anemia (AIHA) (n=4), autoimmune thrombopenia (n=3), acquired hemophilia (n=3), Graves' disease, rheumatoid arthritis, sarcoidosis, antiphospholipid syndrome and psoriatic arthritis in 2 pts each and myasthenia gravis and vasculitis in 1 pt each. Two pts developed two secondary AD. After multivariate analysis age younger than 33 years p=0.016 (overall median age at HSCT), primary systemic lupus erythematosus (SLE) p= 0.003, ex vivo manipulation p= 0.015 and HSCT performed after the year 2002 p=0.02 remained as risk factors for secondary AD. At last follow-up within 5.9 years (0.25-15 years) after HSCT, 28/33 pts with secondary AD were alive and 257/305 nonAD pts. 0ne Systemic Sclerosis pt and one Multiple Sclerosis transplanted pt died from secondary embolic antiphospholipid syndrome and acquired hemophilia respectively. 26 primary AD pts received specific therapy after HSCT for their secondary AD. The pts with acquired hemophilia received steroids plus cyclophosphamide and additional Rituximab or ivIG or plasmapheresis, those with immune thrombocytopenia responded to steroids. One pt with thrombocytopenia followed by AIHA needed additional immunosuppression and Rituximab. Two pts with AIHA received steroids, cyclophosphamide and additional Rituximab, and one case also ivIG and ultimately allogeneic HSCT for secondary AID. At last follow-up, 12 pts remained in remission of secondary AD without treatment, 15 pts needed ongoing therapy, 3 pts had persistent secondary AD without therapy. This first multicenter study after HSCT for primary AD showed that secondary AD occurred in 10% of 338 pts after HSCT and led to death in 2 pts. Younger age and SLE as primary AD were significant risk factors for secondary AD, but contrary to previous single centre US experience, conditioning with ATG or alemtuzumab did not increase the secondary AD risk. Secondary AD after HSCT should be added to the post transplant follow up clinical parameters. Disclosures: Lenhoff: Celgene: Honoraria.

Objective. The clinical course of SSc depends on subtype, organ involvement and age. Few data are reported on patients suffering from late-onset SSc. Methods. We analysed data from 8554 patients prospectively followed in the EULAR Scleroderma Trials and Research (EUSTAR) group database. Late-onset SSc was defined as onset of non-RP disease features at or beyond 75 years of age. Disease characteristics, clinical features, disease course and mortality were evaluated. Results. A total of 123 patients with SSc onset at or beyond 75 years of age were identified. Compared with patients

Objective To define the specificity and extent of duplex sonography (DS) findings suggestive of vessel wall inflammation in patients with giant cell arteritis (GCA). Methods Patients admitted between December 2006 and April 2009 to the University Hospital Basel with a suspicion of GCA were eligible for the study. DS of 2×11 arterial regions was performed in all study participants, and American College of Rheumatology criteria were applied to classify patients into GCA or non-GCA groups. Results GCA was diagnosed in 38 of the 72 participants (53%). A DS pattern suggestive of vessel wall inflammation was not observed in any of the patients in the non-GCA group but, in 21 of the 38 patients with GCA (55%), DS signs suggestive of vessel wall inflammation of ≥1 vessel region were detected. In 12 of the 38 patients with GCA (32%), DS signs of large vessel vasculitis (LVV) were found in ≥1 vessel region(s) of both upper and lower limb vessels. Follow-up DS was performed 6 months after the baseline examination in 9 of the 12 patients with LVV and showed the persistence of most findings despite normalised signs of systemic inflammation. Conclusion DS detects changes in the vessel wall that appear to be specific for GCA; they can be present in upper and lower limb arteries of patients with GCA. Surprisingly, DS-detectable LVV and signs of systemic inflammation are largely dissociated.

Autologous hematopoietic stem-cell transplantation (HSCT) showed promising results for the treatment of primary severe autoimmune diseases (ADs). In this context, development of secondary AD after HSCT has exceptionally been observed, further questioning the roles of patient propensity for AD and of the HSCT procedure. Herein, we report new onset of myasthenia gravis 3 years after successful HSCT in a patient with severe systemic sclerosis, while in complete remission from her first AD. The de novo occurrence of secondary AD (myasthenia gravis) after HSCT was accompanied by the appearance of clonal T-cell expansions measured by the "immunoscope" technique in the context of an ongoing T-cell immune reconstitution. Secondary ADs are increasingly recognized after HSCT for AD. In our case, development of myasthenia followed clonal T-cell expansion. Detailed T-cell repertoire analysis may shed light on autoreactivity mechanisms after HSCT and may help to identify patients at risk.

If leg claudication is the initial presentation of patients with giant cell arteritis (GCA), the diagnosis is challenging even more when inflammation markers are absent. The two patients in the fol...

Patients with fibromyalgia (FM) often describe the presence of dry eyes and other ocular symptoms. It has been claimed that a subgroup of patients with FM might have features suggestive of primary Sjögren syndrome. In others, such a relationship could not be found. The purpose of the present study was to investigate the association and prevalence of keratoconjunctivitis sicca (KCS) in patients with FM. Among 285 patients with FM, 40 patients reporting sicca symptoms were screened with Schirmer's I test, break-up time and Rose-Bengal score. KCS was diagnosed when two of the selected three tests gave pathological results. A detailed ophthalmological examination was also performed. In 15 patients the diagnosis of KCS could be confirmed. Eighteen of 40 patients had been taking low-dose antidepressants and 7 of them had objective signs of KCS. Eight of 40 patients had signs of chronic blepharitis and 4 of them had KCS. Fourteen patients showed unremarkable test results. Chronic blepharitis and the use of tricyclic antidepressants may play a role in developing KCS. It seems that the rate of KCS does not increase in patients with FM and they probably have objective ocular findings comparable with the normal population.

Antineutrophil cytoplasmic antibody-associated (ANCA) vasculitis (AAV) is characterised by necrotising inflammation of small vessel walls, largely due to the accumulation and activation of neutrophils. Disease activity can be difficult to assess.1 Triggering receptor expressed on myeloid cells-1 (TREM-1) is an activating receptor expressed on neutrophils and monocytes recruited into sites of bacterial infection.2 3 By contrast, in a number of non-infectious inflammatory diseases (immune complex vasculitis, psoriasis associated arthritis), infiltrating neutrophils were found to lack significant expression of TREM-1.2 A soluble form of TREM-1 (sTREM-1) is shed from the membrane of activated phagocytes, and has been suggested as a …

Autoimmunity after stem-cell transplantation has been observed over decades. Evidence comes from single case reports or small series. Autoimmune phenomena are known in both the autologous and the allogeneic settings, irrespective of the graft source. Most publications deal with autoantibody production after transplantation; more rarely, the appearance of the associated autoimmune disease is reported. Autoimmune thyroid disease and autoimmune cytopenias are most often described. Homeostatic expansion after transplantation-induced lymphopenia is thought to be a trigger for loss of self-tolerance and proliferation of autoreactive T-cells in these patients. With allogeneic haematopoietic stem-cell transplantation, adoptive transfer of autoimmune disease has been shown, raising the issue of graft quality. Many of the clinical and laboratory features of graft-versus-host disease (GvHD), especially in its chronic form, resemble those of autoimmune diseases, and the pathophysiological mechanisms are similar. Prospective data for a better understanding of autoimmunity and 'altered' immunity after stem-cell transplantation are needed.

Objective: To evaluate the feasibility of haematopoietic stem cell transplantation (HSCT) in vasculitis. Methods: This is a retrospective analysis of patients who had received HSCT for vasculitic diseases and have been reported to the European League Against Rheumatism autoimmune disease or European Bone Marrow Transplantation ProMISe databases. Information about the disease and outcome was obtained by a questionnaire sent to the referring centres. Response of the disease to HSCT was defined as partial or complete responses according to the ability to reduce immunosuppression after HSCT. In addition, the Medline database was searched for reports on HSCT in patients with vasculitis. Results: Detailed information was obtained for 15 patients, whose median age at HSCT was 37 years. The diagnoses were cryoglobulinaemia in four patients, Behcet’s disease in three patients, Wegener’s granulomatosis in three patients, and undifferentiated vasculitis, Churg–Strauss angiitis, polychondritis, Takayasu arteritis and polyarteritis nodosa in one patient each. 14 patients received autologous HSCT and 1 an allogeneic HSCT as the first transplant. In three patients, further transplantation was given because of relapse. The overall response, including all consecutive transplantations (HSCT/patient, n = 1–3, median 1.3) to HSCT, was 93%, with 46% complete responses and 46% partial responses; median (range) duration of response at the time of reporting was 45 (16–84) months. Three patients died, one from advanced disease, one from cancer and one from graft-versus-host disease. The Medline search showed five other patients who were effectively treated with HSCT for vasculitic diseases. Conclusion: This retrospective study suggests that autologous HSCT is feasible for vasculitis. Its value remains to be tested in prospective controlled studies.

Ten years have passed since the first published consensus statement on the use of hematopoietic stem cell transplantation (HSCT) in the treatment of severe autoimmune disease (AD) appeared. During that time, around 700 patients suffering from severe AD have undergone HSCT in the frame of phase I/II clinical trials from over 20 countries including the US. The majority have received an autologous HSCT using one of a limited number of regimens, consistent with the original consensus statement. Long-term drug-free remissions, remission then relapse, no response and treatment-related mortality (TRM) were seen in all the subgroups of AD. An overall TRM of 7% was observed, with marked variation between ADs, i.e. 11% in systemic lupus erythematosus (SLE) and only 1 patient in rheumatoid arthritis (RA). Phase III prospective, comparative randomized trials are running or being planned in multiple sclerosis (MS), systemic sclerosis (SSc), SLE and RA. Basic science programs are also being undertaken to study the immunological mechanisms underlying the clinical events observed.

Transplantation of peripheral blood stem cells (PBSCT) is currently explored in patients with refractory autoimmune diseases,1,2 and results so far show that about two thirds of patients who receive a transplant benefit from this procedure.3 Transplant related mortality in patients with autoimmune disease is similar to that seen in patients with non-Hodgkin’s lymphoma.4 We report on a 34 year old male patient with a 16 year history of psoriatic arthropathy with mutilating bilateral lesions of the wrists, metacarpal, proximal and distal interphalangeal and metatarsal, and lower extremity interphalangeal joints, who was refractory to treatment with multiple disease modifying, immunosuppressive substances, including gold, methotrexate (MTX), MTX plus sulfasalazine, cyclosporin A (CSA), mycophenolate mofetil (MMF) alone or in combination with CSA, steroids, and a combination of CSA, MTX, and MMF. IgA κ monoclonal gammopathy of unknown significance developed later in the course of …

Myeloablative chemotherapy followed by stem cell transplantation is often associated with a prolonged and substantial, potentially detrimental period of T-cell immunodeficiency (1). The depletion of T-cells by intensive chemotherapy may lead to an increased number of viral and fungal infections. For a complete reconstitution of immunity, the generation of de novo T-cells in the thymus with a broad T-cell receptor repertoire is essential (2). However, the thymus is gradually replaced by adipose tissue and its activity is age-dependent (3). Additional factors that influence the thymic activity are graft-versus-host disease and direct damage from chemo- and radiotherapy. Measuring thymopoietic capacity only on the basis of phenotyping naive T-cells is of limited value as CD45RA+ T-cells may immediately convert into memory T-cells, may proliferate antigen-independently or may persist most of their life span. As an alternative approach to monitor thymic activity, the frequency of T-cell receptor excision circles among peripheral blood cells can be determined (4).

The pathophysiology of Epstein–Barr virus (EBV)-associated haemophagocytosis remains poorly understood.1 In EBV-related haemophagocytic lymphohistiocytosis, EBV-infected CD8 T cells and natural killer cells are thought to trigger haemophagocytosis and the associated ‘cytokine-storm’/systemic inflammatory response syndrome (SIRS) directly.2,–,4 By contrast, in the context of uncontrolled proliferation of EBV-infected B cells, hyperactively responding EBV-specific T cells are assumed to mediate haemophagocytosis/SIRS.5 Both the quantity and quality of such deregulated EBV-specific T-cell reactivity remain undefined. Unique insight into basic aspects of the postulated T-cell requirements necessary to trigger haemophagocytosis was provided by the case of a 37-year-old woman with mixed connective tissue disease (ribonucleoprotein-Ab positive, severe pulmonary arterial hypertension, polyarthritis, pericarditis and oesophageal sclerosis). Immunosuppression with azathioprine and ciclosporin, as well as a 3-month trial of oral cyclophosphamide due to progressing pulmonary arterial hypertension was ineffective, yet worsened pre-existing lymphopenia. Based on the severe and cyclophosphamide-resistant course of the disease the indication for haematopoietic stem cell transplantation (HSCT) was established. …

CD8 T cells mediate antiviral immunity but are also implicated in autoimmunity.1,–,2 Responses elicited by immunogenic peptides target only a minute fraction of all potential peptide determinants, a phenomenon termed immunodominance.3–4 Immunodominance can be readily assessed for CD8 T-cell responses targeting Epstein–Barr virus (EBV), a herpes family virus that establishes life-long persistent infection in over 90% of the adult population.5 Here we hypothesised that, largely independent of an individual's medical condition, immunosuppression is inefficient at shifting established immunodominance. To test this hypothesis, we quantitatively assessed CD8 T-cell responses targeting defined EBV-derived peptides in individuals with differing medical histories exposed to immunosuppressive regimens of variable intensity. The frequency of interferon γ-secreting T cells specific for any of 91 defined EBV-derived major histocompatibility complex I epitopes, optimally restricted by a wide range of human leucocyte antigen class I alleles, was quantified by enzyme-linked immunospot assays (ELISpot).6 In …

Our purpose was to evaluate the safety and therapeutic activity of continuously infused mitomycin C in patients with recurring or progressive metastatic gastric cancer following first-line chemotherapy. Patients were treated with mitomycin C 20 mg/m2 i.v. over a time period of 120 h followed by a 3-week rest period. All patients received prednisone 50 mg p.o. prophylactically for 5 days to prevent hemolytic uremic syndrome and pulmonary side effects. Twenty-two consecutively enrolled patients were assessable for toxicity and 20 for response evaluation completing at least one full course of chemotherapy (two patients evaluable but not measurable).median age: 63 years (39-76); Sex (M/ F): 13/9; median Karnofsky status: 70% (50-100%); resection of primary tumor n = 12 (55%); sites of metastases: liver n = 17 (77%), locally advanced n = 10 (45%), peritoneum n = 13 (59%), lungs n=5 (23%), bone n=3 (14%) and lymph nodes n=14 (64%). Previous chemotherapy regimens: bolus 5-FU/folinic acid n=6 (27%), ELF n=4 (18%), EAP n=3 (14%) and continuous 5-FU/folinic acid/cisplatin/paclitaxel n=9 (41%). In 20 evaluable patients one complete and five partial remissions were observed; overall response rate 30.0% [95% confidence interval (CI): 9.1-50.9%] with a median response duration of 2.1 months (range: 2-6). The median survival was 3.6 months (95% CI: 2.1-6.0) resulting in a 6-month survival rate of 30% since start of mitomycin C. WHO grade III/IV mucositis, diarrhea and fever/infection occurred in 9% of patients each. Cumulative thrombo- and leukocytopenia (WHO grade II/IV) were observed in four and two patients, respectively. Treatment had to be stopped early in two patients. No severe renal dysfunction, pulmonary toxicity or evidence of hemolytic uremic syndrome was observed. Fatigue during the 120 h infusion of mitomycin C was common (11 of 22 patients). We conclude that continuous infusion of mitomycin C is feasible on an outpatient basis, revealing an acceptable toxicity. Mitomycin C demonstrates single-agent activity in pretreated gastric cancer, but has only limited efficacy following cisplatin/paclitaxel-based first-line chemotherapy.

We report two patients with lower limb pitting edema and systemic lupus erythematosus (SLE) who showed immediate response to systemic steroids. In one of the patients, the edema had been present for about 6 months and was the first manifestation of her SLE. In the second patient with a long history of SLE and antiphospholipid syndrome, a thrombosis was suspected, but not confirmed. Only after therapy with steroids did the edema disappear completely. Pitting edema of the lower limb could be a rare manifestation of SLE.

To the editor: Bhatia and colleagues[1][1] recently published a comprehensive analysis on late mortality after allogeneic hematopoietic stem cell transplantation (HSCT), providing interesting data about the functional status of 547 recipients and 319 siblings. At the time of this Collaborative Bone

Our objective was to study joint symptoms in patients with relapsing polychondritis (RP) and their relationship to other clinical manifestations and laboratory findings. Fourteen patients who met the diagnostic criteria proposed by Michet et al. for RP were studied. Clinical symptoms were recorded and a detailed laboratory analysis with HLA-DR typing was carried out. In 2 patients arthritis was the first manifestation. During the follow-up, 10 patients developed arthritis. It was polyarticular in 6, and oligoarticular in 4 cases. The development of arthritis was unrelated to the appearance of chondritis at other sites. HLA class II typing was determined in 7 patients. Six of them were positive for HLA-DR4. Arthritis in RP is a frequent manifestation occurring in approximately 70% of patients with an asymmetric articular involvement. There is no correlation between articular involvement and any particular clinical or laboratory feature. Susceptibility to RP is significantly related to the presence of HLA-DR4.

We evaluated the therapeutic activity and safety of continuously infused mitomycin C in patients with metastatic colorectal cancer who had recurred (less than 3 months) or progressed following first- or second-line 5-fluorouracil-based chemotherapy. Treatment consisted of mitomycin C 20 mg/m2 i.v. given over 120 h (5 days) followed by a 3 week rest period. Fifty-two consecutively enrolled patients were assessable for toxicity and 49 for response evaluation (three patients evaluable but not measurable), completing at least one full course of chemotherapy. Previous chemotherapy regimens consisted of bolus 5-fluorouracil/folinic acid (5-FU/FA) (Machover) n=26 (50%) or continuous (24 h) 5-FU+/-FA+/-interferon n=26 (50%). Forty-two percent of patients had received one previous chemotherapy regimen and 58% more than one. One partial remission (2%) lasting 7 months and 11 disease stabilizations (23%) with a median duration of 3.2 months (range 1-8) were achieved in 49 patients. Median survival time since start of mitomycin C was 4.7 months (1.2-28.1) resulting in a 6 month survival rate of 36%. The progression-free interval was 10 weeks (range 4-36). Delayed and cumulative thrombo- and leukocytopenia (WHO grade III/IV) were observed in 19 and 6%, and anemia in 2% of patients. WHO grade I/IV mucositis, diarrhea and fever/infection occurred each in 6% of patients. Treatment delays and dose reductions were necessary in 11 (21%) and 21 (40%) patients, respectively. In three cases treatment was stopped due to cumulative thrombocytopenia (6%). Continuous infusion of single-agent mitomycin C displays modest activity in heavily pretreated 5-FU refractory colorectal cancer patients combined with a low toxicity level.

Gemcitabine (dFdC) is a novel pyrimidine antimetabolite with documented antineoplastic activity against metastatic non-small cell lung cancer (NSCL), pancreatic carcinoma, ovarian and breast cancer. The side effects of gemcitabine are generally mild; severe infections are reported in less than Ilo of patients. In contrast, other new nucleoside analogues such as the purine antimetabolite fludarabine lead to a significant alteration of the CD4/CD8 lymphocyte ratio associated with an increased risk for opportunistic infections. This study investigates the effect of gemcitabine on different lymphocyte subsets during consecutive applications. 16 patients with solid rumours (3 non-small cell lung cancer, 3 pancreas, 3 testicular, 2 breast, ovarian germ-cell, 1 ovarian, 1 small cell lung, 1 gastric cancer, 1 carcinoma of unknown primary); 15 patients were previously treated, received at least 3 applications of gemcitabine (1,000 mg/m(2) as a 30 min infusion, at days 1, 8, 15; q 4 weeks). Lymphocytes surface antigens were analysed by standard technique flow cytometry prior to every infusion. The median number of leukocytes before therapy was 7823/mu l, with lymphocytes 875/mu l, including 68% T-cells (CD3(+)), 9% B-cells (CD19(+); CD20(+)) and 15% NK-cells (CD56(+); CD16(+); CD3(-)), the CD4/CD8 ratio was 1.7. After gemcitabine therapy the median number of leukocytes was 5136/mu l, with lymphocytes 1012/mu l, including 77% T-cells, 8% B-cells and 10% NK-cells and a CD4/CD8 ratio of 2.2. Severe complications or opportunistic infections were not seen in these 16 patients. No significant change of CD4/CD8 ratios and NK-ccll numbers was seen in our patients with solid tumours during weekly treatment with gemcitabine. A severely increased risk for opportunistic infections following treatment with the new antimetabolite gemcitabine appears unlikely.

Background A previous MRI study showed a high prevalence of subclinical peripheral arthritis in patients with skin psoriasis (1). However, there are no controlled data regarding subclinical axial inflammation in this disorder. Objectives To assess the prevalence of axial skeleton changes by whole-body MRI (wbMRI) in skin psoriasis patients without clinical evidence of arthritis and in age- and sex-matched healthy controls. Methods Twenty-five patients (age median 52; range 20-69) with psoriasis vulgaris and no history or clinical evidence of arthritis and twenty-five age- and sex-matched healthy controls with no history of inflammatory back pain or skin psoriasis were recruited by the Nordic questionnaire. All patients and controls were clinically examined by the same dermatologist and rheumatologist according to a standardized protocol including the psoriasis area severity index (PASI), the body surface area (BSA), Menell, Ott and Schober tests, chest expansion and tender/swollen joint count. The patients and controls underwent a standardized unenhanced wbMRI at 1.5 T including coronal and sagittal T1w and STIR sequences. Image sets including both the sacroiliac joints (SIJ) and the entire spine were read in a random order and independently by a radiologist and a rheumatologist blinded to the clinical and demographic parameters. First the readers recorded the presence or absence of spondyloarthritis (SpA) by a global assessment of the SIJ and spine images in both MRI sequences. The confidence with this diagnosis was scored on a scale of 0-10 (0 = definitely no SpA, 10 = definite SpA). Bone marrow edema (BME), fatty marrow infiltration (FMI) and erosive changes in each SIJ quadrant were recorded by the Morpho module. Spinal BME and FMI of all 23 discovertebral units from C2/3 to L5/S1 were assessed according to the CanDen module. Lesion prevalence was analyzed descriptively in each group as mean number/percentage of subjects according to the two readers. Fisher’s exact test was used to test for a significant difference in prevalence between the 2 groups, with a desired level of significance p ≤ 0.05. Results 24% of healthy controls and 30% of skin psoriasis patients were assessed as having axial SpA by global MRI assessment. A high confidence of 8-10 with this diagnosis was recorded in 12% of controls and 18% of patients. The differences between the 2 groups were not statistically significant, both for the global assessment and the lesion analysis in SIJ and spine. Percentage of subjects (mean of 2 readers) with ≥ 2 affected SIJ quadrants or ≥ 2 spinal changes for each lesion type: Conclusions Every fourth healthy control was falsely classified by wbMRI as axial SpA. Skin psoriasis patients without clinical evidence of axial or peripheral arthritis showed a similar frequency for SIJ and spinal changes as healthy controls. References Offidani A et al. Subclinical joint involvement in psoriasis: magnetic resonance imaging and Xray findings. Acta Derm Venereol (Stockh) 1998, 78:463-465 Disclosure of Interest None Declared

Abstract 964 Background: High dose immunosuppressive therapy and hematopoietic stem cell transplantation (HSCT) has shown efficacy in severe or rapidly progressive systemic sclerosis (SSc) in phase 1 and 2 trials with durable responses in two thirds of patients (pts), while a recent phase 2 randomised trial in 19 SSc pts showed superior benefit of HSCT over iv pulse cyclophosphamide (Cy) on skin score and lung function. Methods: The ASTIS-trial (Autologous Stem cell Transplantation International Scleroderma trial) is a multinational prospective randomized controlled phase 3 trial, comparing safety and efficacy of HSCT versus Cy in early progressive dcSSc pts with disease duration of a) 4 years or less and evidence of organ involvement or b) of 2 years or less and evidence of systemic inflammation with or without major organ involvement. Major exclusion criteria were: concomitant severe SSc disease (mean PAP > 50 mmHg, DLCO < 40% predicted, creatinine clearance (CCl) 5gr iv or >3months oral) treatment), liver failure. Pts randomized to the transplant arm underwent mobilization with Cy 2×2 g/m2 + G-CSF 10mcg/kg/d, conditioning with Cy 200 mg/kg, rbATG 7.5 mg/kg, followed by reinfusion of CD34+ autologous HSCT. Controls were treated with 12× monthly iv pulse Cy 750 mg/m2. Crossing over was allowed after 2 years. The primary endpoint was event-free survival (EFS), defined as survival until death or development of major organ failure at 2 yrs. Toxicity according to WHO criteria and progression free survival (defined as worsening of modified Rodnan skin score, functional ability, major organ function) were the main secondary endpoints. The effects of treatment were analyzed on an ITT basis and by comparing EFS using the KM survival curves (using log-rank test) and Cox models. Results: 156 pts (female 59%), from 27 centers were enrolled in 10 countries from March 2001 until October 2009 and randomized to HSCT (n=79) or iv pulse Cy (n=77). Seventy-five pts in each arm started treatment, 70 pts in HSCT and 58 pts in control groups completed treatment. The median time (Interquartile Range (IR)) from randomization to completion of treatment was 93 (43.0) days in the HSCT and 338 (41.75) days in the control groups respectively. Baseline characteristics (mean (SD)) of the pts were: age 44 (11.2) yrs, SSc duration 1.4 (1.3) yrs, BMI 24 (14.4), Rodnan skin score 25 (8), HAQ 1.35 (0.8), prior Cy therapy 22%, creat cl 116 (39.5) ml/min, LVEF 65% (8.5), DLCO 59% (14), with no significant differences between the 2 arms. With data cut at 1 May 2012, median follow-up (IR) are 33 (42.0) and 27 (34.0) months in the HSCT and control groups respectively. Forty two events occurred : 18 in the HSCT group (16 deaths and 2 irreversible renal failures) and 24 in the control group (24 deaths). Event-free survival was time-dependent with a hazard ratio at 84 months of 0.22 (95% CI 0.08–0.58, P= 0.002). Eight deaths (including 1 during mobilization and 1 after conditioning) in the HSCT group were deemed treatment-related by the independent data monitoring committee with heart failure (3), ARDS (2), multiple organ failure (2) and pulmonary oedema (1) as the causes of death. In the control group, none died from treatment causes and most deaths were due to progressive disease. Eight pts in the control arm received rescue HSCT treatment, one of whom later died from secondary acute myeloid leukaemia. Two HSCT pts received rescue iv Cy therapy. Conclusions: The ASTIS-trial is the first international, investigator-initiated, phase 3 HSCT trial in early diffuse cutaneous systemic sclerosis. The data show that despite 10% treatment-related mortality, long term event-free survival and overall survival were better in the HSCT group than in the group treated with iv pulse cyclophosphamide. (Funded by the European Group for Blood and Marrow Transplantation, European League Against Rheumatism, AP-HP, NIHR, DIGR, Imtix-Sangstat, Miltenyi-Biotec, Amgen Europe; Current Controlled Trials number, ISRCTN 54371254). Disclosures: No relevant conflicts of interest to declare.

To enrich low-density human bone marrow (BM) cells for putative progenitors of T-lymphocytes, CD7+ CD3- cells were sorted (purity was estimated at > 99.9%) and cultured under limiting dilution conditions with irradiated allogeneic stimulator cells, interleukin (IL) 2, and PHA. Clonal populations were available for analysis from Day 25 onward. By this time, all clones (n = 54) expressed CD3 and alpha/beta-T cell receptor (TCR2). Fifty percent of the clones were CD4+ and 50% were CD8+, with no double positives, whereas almost all clones obtained under identical conditions from peripheral blood (PB) cells were CD4+. All clones were capable of autocrine proliferation, which was blocked by CD25 or CD71 mAb. Most or all clones tested (n = 15) responded to IL 4 and IL 7 as well as IL 2, but not to IL 3 or GM-CSF and only two responded to IL 9. Most clones accumulated mRNA for GM-CSF, IL 2, IL 3, IL 4, IL 5 and also IL 9, but 6 of 11 were negative for IFN-gamma mRNA, and all were negative for IL 6 mRNA. Sixty-two percent of CD4+ and 85% of CD8+ clones (total 70% of all clones) mediated lectin-dependent cell lysis; but whereas 35% of CD4+ and 65% of CD8+ clones (total 46% of all clones) lysed K562 natural killer (NK)-susceptible targets, only 24% of CD4+ and 5% of CD8+ clones (total 17% of all clones) killed lymphokine-activated killer (LAK)-susceptible Daudi cells. Only three clones lysed allogeneic LCL targets and none lysed autologous targets. Furthermore, none of the clones proliferated when stimulated by autologous cells, neither did they suppress proliferative responses of autologous cells. These results suggest that CD3- cells from the bone marrow can acquire functional cytotoxic and proliferative programs extrathymically during in vitro culture with IL 2, mitogens and allogeneic cells, but do not manifest autoreactivity in the three test systems, cytotoxicity, suppression, or autocrine proliferation.