EULAR recommendations for cardiovascular risk management in rheumatic and musculoskeletal diseases, including systemic lupus erythematosus and antiphospholipid syndrome.

OBJECTIVE: To develop recommendations for cardiovascular risk (CVR) management in gout, vasculitis, systemic sclerosis (SSc), myositis, mixed connective tissue disease (MCTD), Sjögren's syndrome (SS), systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). METHODS: Following European League against Rheumatism (EULAR) standardised procedures, a multidisciplinary task force formulated recommendations for CVR prediction and management based on systematic literature reviews and expert opinion. RESULTS: Four overarching principles emphasising the need of regular screening and management of modifiable CVR factors and patient education were endorsed. Nineteen recommendations (eleven for gout, vasculitis, SSc, MCTD, myositis, SS; eight for SLE, APS) were developed covering three topics: (1) CVR prediction tools; (2) interventions on traditional CVR factors and (3) interventions on disease-related CVR factors. Several statements relied on expert opinion because high-quality evidence was lacking. Use of generic CVR prediction tools is recommended due to lack of validated rheumatic diseases-specific tools. Diuretics should be avoided in gout and beta-blockers in SSc, and a blood pressure target <130/80 mm Hg should be considered in SLE. Lipid management should follow general population guidelines, and antiplatelet use in SLE, APS and large-vessel vasculitis should follow prior EULAR recommendations. A serum uric acid level <0.36 mmol/L (<6 mg/dL) in gout, and disease activity control and glucocorticoid dose minimisation in SLE and vasculitis, are recommended. Hydroxychloroquine is recommended in SLE because it may also reduce CVR, while no particular immunosuppressive treatment in SLE or urate-lowering therapy in gout has been associated with CVR lowering. CONCLUSION: These recommendations can guide clinical practice and future research for improving CVR management in rheumatic and musculoskeletal diseases.

Hematopoietic stem cell transplantation for autoimmune diseases: more than just prolonged immunosuppression.

PURPOSE OF REVIEW: To summarize the current clinical experience in the use of autologous hematopoietic stem cell transplantation (HSCT) in autoimmune disease and to explore the concept of durable remission induction and tissue de-remodeling via restoration of normal niche function and "immune reset.' RECENT FINDINGS: Controlled clinical trials in systemic sclerosis, multiple sclerosis, and Crohn's disease as well as extensive uncontrolled trial and registry data have established the unique role of HSCT in selected cases. Although HSCT for multiple sclerosis and systemic sclerosis has recently entered several official treatment guidelines, mechanistic studies are few but indicate some possible modes of action, for example, increase of regulatory T cells. Toxicity of HSCT remains high but is improving with protocol modifications and more precise patient selection. SUMMARY: For the first time, it has been demonstrated that strategies exist which may permanently reprogram an autoaggressive immune system to one of self-tolerance independent of ongoing immunosuppression. In addition, some tissues have the capacity to repair damage via normal regenerative processes. The exact mechanism(s) as to how this is achieved in certain cases and not others are emerging. Such knowledge, together with adoption of recently developed less toxic and more targeted regimens from the hematology/oncology field may translate to a safer yet still effective treatment for autoimmune disease.

Update of EULAR recommendations for the treatment of systemic sclerosis.

The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.

Prediction of worsening of skin fibrosis in patients with diffuse cutaneous systemic sclerosis using the EUSTAR database.

OBJECTIVES: To identify predictive parameters for the progression of skin fibrosis within 1 year in patients with diffuse cutaneous SSc (dcSSc). METHODS: An observational study using the EUSTAR database was performed. Inclusion criteria were dcSSc, American College of Rheumatology (ACR) criteria fulfilled, modified Rodnan skin score (MRSS) ≥7 at baseline visit, valid data for MRSS at 2nd visit, and available follow-up of 12±2 months. Worsening of skin fibrosis was defined as increase in MRSS >5 points and ≥25% from baseline to 2nd visit. In the univariate analysis, patients with progressive fibrosis were compared with non-progressors, and predictive markers with p<0.2 were included in the logistic regression analysis. The prediction models were then validated in a second cohort. RESULTS: A total of 637 dcSSc patients were eligible. Univariate analyses identified joint synovitis, short disease duration (≤15 months), short disease duration in females/patients without creatine kinase (CK) elevation, low baseline MRSS (≤22/51), and absence of oesophageal symptoms as potential predictors for progressive skin fibrosis. In the multivariate analysis, by employing combinations of the predictors, 17 models with varying prediction success were generated, allowing cohort enrichment from 9.7% progressive patients in the whole cohort to 44.4% in the optimised enrichment cohort. Using a second validation cohort of 188 dcSSc patients, short disease duration, low baseline MRSS and joint synovitis were confirmed as independent predictors of progressive skin fibrosis within 1 year resulting in a 4.5-fold increased prediction success rate. CONCLUSIONS: Our study provides novel, evidence-based criteria for the enrichment of dcSSc cohorts with patients who experience worsening of skin fibrosis which allows improved clinical trial design.

FGF2 induces RANKL gene expression as well as IL1ß regulated MHC class II in human bone marrow-derived mesenchymal progenitor stromal cells.

OBJECTIVE: Human bone marrow mesenchymal stromal cells (hBM-MSC) are being applied in tissue regeneration and treatment of autoimmune diseases (AD). Their cellular and immunophenotype depend on isolation and culture conditions which may influence their therapeutic application and reflect their in vivo biological functions. We have further characterised the phenotype induced by fibroblast growth factor 2 (FGF2) on healthy donor hBM-MSC focusing on the osteoimmunological markers osteoprotegerin (OPG), receptor activator of nuclear factor kB (RANK), RANK ligand (RANKL) and HLA-DR and their regulation of expression by the inflammatory cytokines IL1ß and IFNγ. METHODS: RANK, RANKL, OPG and HLA-DR expression in hBM-MSC expanded under specific culture conditions, were measured by RT-PCR and flow cytometry. MAPKs induction by FGF2, IL1ß and IFNγ in hBM-MSC was analysed by immunoblotting and RT-PCR. RESULTS: In hBM-MSC, OPG expression is constitutive and FGF2 independent. RANKL expression depends on FGF2 and ERK1/2 activation. IL1ß and IFNγ activate ERK1/2 but fail to induce RANKL. Only IL1ß induces P38MAPK. The previously described HLA-DR induced by FGF2 through ERK1/2 on hBM-MSC, is suppressed by IL1ß through inhibition of CIITA transcription. HLA-DR induced by IFNγ is not affected by IL1ß in hBM-MSC, but is suppressed in articular chondrocytes and lung fibroblasts. CONCLUSIONS: RANKL expression and IL1ß regulated MHC-class II, both induced via activation of the ERK1/2 signalling pathway, are specific for progenitor hBM-MSC expanded in the presence of FGF2. HLA-DR regulated by IL1ß and ERK1/2 is observed on hBM-MSC during early expansion without FGF2 suggesting previous in vivo acquisition. Stromal progenitor cells with this phenotype could have an osteoimmunological role during bone regeneration.

Haematopoietic stem cell transplantation for poor-prognosis systemic sclerosis.

Haematopoietic stem cell transplantation (HSCT) following intensive immune suppression has been used in >2000 patients with severe autoimmune diseases for 18 years, including 300 with SSc. The concept is to profoundly reduce the bulk of auto-aggressive immune competent cells and then rescue the patient's ablated haematopoiesis via an autologous HSCT. An early analysis of uncontrolled phase I/II data suggested that approximately one-third of these achieved a substantial improvement, with a relapse rate of 25% and a treatment-related mortality ranging from 6% to 23% across different studies. These early results led to three prospective randomized controlled trials, two of which are completed, confirming that HSCT shows clear advantages over conventional immunosuppression, but with significant toxicity. In some patients, sustained complete normalization of skin changes, reversal of positive autoantibody status and withdrawal of immunosuppressive medication were observed. These results attest to the profound effects of HSCT.

Twenty-two points to consider for clinical trials in systemic sclerosis, based on EULAR standards.

OBJECTIVE: SSc is clinically and aetiopathogenically heterogeneous. Consensus standards for more uniform trial design and selection of outcome measures are needed. The objective of this study was to develop evidence-based points to consider (PTCs) for future clinical trials in SSc. METHODS: Thirteen international SSc experts experienced in SSc clinical trial design were invited to participate. One researcher with experience in systematic literature review and three trainees were also included. A systematic review using PubMed and the Cochrane Central Register of Controlled Trials was conducted and PTCs when designing clinical trials in SSc were developed. As part of that development we conducted an Internet-based Delphi exercise regarding the main points to be made in the consensus statement. Consensus was defined as achieving a median score of ≥7 of 9. RESULTS: By consensus, the experts decided to develop PTCs for each individual organ system. The current document provides a unifying outline on PTCs regarding general trial design, inclusion/exclusion criteria and analysis. Consensus was achieved regarding all the main points of the PTCs. CONCLUSION: Using European League Against Rheumatism suggestions for PTCs, a general outline for PTCs for controlled clinical trials in SSc was developed. Specific outlines for individual organ systems are to be published separately. This general outline should lead to more uniform and higher-quality trials and clearly delineate areas where further research is needed.

An observational cohort study of patients with newly diagnosed digital ulcer disease secondary to systemic sclerosis registered in the EUSTAR database.

OBJECTIVES: This study describes clinical characteristics, prognostic factors, and quality of life in patients with newly diagnosed (incident) digital ulcers (DU). METHODS: Observational cohort study of 189 consecutive SSc patients with incident DU diagnosis identified from the EUSTAR database (22 centres in 10 countries). Data were collected from medical charts and during one prospective visit between 01/2004 and 09/2010. RESULTS: Median age at DU diagnosis was 51 years, majority of patients were female (88%), and limited cutaneous SSc was the most common subtype (61%). At incident DU diagnosis, 41% of patients had one DU and 59% had ≥2 DU; at the prospective visit 52% had DU. Pulmonary arterial hypertension (PAH) and multiple DU at diagnosis were associated with presence of any DU at the prospective visit (odds ratios: 4.34 and 1.32). During the observation period (median follow-up was 2 years) 127 patients had ≥1 hospitalisation. The event rate of new DU per person-year was 0.66, of DU-associated complications was 0.10, and of surgical or diagnostic procedures was 0.12. At the prospective visit, patients with ≥1 DU reported impairment in daily activities by 57%, those with 0 DU by 37%. The mean difference between patients with or without DU in the SF-36 physical component was 2.2, and in the mental component 1.4. DU patients were not routinely prescribed endothelin receptor antagonists or prostanoids. CONCLUSIONS: This real world cohort demonstrates that DU require hospital admission, and impair daily activity. PAH and multiple DU at diagnosis were associated with future occurrence of DU.

Autologous Hematopoetic Stem Cell Transplantation for Refractory Crohn Disease: A Randomized Clinical Trial.

IMPORTANCE: Case reports and series suggest hematopoietic stem cell transplantation (HSCT) may benefit some patients with Crohn disease. OBJECTIVE: To evaluate the effect of autologous HSCT on refractory Crohn disease. DESIGN, SETTING, AND PARTICIPANTS: Parallel-group randomized clinical trial conducted in 11 European transplant units from July 2007 to September 2011, with follow-up through March 2013. Patients were aged 18 to 50 years with impaired quality of life from refractory Crohn disease not amenable to surgery despite treatment with 3 or more immunosuppressive or biologic agents and corticosteroids. INTERVENTIONS: All patients underwent stem cell mobilization before 1:1 randomization to immunoablation and HSCT (n = 23) or control treatment (HSCT deferred for 1 year [n = 22]). All were given standard Crohn disease treatment as needed. MAIN OUTCOMES AND MEASURES: Sustained disease remission at 1 year, a composite primary end point comprising clinical remission (Crohn Disease Activity Index (CDAI) <150 [range, 0-600]), no use of corticosteroids or immunosuppressive or biologic drugs for at least the last 3 months, and no endoscopic or radiological evidence of active (erosive) disease anywhere in the gastrointestinal (GI) tract. Secondary outcomes were individual components of the primary composite outcome and other measures of disease activity, laboratory results, quality of life and functional status, and GI tract imaging. RESULTS: Twenty-three patients underwent HSCT and 22 received standard Crohn disease treatment (controls). Sustained disease remission was achieved in 2 patients undergoing HSCT (8.7%) vs 1 control patient (4.5%) (absolute difference, 4.2% [95% CI, -14.2% to 22.6%]; P = .60). Fourteen patients undergoing HSCT (61%) vs 5 control patients (23%) had discontinued immunosuppressive or biologic agents or corticosteroids for at least 3 months (difference, 38.1% [95% CI, 9.3% to 59.3%]; P = .01). Ten vs 2 patients had a CDAI less than 150 (remission) at the final evaluation, 8 (34.8%) vs 2 (9.1%) for 3 or more months (difference, 25.7% [95% CI, 1.1% to 47.1%]; P = .052). Eight (34.8%) vs 2 (9.1%) patients were adjudicated free of active disease on endoscopy and radiology at final assessment (difference, 25.7% [95% CI, 1.1% to 47.1%]; P = .054). There were 76 serious adverse events in patients undergoing HSCT vs 38 in controls. One patient undergoing HSCT died. CONCLUSIONS AND RELEVANCE: Among adult patients with refractory Crohn disease not amenable to surgery who had impaired quality of life, HSCT, compared with conventional therapy, did not result in a statistically significant improvement in sustained disease remission at 1 year and was associated with significant toxicity. These findings do not support the widespread use of HSCT for patients with refractory Crohn disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00297193.

Ten years EULAR Scleroderma Research and Trials (EUSTAR): what has been achieved?

Ten years ago a group of researchers interested in and dedicated to the field of systemic sclerosis started a unique experiment called European League Against Rheumatism (EULAR) Scleroderma Trials And Research (EUSTAR) that was designed to establish a large-scale database in a rare disease to facilitate the exact characterisation of this debilitating disease, spread the knowledge even beyond the borders of Europe and stimulate innovative research targeting the major problems of the affected patients. This EUSTAR experiment, with all its facets, including the creation of a large-scale database, the initiation of more than 40 investigator-driven clinical and basic science projects, the teaching of more than 400 young clinicians in the field of systemic sclerosis and the realisation of multicenter EU grants, which were all facilitated by an initial research grant from EULAR, is outlined and commented upon by the members of the steering committee in this viewpoint article on behalf of the now more than 150 contributing centres and the international systemic sclerosis patients' association, the Federation of European Scleroderma Associations.

Preliminary analysis of the very early diagnosis of systemic sclerosis (VEDOSS) EUSTAR multicentre study: evidence for puffy fingers as a pivotal sign for suspicion of systemic sclerosis.

OBJECTIVES: The EULAR (European League Against Rheumatism) Scleroderma Trials and Research Group (EUSTAR) has identified preliminary criteria for very early diagnosis of systemic sclerosis (SSc). Our aim was to assess the prevalence of each proposed diagnostic item in a large observational patient cohort with Raynaud's phenomenon (RP). METHODS: Baseline data of 469 RP patients enrolled into the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) cohort are presented. RESULTS: 68% of all RP patients were antinuclear antibody (ANA) positive. ANA+ RP patients more frequently had previous or current puffy fingers (PuFi) (38.5% and 23.3%, p<0.01) and an SSc pattern on nailfold capillaroscopy (NC) (53.6% and 13.4%, p<0.001) than ANA- patients. Telangiectasia, current digital ulcers and digital pitting scars were also commoner in ANA+ RP patients. 38% of ANA+ patients presented with all three features, which should raise suspicion of very early SSc (ANA+RP+PuFi constitutes a 'red flag'). These patients more frequently exhibited an NC SSc pattern, sclerodactyly and telangiectases compared to ANA+ patients without PuFi. Almost 90% of patients with 'red flags' had anti-centromere or anti-topoisomerase I antibodies and/or an NC SSc pattern, and fulfilled the EUSTAR criteria for very early SSc. Previous or current PuFi were present in 23.3% of ANA- RP patients, eight of whom also had an NC SSc pattern. CONCLUSIONS: In addition to well-characterised predictive factors, PuFi is an important sign raising suspicion for underlying very early SSc in patients with RP. The relevance of PuFi in ANA- RP patients should be clarified.

2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative.

OBJECTIVE: The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS: Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS: It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSION: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

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.

[Biologics and infections in rheumatic diseases]. / Biologika und Infekte in der Rheumatologie.

The successful use of a chimeric monoclonal antibody targeting TNF alpha (infliximab) to treat rheumatoid arthritis (RA) two decades ago, ushered in a new era of therapy with the so-called biopharmaceuticals, commonly referred to as "biologics". Their use rapidly spread to other indications such as Crohns disease, and their commercial success led to rapid extension of the concept using other forms of monoclonal antibodies and receptor recombinant molecules with specificities to other cytokines, growth factors and immune cell subsets. Soon after their introduction into the clinic, the first indications of increased risk of infection appeared in the form of reactivation of tuberculosis, mostly in the first months after treatment and often extrapulmonary. It was later recognised that an overall increased risk of bacterial infection under TNF-alpha blockade exists with a relative increased risk of around 2 - 3, and that classical symptoms of infection may be masked by cytokine blockade. Biologics against other cytokines such as IL-6, co-stimulatory molecules, and anti B cells seem less associated with infection, though this may be in part related to more careful patient monitoring. Increasing experience led to guidelines concerning pre-treatment screening, vaccination and perioperative advice, as well as the use of biologics in the presence of chronic viral infection, e. g. HIV, hepatitis B and C. Biologics have changed the outcome for patients with RA and other autoimmune diseases, but this success should not lead to complacency when assessing potential infectious complications of treatment in individual patients.

The differential diagnosis of systemic sclerosis.

PURPOSE OF REVIEW: The new American College of Rheumatology/European League Against Rheumatism classification criteria will enable earlier diagnosis and, therefore, the use of newer treatment modalities for systemic sclerosis (SSc). It is therefore critical to exclude non-SSc causes for diffuse skin thickening as early as possible. RECENT FINDINGS: The recently described gadolinium-induced nephrogenic systemic fibrosis may mimic SSc as may other conditions which require a different treatment strategy. Recently, treatment with immunoablation and autologous stem cell transplantation has been shown to significantly benefit some patients with conditions such as scleromyxoedema and SSc. The more accurate measurement of SSc-specific autoantibodies such as topoisomerase 1, centromere and RNA polymerase has recently allowed a more precise subclassification of SSc with implications for treatment and prognosis. SUMMARY: Skin thickening is a nonspecific manifestation of many different processes including (rarely) early scleroderma, which is mostly symmetrical and associated with Raynaud's phenomenon, nailfold capillaroscopic changes and antinuclear antibodies. If the latter three factors are absent, then other conditions must be excluded, the commonest being eosinophilic fasciitis. Skin biopsy (looking for eosinophil infiltration, increased mucin or amyloid deposition), SSc-specific autoantibodies or paraproteins in blood and a careful medical history and system screening will exclude nonscleroderma conditions.

2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative.

OBJECTIVE: The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS: Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by (1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and (2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS: It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, seven additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSIONS: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

Systemic sclerosis without antinuclear antibodies or Raynaud's phenomenon: a multicentre study in the prospective EULAR Scleroderma Trials and Research (EUSTAR) database.

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. There was 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.

Secondary autoimmune diseases occurring after HSCT for an autoimmune disease: a retrospective study of the EBMT Autoimmune Disease Working Party.

To specify the incidence and risk factors for secondary autoimmune diseases (ADs) after HSCT for a primary AD, we retrospectively analyzed AD patients treated by HSCT reported to EBMT from 1995 to 2009 with at least 1 secondary AD (cases) and those without (controls). After autologous HSCT, 29 of 347 patients developed at least 1 secondary AD within 21.9 (0.6-49) months and after allogeneic HSCT, 3 of 16 patients. The observed secondary ADs included: autoimmune hemolytic anemia (n = 3), acquired hemophilia (n = 3), autoimmune thrombocytopenia (n = 3), antiphospholipid syndrome (n = 2), thyroiditis (n = 12), blocking thyroid-stimulating hormone receptor antibody (n = 1), Graves disease (n = 2), myasthenia gravis (n = 1), rheumatoid arthritis (n = 2), sarcoidosis (n = 2), vasculitis (n = 1), psoriasis (n = 1), and psoriatic arthritis (n = 1). After autologous HSCT for primary AD, the cumulative incidence of secondary AD was 9.8% ± 2% at 5 years. Lupus erythematosus as primary AD, and antithymocyte globulin use plus CD34(+) graft selection were important risk factors for secondary AD by multivariate analysis. With a median follow-up of 6.2 (0.54-11) years after autologous HSCT, 26 of 29 patients with secondary AD were alive, 2 died during their secondary AD (antiphospholipid syndrome, hemophilia), and 1 death was HSCT-related. This European multicenter study underlines the need for careful management and follow-up for secondary AD after HSCT.

Th17 cells, not IL-17+ γδ T cells, drive arthritic bone destruction in mice and humans.

The mechanism whereby IL-17 drives rheumatoid arthritis remains incompletely understood. We demonstrate that anti-IL-17 therapy in collagen-induced arthritis ameliorates bone damage by reducing the number of osteoclasts in joints. We found equal numbers of CD4(+) Th17 and IL-17 producing γδ T cells in the joints of arthritic mice, and in vitro, both populations similarly induced osteoclastogenesis. However, individual depletion and adoptive transfer studies revealed that in vivo, Th17 cells dominated with regard to bone destruction. Unlike γδ T cells, Th17 cells were found in apposition to tartrate-resistant acid phosphatase positive osteoclasts in subchondral areas of inflamed joints, a pattern reproduced in patient biopsies. This localization was caused by Ag-specific retention, because OVA-primed Th17 cells showed a γδ T cell-like diffuse distribution. Because IL-23, as produced by osteoclasts, enhanced T cell-mediated osteoclastogenesis, we propose that Ag-specific juxtaposition is key to foster the molecular cross talk of Th17 cells and osteoclasts, thus driving arthritic bone destruction.