Relevance of gastrointestinal manifestations in a large Spanish cohort of patients with systemic lupus erythematosus: what do we know?

OBJECTIVE: SLE can affect any part of the gastrointestinal (GI) tract. GI symptoms are reported to occur in >50% of SLE patients. To describe the GI manifestations of SLE in the RELESSER (Registry of SLE Patients of the Spanish Society of Rheumatology) cohort and to determine whether these are associated with a more severe disease, damage accrual and a worse prognosis. METHODS: We conducted a nationwide, retrospective, multicentre, cross-sectional cohort study of 3658 SLE patients who fulfil ≥4 ACR-97 criteria. Data on demographics, disease characteristics, activity (SLEDAI-2K or BILAG), damage (SLICC/ACR/DI) and therapies were collected. Demographic and clinical characteristics were compared between lupus patients with and without GI damage to establish whether GI damage is associated with a more severe disease. RESULTS: From 3654 lupus patients, 3.7% developed GI damage. Patients in this group (group 1) were older, they had longer disease duration, and were more likely to have vasculitis, renal disease and serositis than patients without GI damage (group 2). Hospitalizations and mortality were significantly higher in group 1. Patients in group 1 had higher modified SDI (SLICC Damage Index). The presence of oral ulcers reduced the risk of developing damage in 33% of patients. CONCLUSION: Having GI damage is associated with a worse prognosis. Patients on a high dose of glucocorticoids are at higher risk of developing GI damage which reinforces the strategy of minimizing glucocorticoids. Oral ulcers appear to decrease the risk of GI damage.

Evaluación ecográfica en pacientes gotosos con actividad clínica persistente a pesar de uricemia dentro de objetivo requerido por «treat to target» / Ultrasound evaluation in gouty patients with persistent clinical activity despite uricaemia within the objective required by «Treat to Target»

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A treat-to-target approach for gout confers renoprotective effect in patients with chronic kidney disease stage 3.

The aim of this study was to assess changes in the estimated glomerular filtration rate (eGFR) in gouty patients with chronic kidney disease (CKD) using a "treat-to-target" (T2T) approach in gout. This multicenter observational retrospective study included patients diagnosed with gout and CKD stage 3 taking xanthine oxidase inhibitors (XOIs) (allopurinol or febuxostat) for at least 12 months. All patients were treated using a T2T strategy according to national gout guidelines to achieve the target levels of serum uric acid (sUA; < 5-6 mg/dl) within 6 months of the first visit. The primary outcome was to assess changes in eGFR. The effects of independent variables were analyzed over eGFR in a linear mixed-effects (LME) model. Fifty patients with gout and CKD stage 3 treated with XOIs with a T2T strategy for 12 months were included. Eighty-two percent of the patients achieved the sUA target during the study period. The improvement seen in eGFR was higher during the first 6 months, showing a median increase of 7.54 ml/min/m2 (SE = 1.25) and trending towards stability over 12 months. For every 1 mg/dl of decrease in sUA, an improvement of 1.5 ml/min/m2 in eGFR was observed (coefficient ± SE: - 1.58 ± 0.26) (p < 0.001) with no differences between type and dosage of XOIs treatment, colchicine administration, age, sex, and smoking status. A reduction in sUA levels using a T2T approach with XOIs at an optimal dose is possible and could help conserve and improve renal function in gouty patients with CKD stage 3.

Revised European Scleroderma Trials and Research Group Activity Index is the best predictor of short-term severity accrual.

BACKGROUND: The European Scleroderma Trials and Research Group (EUSTAR) recently developed a preliminarily revised activity index (AI) that performed better than the European Scleroderma Study Group Activity Index (EScSG-AI) in systemic sclerosis (SSc). OBJECTIVE: To assess the predictive value for short-term disease severity accrual of the EUSTAR-AI, as compared with those of the EScSG-AI and of known adverse prognostic factors. METHODS: Patients with SSc from the EUSTAR database with a disease duration from the onset of the first non-Raynaud sign/symptom ≤5 years and a baseline visit between 2003 and 2014 were first extracted. To capture the disease activity variations over time, EUSTAR-AI and EScSG-AI adjusted means were calculated. The primary outcome was disease progression defined as a Δ≥1 in the Medsger's severity score and in distinct items at the 2-year follow-up visit. Logistic regression analysis was carried out to identify predictive factors. RESULTS: 549 patients were enrolled. At multivariate analysis, the EUSTAR-AI adjusted mean was the only predictor of any severity accrual and of that of lung and heart, skin and peripheral vascular disease over 2 years. CONCLUSION: The adjusted mean EUSTAR-AI has the best predictive value for disease progression and development of severe organ involvement over time in SSc.

Overlap myositis, a distinct entity beyond primary inflammatory myositis: A retrospective analysis of a large cohort from the REMICAM registry.

BACKGROUND: Inflammatory idiopathic myositis (IIM) comprises a heterogeneous group of systemic muscular diseases that can occur together with other connective tissue diseases (CTD), named overlap myositis (OM). The question of whether OM is a distinct entity still remains controversial. AIM: The present study was conducted to assess the clinical and prognostic differences between patients diagnosed with OM, primary polymyositis (PM) and primary dermatomyositis (DM). METHOD: The study consists of a retrospective longitudinal and multicenter series of IIM patients. Patients were classified as OM, PM and DM. Overlap myositis was defined as patients fulfilling criteria for IIM plus criteria for other CTD (namely systemic sclerosis, systemic lupus erythematosus, mixed connective tissue disease, rheumatoid arthritis and primary Sjögren's syndrome). RESULT: A total of 342 patients were included (98 OM, 137 PM and 107 DM). Overlap myositis patients, in comparison with PM and DM, showed significant differences, with more extramuscular involvement, particularly more arthritis (66%, 34.6% and 48.1%, respectively), puffy fingers (49.5%, 11.1% and 24.3%), sclerodactyly (45.4%, 2.2% and 2%), dysphagia (41.8%, 18.2% and 26.4%), Raynaud phenomenon (65.3%, 16.9% and 19.8%), leucopenia (28.9%, 2.2% and 8.4%), thrombocytopenia (8.2%, 2.2% and 1.9%), interstitial lung disease (ILD) (48%, 35% and 30.8%), renal manifestations (13.4%, 3.7% and 1.9%), and more severe infections (41.3%, 26.7% and 21%). No significant differences were found in survival between groups in log rank test (P = 0.106). Multivariate adjusted survival analyses revealed a worse prognosis for severe infections, ILD and baseline elevation of acute phase reactants. CONCLUSION: Overlap myositis stands out as a distinct entity as compared to PM and DM, featuring more extramuscular involvement and more severe infections. Close monitoring is recommended in this subset for early detection and treatment of possible complications.

Functional disability and its predictors in systemic sclerosis: a study from the DeSScipher project within the EUSTAR group.

Objectives: The multisystem manifestations of SSc can greatly impact patients' quality of life. The aim of this study was to identify factors associated with disability in SSc. Methods: SSc patients from the prospective DeSScipher cohort who had completed the scleroderma health assessment questionnaire (SHAQ), a disability score that combines the health assessment questionnaire and five visual analogue scales, were included in this analysis. The effect of factors possibly associated with disability was analysed with multiple linear regressions. Results: The mean SHAQ and HAQ scores of the 944 patients included were 0.87 (s.d. = 0.66) and 0.92 (s.d. = 0.78); 59% of the patients were in the mild to moderate difficulty SHAQ category (0 ⩽ SHAQ < 1), 34% in the moderate to severe disability category (1 ⩽ SHAQ < 2) and 7% in the severe to very severe disability category (2 ⩽ SHAQ ⩽ 3). The means of the visual analogue scales scores were in order of magnitude: overall disease severity (37 mm), RP (31 mm), pulmonary symptoms (24 mm), gastrointestinal symptoms (20 mm) and digital ulcers (19 mm). In multiple regression, the main factors associated with high SHAQ scores were the presence of dyspnoea [modified New York Heart Association (NYHA) class IV (regression coefficient B = 0.62), modified NYHA class III (B = 0.53) and modified NYHA class II (B = 0.21; all vs modified NYHA class I)], FM (B = 0.37), muscle weakness (B = 0.27), digital ulcers (B = 0.20) and gastrointestinal symptoms (oesophageal symptoms, B = 0.16; stomach symptoms, B = 0.15; intestinal symptoms, B = 0.15). Conclusion: SSc patients perceive dyspnoea, pain, digital ulcers, muscle weakness and gastrointestinal symptoms as the main factors driving their level of disability, unlike physicians who emphasize objective measures of disability.

Osteosarcoma en gota tofácea: descripción de un caso clínico y revisión de la literatura / Osteosarcoma in tophaceous gout: a case report and literature review

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Efficacy of Raynaud's phenomenon and digital ulcer pharmacological treatment in systemic sclerosis patients: a systematic literature review.

To evaluate the efficacy of current treatments for the Raynaud phenomenon (RP) in patients with systemic sclerosis (SSc), a systematic literature search was performed using Medline, EMBASE, and Cochrane Central Register of Controlled Trials (from 1961 to October 2011). We included meta-analyses, systematic reviews, clinical trials, and high-quality cohort studies published in English or Spanish. Patient populations had to include adults diagnosed with limited cutaneous or diffuse SSc who had associated RP and/or digital ulcers under pharmacological treatment. Efficacy of treatments was evaluated based on: number of RP episodes, RP severity, episode-free time, ulcer improvement/healing, and appearance of new ulcers. We used the Jadad scale of methodological quality to evaluate the quality of randomized clinical trials, and the 2009 Oxford Centre for Evidence-Based Medicine classification for other studies. Of a total of 1617 studies identified, only 27 fulfilled inclusion criteria. Drugs received the following grade recommendations: Grade A for nifedipine, nicardipine, quinapril, IV iloprost, bosentan, tadalafil, and MQx-503; Grade B for beraprost, cicaprost, DMSO, cyclofenil, and atorvastatin; and Grade C for misoprostol, prazosin, OPC-2826, enalapril, sildenafil, antioxidant, and stanazolol. Calcium channel blockers, prostanoids, tadalafil, and bosentan received the highest recommendation level for their effectiveness. However, most systematic reviews reviewed just a handful of studies with small sample sizes and short follow-ups. Our review shows that the existing evidence on the efficacy of RP treatment in SSc patients is inconclusive which calls for further research, especially in the form of prospective studies of high quality with long-term follow-ups.

Nailfold capillary abnormalities in erectile dysfunction of systemic sclerosis: a EUSTAR group analysis.

OBJECTIVE: The objective of this study was to analyse an association between nailfold capillary abnormalities and the presence and severity of erectile dysfunction (ED) in men with SSc. METHODS: A cross-sectional analysis of the prospective European League Against Rheumatism (EULAR) Scleroderma Trial and Research database was performed. Men with SSc were included if they had undergone nailfold capillaroscopy and simultaneous ED assessment with the 5-item International Index for Erectile Function (IIEF-5). RESULTS: Eighty-six men met the inclusion criteria. Eight men (9.3%) had not had sexual intercourse and could not be assigned an IIEF-5 score. Sixty-nine of the 78 men (88.5%) with an IIEF-5 score had nailfold capillary abnormalities, of whom 54 (78.3%) suffered from ED. Nine men (11.5%) had no nailfold capillary abnormalities, of whom six (66.7%) had ED (P = 0.44). ED was more frequent in older men (P = 0.002) and in men with diffuse disease (P = 0.06). Men with abnormal capillaroscopy had a higher median EULAR disease activity than men without (P = 0.02), a lower diffusing capacity of the lung (P = 0.001) and a higher modified Rodnan skin score (P = 0.04), but mean IIEF-5 scores did not differ [15.7 (S.D. 6.2) vs 15.7 (S.D. 6.3)]. IIEF-5 scores did not differ between men with early (n = 12), active (n = 27) or late (n = 27) patterns (IIEF-5 scores of 17.9, 16.3 and 14.7, respectively). There were no differences in the prevalence of early, active and late capillaroscopy patterns between men with or without ED. CONCLUSION: Neither the presence or absence of abnormal capillaroscopy findings nor the subdivision into early, active and late patterns is associated with coexistent ED in SSc.

Is there a role for TNFα antagonists in the treatment of SSc? EUSTAR expert consensus development using the Delphi technique.

OBJECTIVES: To obtain experiences and expert opinion on treatment of SSc patients with TNF-α antagonists. METHODS: An investigation was carried out among the EUSTAR centres into their expertise on use of TNF-α antagonists. Assessment forms on the frequency of TNF-α inhibitor use were distributed to EULAR Scleroderma Trials and Research Group (EUSTAR) centres. Afterwards, a three round Delphi exercise was performed to obtain expert consensus on the use of TNF-α inhibitors in SSc. RESULTS: Seventy-nine centres returned information on use of TNF-α antagonists in SSc patients. A total of 65 patients were treated with TNF-α inhibitors in 14 different centres. Forty-eight of the 65 patients treated with TNF-α inhibitors improved. Improvement was mainly seen in patients with arthritis, whereas the effects on fibrosis varied. In the first round of the subsequent Delphi approach, 71 out of 79 experts stated that they would use TNF-α antagonists in SSc. Arthritis was suggested as an indication for TNF-α antagonists by 75% of the experts. However, after the third stage of the Delphi exercise, the acceptance for the off-label use of TNF-α antagonists decreased and 59% recommended that TNF-α antagonists should not be used or only used in clinical trials in SSc patients, while 38% of the experts suggested the use of TNF-α antagonists for arthritis associated with SSc. CONCLUSIONS: Most of the experts do not recommend the routine use of TNF-α antagonists in systemic sclerosis. Arthritis might be a potential indication in SSc, although controlled clinical trials with TNF-α antagonists are needed before general recommendations can be given.

Aspectos clínicos novedosos en la esclerodermia / New clinical features in scleroderma

La esclerosis sistémica (ES) se caracteriza por ser una enfermedad cuyo manejo resulta, en muchas ocasiones, frustrante tanto para el paciente como para el médico, dada la falta de terapias eficaces. Resulta cuando menos esperanzador que en la última década se hayan producido novedades que nos ayudan a realizar un mejor seguimiento de los pacientes y que se hayan abierto las puertas hacia nuevas y futuras terapias (AU)

Systemic sclerosis (SS) is a disease whose handling is, in many occasions, frustrating for the patient as for the doctor, given the lack of effective therapies. It is hopeful at least, the fact that in the last decade new features have taken place that help us to make a better pursuit of the patients and who have opened the doors towards new and future therapies (AU)

A combined SDS-PAGE and proteomics approach to identify target autoantigens in healthy individuals and patients with autoimmune diseases.

We here present a method for the identification of antigens recognized by autoantibodies in healthy individuals and patients with autoimmune diseases. We have analyzed IgG reactivities from healthy individuals and patients with autoimmune diseases with endothelial cell antigens by combining a one-dimensional (1D) quantative immunoblotting technique and a 2D immunoblotting technique. Whole-cell protein extracts obtained from human umbilical vein endothelial cells (HUVEC) were used as a source of antigens. Serum IgG from healthy blood donors and from patients with autoimmune diseases were tested at a concentration of 200 microg/mL. One-dimensional immunoblotting was first performed to detect candidate reactivity bands and 2D immunoblotting was secondly performed following 2D electrophoresis to identify protein spots. The gels and 2D blots were scanned and analyzed by imaging software. The matching permitted exact localization of particular relevant protein spots hybridized by antibodies on the 2D blots. The targeted bands from 1D spots and the targeted spots from 2D gels were identified by Edman's N-terminal sequencing and mass spectrometry, respectively. This approach is applicable to both normal and pathological conditions, potentially leading to the identification of new relevant target antigens.

Anti-endothelial cell antibodies from patients with limited cutaneous systemic sclerosis bind to centromeric protein B (CENP-B).

By using a quantitative immunoblotting technique on protein extracts of human macrovascular and microvascular endothelial cells, we have analyzed the self-reactive repertoires of IgG from 20 patients with limited cutaneous SSc, 40 patients with diffuse SSc and 60 age- and sex-matched healthy controls. Serum IgG from 15/20 patients with limited cutaneous SSc and anti-centromere antibodies bound to at least one of the two 75- and 85-kDa protein bands in the different endothelial cell extracts, whereas IgG from healthy controls or patients with diffuse SSc did not. N-terminal sequencing of the 75- and 85-kDa bands identified CENP-B as the sole antigen in both bands. Moreover, IgG from all of the SSc patients who recognized the 75- and/or 85-kDa bands bound to a full-length recombinant CENP-B protein as assessed by ELISA, whereas IgG from other SSc patients did not. The main target of anti-endothelial cell antibodies in patients with limited cutaneous SSc is the nuclear and ubiquitous protein CENP-B.

IgG reactivity with a 100-kDa tissue and endothelial cell antigen identified as topoisomerase 1 distinguishes between limited and diffuse systemic sclerosis patients.

We have analyzed antibody (Ab) reactivities of patients with limited systemic sclerosis (SSc) and anti-centromere Ab, patients with diffuse SSc and anti-topoisomerase 1 (anti-topo 1) Ab, patients with diffuse SSc without anti-topo 1 or anti-centromere Ab and age- and gender-matched healthy controls with normal human tissue and endothelial cell (EC) antigens. IgG reactivities with tissue antigens differed significantly between patients with anti-topo 1 Ab and patients with anti-centromere Ab. One 100-kDa band identified as topoisomerase 1 in macrovascular and microvascular EC extracts was recognized by IgG from patients with anti-topo 1 Ab and 50% of patients without specific Ab. IgG from patients with limited SSc and anti-centromere Ab, but not those of other patients or controls specifically recognized a 80-kDa band only in microvascular EC. Our results indicate that Ab from patients with limited or diffuse SSc with or without anti-topo 1 Ab exhibit specific and mutually exclusive reactivity patterns.

IgM and IgG autoantibodies from microscopic polyangiitis patients but not those with other small- and medium-sized vessel vasculitides recognize multiple endothelial cell antigens.

Using a quantitative immunoblotting technique on extracts of macrovascular and microvascular endothelial cells (EC), we analyzed serum IgM and IgG reactivities of patients with active disease fulfilling the ACR and Chapel Hill criteria for the diagnosis of polyarteritis nodosa (PAN) (n = 8), PAN related to hepatitis B virus (HBV) infection (HBV-PAN) (n = 5), Wegener's granulomatosis (n = 6), microscopic polyangiitis (MPA) (n = 18), Churg-Strauss syndrome (n = 8), and patients with chronic HBV infection without PAN (n = 5) and age- and gender-matched healthy individuals (n = 45). MPA patients' IgM bound to 200-, 105-, 80-, 65-, 45-, 35-, and 33-kDa major bands, whereas IgM from controls and other patients bound predominantly to the 65-kDa band in EC extracts. MPA patients' IgG reacted mainly with 105-, 70-, 55-, and 38-kDa protein bands, whereas IgG from controls and other patients did not. Our results provide evidence that IgM and to a lesser degree IgG from MPA patients specifically recognize multiple EC antigens.

[Psychiatric manifestations of systemic sclerosis]. / Les manifestations psychiatriques de la sclérodermie.

Systemic sclerosis (SSc) is a rare conjuctive tissue disorder that is characterized by fibrosis of the skin and internal organs as well as vascular obliteration phenomenons. SSc is responsible for increased morbidity and mortality, and skin fibrosis may be responsible for major body changes. These phenomenons may contribute to the occurrence of psychological disturbances such as anxiety and depression, whereas the incidence of psychotic symptoms is very low in SSc patients. However, the prevalence of psychiatric symptoms during the course of SSc has not been evaluated yet with standardized evaluation scales, and an important breakthrough can be made in understanding the underlying mechanisms of psychiatric manifestations, in order to improve therapeutic management and quality of life.

[Long-term treatments for systemic sclerosis: what are the perspectives?]. / Traitements de fond de la sclérodermie systémique: quelles perspectives?

Systemic sclerosis (SSc) is responsible for fibrosis of the dermis and other organs as well as vascular abnormalities. While the pathogenesis of SSc is continually being better understood, there is still no single therapeutic agent that has been shown to increase survival in a prospective randomized trial. Traditional medications such as colchicine and D-penicillamine are disappointing in clinical practice, and the latter one failed to clearly show benefit when tested in a prospective placebo controlled trial comparing conventional high dose versus low dose. Conversely, new disease modifying agents are emerging such as cyclophosphamide (CYC) in interstitial pulmonary disease and stem cell autograft after high dose CYC therapy in patients who develop visceral involvement in the three first years of evolution of the disease. Organ specific therapy may show dramatic benefit, such as angiotensin converting enzyme inhibitors in renal crisis and epoprostenol in primary pulmonary hypertension. We will try to review disease modifying agents available in SSc and emphasize new therapeutic agents that are currently being evaluated, including vasodilators, anti-inflammatory, anti-fibrosing agents and immunosuppressive molecules.

[Pathogenesis of systemic scleroderma: immunological aspects]. / Pathogénie de la sclérodermie systémique: aspects immunologiques.

Systemic sclerosis (SSc) is a connective tissue disorder that is characterized by excessive collagen synthesis by fibroblasts and by vascular hyperreactivity and obliteration phenomena. Excessive collagen production is the consequence of abnormal interactions between endothelial cells, fibroblasts and mononuclear cells. Immunological abnormalities are present very early in the development of SSc. Mononuclear cells, particularily macrophages and T lymphocytes play a prominent role in fibroblast activation and collagen synthesis through the cytokines they produce. Thus, lymphocytic infiltrates in the skin and in the lung are preferentially composed of CD8+ T lymphocytes, that produce important amounts of interleukin 4 (IL-4). The effects of IL-4 are added to these of transforming growth factor B (TGF-B) and connective tissue growth factor (CTGF) that stimulate collagen synthesis by fibroblasts. T lymphocytes produce important amounts of gamma interferon (INF-gamma) that is the best inhibitor of collagen synthesis by fibroblasts. However, the inhibitory effect of INF-gamma on collagen synthesis is diminished in SSc patients. Numerous autoantibodies can be evidenced in the serum of SSc patients. Three of them are specific for SSc and mutually exclusive: anti-centromere antibodies (Ab) in limited SSc, anti-Scl70 Ab in diffuse SSc and anti-RNA polymerase III Ab in diffuse SSc with renal involvement. These autoantibodies are good prognosis markers but their pathogenic role remains uncertain.