Alina Dima

Is there still a place for erythrocyte sedimentation rate and C-reactive protein in systemic lupus erythematosus?

The inflammatory response during systemic lupus erythematosus (SLE) flares is known to be atypical, characterized by a disproportionately lower C-reactive protein (CRP) elevation when compared with erythrocyte sedimentation rate (ESR). Thus, in these patients, the analysis of inflammatory markers might be challenging in daily clinical practice. Clinicians need frequently to distinguish lupus reactivations and infectious conditions, and the significance of ESR and CRP seems to be different. Even though a non-specific marker of inflammation, ESR utility in SLE should not be neglected and it appears to be a useful biomarker for SLE activity assessment. Describing a specific cut-off for ESR in SLE is important for patients’ follow-up, and levels up to 25–30 mm/h have been proposed as an upper limit of the normal range. Regarding CRP, even though higher baseline levels are described in SLE when compared with controls, including in remission periods, its response during flares seems to be incomplete and not always correlated with disease activity; while CRP values greater than 10 mg/l could be indicative for severe flares, when there is no serositis or arthritis, higher CRP levels above 50–60 mg/l may be associated with infection.

Influence of decision-aids on oral anticoagulant prescribing among physicians: a randomized trial

Oral anticoagulants (OAC) are underused in treatment of atrial fibrillation (AF), with differences in patient and physician preferences. For risk communication, the graphic showing risks on treatment contains all the information, therefore, the graphic showing risks without treatment may not be necessary. Here, our objective was to assess whether decision aids require information of risks without treatment and specifically whether presentation of 5‐year stroke risk in patients with AF increases use of OACs compared with presentation of 1‐year risk and whether decisions on treatment are different when physicians decide their own treatment vs. that of the patient.

Association of common comorbidities with osteonecrosis: a nationwide population-based case–control study in Denmark

Objective To examine recent time trends in the incidence of osteonecrosis (ON) in Denmark and to investigate different common comorbidities association with ON in a population-based setting. Methods Using Danish medical databases, we included all patients with a first-time hospital diagnosis of ON during 1995–2012. Each ON case was matched with 10 randomly selected population control subjects from general population. For all participants, we obtained a complete hospital history of comorbidities included in the CharlsonComorbidity Index 5 years preceding the inclusion date. Results 4107 ON cases and 41 063 controls were included. The incidence of ON increased from 3.9 in 1995 to 5.5 in 2012 per 100 000 inhabitants. Solid cancer was the most common comorbidity, associated with an adjusted OR (aOR) for ON of 2.0 (95% CI 1.7 to 2.2). For advanced metastatic cancer, leukaemia and lymphoma, aORs of ON were 3.4 (95% CI 2.5 to 4.5), 4.3 (95% CI 2.7 to 7.0) and 5.8 (95% CI 4.3 to 7.8), respectively. Among other chronic conditions, aORs were 3.5 (95% CI 3.0 to 4.1) for connective tissue diseases and 2.3 (95% CI 2.0 to 2.7) for chronic pulmonary diseases. aORs were also increased at 2.8 (95% CI 1.9 to 4.1) and 4.5 (95% CI 2.5 to 8.2) for mild and moderate-to-severe liver disease, respectively, and 4.2 (95% CI 3.4 to 5.2) for renal disease. Conclusion This large population-based study provides evidence for an increasing ON incidence in the general population and documents an association between several common comorbid conditions and risk of ON.

Rheumatologic manifestations in celiac disease: what we should remember?

Data regarding celiac disease (CD) have advanced greatly in the past years. Described initially as a gastroenterological entity with rare occurrence, we now admit for CD a prevalence of 1% and systemic involvement [1–4]. However, CD remains still an underdiagnosed disease [3, 4] and awareness should be raised especially for its nondigestive, non-classical clinical presentation [2, 5]. Therefore, we aim to shortly review here the musculoskeletal involvements described in or associated with adult CD, useful for internal medicine practice. CD has some specific features: it is an immune (anti-deamidated gliadin antibodies – DGP) and autoimmune (anti-endomysial antibodies – EMA, anti-tissue transglutaminase antibodies – tTG) condition that occurs in genetic susceptible individuals (90–95% HLA-DQ2 and for the rest HLA-DQ8) [1, 3]. The main pathogenic process is developing in the intestinal mucosa by lymphocytic infiltration with subsequent destruction of the intestinal villi architecture. CD diagnosis should be confirmed by intestinal biopsy in patients with positive serology before initiating the gluten-free diet (GFD). The GFD is easily accessible and has good rates of response for the CD symptoms [3, 4]. When the intestinal histology features suggestive for CD are found in seronegative patients, differential diagnosis should include also other autoimmune diseases that might mimics CD, like autoimmune enteropathy, Graves or Hashimoto disease, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren’s syndrome or type I diabetes [4]. During the last years, the systemic involvement in CD was more studied and musculoskeletal manifestations were also described. Jericho et al. identified extra-intestinal manifestations in 62% adults and 60% children known with CD (interestingly, 9% adults and 18% children presented only extraintestinal CD manifestations) [6]. In the same study, an important number of adult patients presented musculoskeletal manifestations: arthralgia (16%), arthritis (15%), and myalgia (8%). After the introduction of the GFD, the rates of clinical response were important: 69% for arthritis, 54% for arthralgia, and 50% for myalgia [6]. In a recent meta-analysis that comprised data up to August 2016, Daron et al. found cumulative incidence of 18.3 (4.7–38.1)% for osteomalacia, 22.1 (7.9–40.9)% for arthritis, 30.3 (19.2–42.8)% for arthralgia, and 6.1 (0.5–17.0)% for bone pain [7]. Moreover, they showed higher cumulative incidence in CD when compared to controls of 16.6% vs. 9.9%, 9.8% vs. 4.2%, and 18.1% vs. 5.0% for unspecified site, femoral, and spinal osteoporosis, respectively [7]. The relative risk of any site osteoporosis in CD patients when compared to controls was 2.7 (1.9– 4.0) [7]. Results of meta-analysis showed that there is an association between CD and bone fracture [8,9]: 30% (CI 1.1–1.5) for any site and 69% (CI 1.1–2.6) increase in risk for the hip fracture [9]. Furthermore, in middle-aged women, the tTG-IgA positivity was associated with bone mass density loss and osteoporosis; fractures were more prevalent in cases with high tTG-IgA levels [10]. Nuti et al. included in their research only women with osteoporosis and identified significant lower serum vitamin D in patients with positive AGA and tTG: 17.8 vs. 55.1 nmol/L [11]. The pathogenic mechanisms involved in osteopenia/ osteoporosis in CD are mainly related to vitamin D and calcium malabsorption due to villous atrophy. These are added to secondary hyperparathyroidism in patients with hypocalcemia, systemic inflammation with high serum levels of proinflammatory cytokines (IL-1, IL-6, TNF-alpha) as well as to hypogonadism and sexual hormones metabolism disturbances that also have impact on the bone turnover [1]. However, the risk of osteoporosis seems to be equal for both women and

Antiphosphatidylethanolamine Antibodies and Deep Vein Thrombosis in Lupus Patients with Antiphospholipid Syndrome

Abstract Backgroud. Which factors determine venous thrombotic events in some antiphospholipid syndrome (APS) patients and arterial thrombosis or conditions related to pregnancy in others has not been established yet. Purpose. The aim of this study was to search the antiphospholipid antibodies (APLAs) correlates in regard to deep vein thrombosis (DVT) in patients with systemic lupus erythematosus (SLE) and APS. Methods. Twenty-nine patients fulfilling the criteria of both SLE and APS were included. Complete anamnesis and clinical examination was performed on inclusion. Also, for all patients, disease activity was assessed by the SLEDAI score. An extended APLAs profile, ten Abs, was searched. Results. The titers of IgG anticardiolipin (aCL), IgG anti-β2 glycoprotein I (aβ2GPI), IgG antiphosphatidylethanolamine (aPE), and also of IgG antiprothrombin (aPT) were significant higher in patients with DVT history. After analysis by ROC curve and univariate logistic regression, the strongest association was found for IgG aPE. Also, in multivariate analysis, SLEDAI score correlated with the DVT antecedents. Conclusions. IgG aPE might be involved in DVT pathogenic pathways in patients with SLE and APS as their titers remain significantly higher in patients with previous DVT. Lupus patients with DVT events represent a subgroup of patients with more severe underlying pathology.

Impaired ankle-brachial index in antiphospholipid syndrome: Beyond the traditional risk factors

The patients with antiphospholipid syndrome (APS) associate an increased risk of atherosclerosis.

Salivary biomarkers of inflammation in systemic lupus erythematosus

Saliva is currently used as a reliable diagnostic fluid in a wide range of local and systemic diseases. However, the link between salivary diagnosis and the inflammatory process in autoimmune diseases has not yet been explored. The aim of our study is to assess possible correlations between salivary inflammatory markers and systemic lupus erythematosus (SLE). Patients fulfilling the Systemic Lupus International Collaborating Clinics (SLICC) diagnosis criteria were included. Salivary and serum levels of interleukin-6 (IL-6), leptin, monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) were determined using stochastic sensors. Serum leptin and IL-6 had significantly higher levels in SLE patients compared to non-SLE. Also, salivary IL-6 levels highly correlated with the serum IL-6 levels. A positive correlation was found between salivary and serum levels of IL-6, signaling salivary IL-6 as a reliable marker for assessing the inflammation process in SLE.

Immune and autoimmune gluten-related phenomenon in systemic lupus erythematosus

Sir, Although systemic lupus erythematosus (SLE) and celiac disease (CD) might share common genetic features, their concomitance was only occasionally presented, mostly as case reports. The SLE risk of occurrence appears to be increased three-fold in CD when compared with the general population, but the absolute excess of risk proved to be actually low. In relation to CD serology in lupus, positive anti-deamidated gliadin peptides antibodies (DGPs) seem commonly encountered. Immunoglobulin (Ig)A and IgG DGPs were found in 23% to 29% lupus patients. Occurrence of both DGP and anti-tissue transglutaminase antibodies (tTGs) was found in 8% of SLE patients. Moreover, anti-endomysium antibodies (EMAs) IgA serotype seem associated with lupus disease. Our aim was to evaluate the gluten-induced immune and autoimmune phenomenon in SLE patients. Therefore, quantitative determination of serum IgA, tTG-IgA, DGP, and EMA was done in 126 SLE patients. None of the patients were previously diagnosed with CD and they all consumed a gluten-containing diet. At inclusion, 14 patients (11.1%) followed a treatment with azathioprine, 2 patients (1.6%) with mycophenolate mofetil, and 1 patient (0.8%) with methotrexate or cyclophosphamide. A total of 104 patients (82.5%) were under corticosteroids, with a median daily prednisone dose of 10mg and a similar proportion of patients, 82.5% presented hydroxychloroquine treatment. Variables were presented as median (med) and quartile (q) 1; 3 and the non-parametric Spearman’s rho coefficient (r) was used in all univariate correlations. Differences of sub-groups characteristics were assessed by a Mann Whitney test. Ethical approval was obtained from Colentina Hospital and Institute for Mother and Child Care, Bucharest, Romania, and written informed consent was obtained in all cases. All samples analyzed presented total serum IgA of more than 0.07 g/l. Serum levels of IgA, tTGIgA, and DGP found were: 2.73 (2.09; 3.63) g/l, 6.5 (5.0; 9.0) U, and 8.0 (5.0; 11.0) U respectively. Overall, four samples were positive for tTG-IgA (cut-off: 20 U), 6 for DGP (cut-off: 20 U), and one for EMA (serum dilution titer 1:200, cut-off 1:5), corresponding to 3.2%, 4.8%, and 0.8% prevalence of gluten-induced antibodies in lupus, respectively. tTG-IgA levels were correlated with those of total IgA and DPG (r1⁄4 0.602; p< 0.001 and r1⁄4 0.603; p< 0.001). Among patients with positive tTG-IgA, one had antiphospholipid syndrome (APS), one Sjogren’s syndrome (S’sS), while none had autoimmune thyroiditis (AT). Moreover, in those with positive DGP, one patient had APS, one patient had S’sS, and none had AT. With regard to SLE’s clinical criteria, we found significantly higher tTG-IgA titers in patients presenting with hematological involvement at inclusion: 8.0 (6.0; 11.0) U versus 6.0 (5.0; 8.0) U, p1⁄4 0.004. No significant differences in relation to other active clinical involvements were found for tTG-IgA. No correlation of DGP with any lupus clinical features was identified. Moreover, tTG-IgA titers proved to be indirectly correlated with leucocytes (r1⁄4 0.196, p1⁄4 0.029) and lymphocytes (r1⁄4 0.235, p1⁄4 0.008), but not with hemoglobin levels or platelet counts (p> 0.05). As to parameters related to immune activity, we found that tTG-IgA levels were indirectly correlated to C4 complement (r1⁄4 0.238, p1⁄4 0.011). DGP titers again correlated to both C4 and C3 fractions (r1⁄4 0.319, p1⁄4 0.005 and r1⁄4 0.229, p1⁄4 0.044). tTG-IgA and EMA are considered highly CD-specific. Our finding of 3% positivity for tTG-IgA in SLE is higher than by chance alone as reported CD prevalence is around 1%. Our data are intriguing, although no control group was available for this study. Our results indicate gluten-induced immune phenomenon to occur in patients with SLE. However, low positive but unspecific titers of tTG-IgA have been detected in other pathologies including autoimmunity, while EMA is more specific for CD. In the present study EMA positivity was at 0.8%, similar to the general population. CD prevalence in SLE patients could not be defined in the present study due to no available endoscopic confirmation of gluteninduced small-intestinal mucosal injury. Correspondence to: A Popp, Institute for Mother and Child Care, Lacul Tei Street 120, 020395 Bucharest, Romania. Email: alina.popp@uta.fi Received 10 July 2016; accepted 21 February 2017

Extended Antiphospholipid Antibodies Screening in Systemic Lupus Erythematosus Patients

Abstract Background. The antiphospholipid syndrome (APS) is one of the most encountered autoimmunity in systemic lupus erythematosus (SLE) patients and pathogenesis of these two seems to be intricate. Aim. To investigate the association of antiphospholipid antibodies (APLAs) titer with the presence of secondary APS diagnosis in SLE patients. Methods. 65 patients fulfilling the 2012 Systemic Lupus Collaborating International Clinics (SLICC) SLE’s criteria were included. The APS diagnosis was sustained according to the 2006 Sydney APS’s criteria. Three groups of patients were defined: SLE patients with secondary APS, SLE with history of positive “criteria” APLAs but without APS clinical features, respectively SLE patients without positive APLAs or clinical APS criteria. An extended APLAs panel was searched in all cases: both IgM and IgG of anticardiolipin antibodies (aCL), anti-β2 glycoprotein I antibodies (aβ2GPI), antiphosphatidylethanolamine antibodies (aPE), antiphosphatidylserine antibodies (aPS), respectively antiprothrombin antibodies (aPT). Results. Only the aβ2GPI, both IgM and IgG serotypes, had significantly higher titers in patients with SLE and secondary APS compared to no APS (with/without positive APLAs): median (min; max) 7.0 (0.0-300.0) vs. 1.0 (0.0-28.0) vs. 1.0 (0.0-12.0), respectively 3.0 (0.0-79.0) vs. 1.0 (0.0-3.0) vs. 1.0 (0.0-12.0) (p<0.001, Kruskal-Wallis test)]. Also, in regression logistic models, only the aβ2 GPI (IgG and IgM) were identified as risk factors for secondary APS diagnosis in the SLE patients: OR(95%CI) 5.9 (2.2-15.7), respectively 1.3 (1.1-1.5). In regard with the SLE markers, the IgG serotypes of the “non-criteria” APLAs analyzed (aPS, aPT, aPE) were correlated with the antiDNA titers while the IgM serotypes inversely associated with the complement C3 levels. Conclusions. IgG aβ2 GPI are accompanied by almost 6-fold increase risk of secondary APS when screening SLE patients. On the contrary, the “non-criteria” APLAs do not seem associated with the APS diagnosis in SLE patients. Some correlates of the “non-criteria” APLAs with the antiDNA and complement C3 levels were also observed.