Ioana Ruiz-Arruza

Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: Report of a Task Force at the 13th International Congress on Antiphospholipid Antibodies:

The antiphospholipid syndrome (APS) is defined by the presence of thrombosis and/or pregnancy morbidity in combination with the persistent presence of circulating antiphospholipid antibodies: lupus anticoagulant, anticardiolipin antibodies and/or anti-β2-glycoprotein I antibodies in medium to high titers. The management of thrombosis in patients with APS is a subject of controversy. This set of recommendations is the result of an effort to produce guidelines for therapy within a group of specialist physicians in Cardiology, Neurology, Hematology, Rheumatology and Internal Medicine, with a clinical and research focus on APS.

Predictors of major infections in systemic lupus erythematosus

IntroductionInfections commonly complicate the course of systemic lupus erythematosus (SLE). Our aim is to investigate the clinical predictors of major infections in patients with SLE.MethodsA nested case–control study design was used within the prospective Lupus-Cruces cohort. The endpoints of the study were major infections. Cases were defined as patients with a major infection. Two controls (SLE patients without major infections), matched for time of follow-up until the event and age at diagnosis, were selected for each case. Univariate analysis and logistic regression models were used for the analysis of data.ResultsTwo hundred and forty-nine patients (83 cases, 166 controls) were selected. Eighty-three episodes of major infections were analyzed; E. coli, S. aureus, M. tuberculosis and S. pneumoniae being the most frequent isolates. Univariate analysis identified several variables related with infection: lung and renal involvement, at or previous to the study point; leukopenia at the study point; antiphospholipid antibody-positivity and treatment with prednisone within 3 months previous to the study point, and the dose of prednisone received. Treatment with antimalarials, on the other hand, showed a strong inverse association with major infections. Logistic regression models identified treatment with antimalarials (odds ratio (OR) = 0.06, 95% confidence interval (CI) = 0.02 to 0.18), prednisone dose (OR = 1.12, 95% CI = 1.04 to 1.19) and lung involvement (OR = 4.41, 95% CI = 1.06 to 18.36) as significant and independent predictors of major infections. No significant interactions among these three variables were found. Further adjustment for potential confounders related with antimalarial treatment did not change the results.ConclusionsThe risk of major infections in patients with SLE is mostly influenced by treatment. Prednisone treatment, even at moderate doses, increases the risk, whilst antimalarials have a protective effect.

Glucocorticoids and irreversible damage in patients with systemic lupus erythematosus

OBJECTIVE The aim of this study was to analyse the relationship between glucocorticoids and damage accrual in SLE. METHODS We report an observational cohort study including 230 patients with SLE enrolled at diagnosis with 5 years of follow-up. Damage was calculated using the SLICC damage index. Glucocorticoid-related damage was defined as avascular osteonecrosis, osteoporotic fractures, diabetes mellitus or cataracts. Prednisone doses were calculated at the end of the fourth year of follow-up (prednisone-4). A categorical prednisone-4 variable was constructed: no prednisone, ≤7.5 mg/day (low dose), >7.5 mg/day (medium-high dose). The relationship between methylprednisolone pulses and damage was also tested. RESULTS By the fifth year, 188 patients (82%) had been treated with prednisone. Eighty-seven patients (37.8%) had accrued damage at 5 years. Patients with damage at year 5 had received a higher mean daily prednisone-4 dose (10.4 vs 6 mg/day, P < 0.001). The mean daily prednisone-4 dose was higher in patients accruing glucocorticoid-attributable damage (11 vs 7 mg/day, P = 0.04). Patients taking medium-high doses of prednisone-4 had a higher risk of accruing damage than those taking no prednisone [adjusted odds ratio (OR) 5.39, 95% CI 1.59, 18.27]. Patients taking medium-high doses of prednisone-4 were more likely to develop glucocorticoid-related damage than those on no prednisone (adjusted OR 9.9, 95% CI 1.1, 84). No differences were seen between patients on low doses and those on no prednisone. The cumulative dose of i.v. methylprednisolone-4 was not associated with global or glucocorticoid-related damage. CONCLUSION Prednisone causes damage in SLE. Doses <7.5 mg/day and methylprednisolone pulses are not associated with damage accrual.

Comparison of high versus low–medium prednisone doses for the treatment of systemic lupus erythematosus patients with high activity at diagnosis

OBJECTIVE To compare the efficacy and safety of high vs. low-moderate oral doses of prednisone to treat patients with highly active lupus at diagnosis. PATIENTS AND METHODS Patients from the Lupus-Cruces cohort with an SLEDAI score ≥6 at diagnosis and treated with regimes containing low-medium prednisone doses (≤30 mg/day) were identified (group M). They were matched by sex and SLEDAI score with historical patients treated with high doses (>30 mg/day) at diagnosis (group H). Patients with proliferative nephritis were excluded. The difference in SLEDAI scores between baseline (SLEDAI-0) and year one (SLEDAI-1) was the efficacy variable. Damage at 5 years was calculated using the SLICC damage index (SDI) and regarded as the safety variable. Glucocorticoid related damage was considered in the presence of cataracts, osteonecrosis, osteoporotic fractures and/or diabetes mellitus. RESULTS 30 patients were included in each group. Patients in group H received 5-fold higher doses of prednisone, less hydroxychloroquine and less methyl-prednisolone pulses. SLEDAI improvement was similar in both groups. Patients in group H were more likely to accrue new damage (adjusted HR 3.85 (95% CI 1.03-14.2)). No patients in group M suffered glucocorticoid-related damage, vs. 5 patients in group H (p=0.02). The average daily prednisone dose during the first year predicted accrual of new damage (adjusted HR 1.03, 95% CI 1.0-1.07, p=0.056) and accrual of glucocorticoid-related damage (adjusted HR 1.06, 95% CI 1.01-1.13, p=0.03). Likewise, average doses of prednisone >7.5mg/day were an independent predictor of new damage (adjusted HR 4.8, 95% CI 1.2-19.1). CONCLUSION Prednisone doses ≤30 mg/day are similarly effective and safer than higher doses for treating active lupus.

Evaluation of phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome: results of an international multicentre study.

Objective A task force of scientists at the International Congress on Antiphospholipid Antibodies recognized that phosphatidylserine-dependent antiprothrombin antibodies (aPS/PT) might contribute to a better identification of antiphospholipid syndrome (APS). Accordingly, initial and replication retrospective, cross-sectional multicentre studies were conducted to ascertain the value of aPS/PT for APS diagnosis. Methods In the initial study (eight centres, seven countries), clinical/laboratory data were retrospectively collected. Serum/plasma samples were tested for IgG aPS/PT at Inova Diagnostics (Inova) using two ELISA kits. A replication study (five centres, five countries) was carried out afterwards. Results In the initial study (n = 247), a moderate agreement between the IgG aPS/PT Inova and MBL ELISA kits was observed (k = 0.598). IgG aPS/PT were more prevalent in APS patients (51%) than in those without (9%), OR 10.8, 95% CI (4.0–29.3), p < 0.0001. Sensitivity, specificity, positive (LR+) and negative (LR–) likelihood ratio of IgG aPS/PT for APS diagnosis were 51%, 91%, 5.9 and 0.5, respectively. In the replication study (n = 214), a moderate/substantial agreement between the IgG aPS/PT results obtained with both ELISA kits was observed (k = 0.630). IgG aPS/PT were more prevalent in APS patients (47%) than in those without (12%), OR 6.4, 95% CI (2.6–16), p < 0.0001. Sensitivity, specificity, LR + and LR– for APS diagnosis were 47%, 88%, 3.9 and 0.6, respectively. Conclusions IgG aPS/PT detection is an easily performed laboratory parameter that might contribute to a better and more complete identification of patients with APS.

Dexamethasone intravitreal implants in the management of tubercular multifocal serpiginoid choroiditis

BackgroundContinuous progression of lesions despite an adequate treatment has been described in tubercular multifocal serpiginoid choroiditis. Reported treatments for this paradoxical response include systemic steroids, immunosuppressive drugs, and intravitreal methotrexate. We describe the use of dexamethasone intravitreal implants in a patient presenting with this condition.FindingsA 46-year-old woman sought medical attention for scotomas in her left eye. Tests suggested multifocal serpiginoid choroiditis associated with latent tuberculosis infection, and hence, she was started on anti-tuberculosis drugs in combination with corticosteroids. Given that lesions progressed despite this treatment, we began treatment with dexamethasone intravitreal implants. After injection of the second implant, we succeeded in inactivating the inflammatory process.ConclusionsDexamethasone intravitreal implants may be a suitable alternative to systemic steroids or immunosuppressive therapy in the management of continuous progression of lesions in tubercular multifocal serpiginoid choroiditis.

New insights into the genetic component of non-infectious uveitis through an Immunochip strategy

Background Large-scale genetic studies have reported several loci associated with specific disorders involving uveitis. Our aim was to identify genetic risk factors that might predispose to uveitis per se, independent of the clinical diagnosis, by performing a dense genotyping of immune-related loci. Methods 613 cases and 3693 unaffected controls from three European case/control sets were genotyped using the Immunochip array. Only patients with non-infectious non-anterior uveitis and without systemic features were selected. To perform a more comprehensive analysis of the human leucocyte antigen (HLA) region, SNPs, classical alleles and polymorphic amino acid variants were obtained via imputation. A meta-analysis combining the three case/control sets was conducted by the inverse variance method. Results The highest peak belonged to the HLA region. A more detailed analysis of this signal evidenced a strong association between the classical allele HLA-A*2902 and birdshot chorioretinopathy (p=3.21E-35, OR=50.95). An omnibus test yielded HLA-A 62 and 63 as relevant amino acid positions for this disease. In patients with intermediate and posterior uveitis, the strongest associations belonged to the rs7197 polymorphism, within HLA-DRA (p=2.07E-11, OR=1.99), and the HLA-DR15 haplotype (DRB1*1501: p=1.16E-10, OR=2.08; DQA1*0102: p=4.37E-09, OR=1.77; DQB1*0602: p=7.26E-10, OR=2.02). Outside the HLA region, the MAP4K4/IL1R2 locus reached statistical significance (rs7608679: p=8.38E-07, OR=1.42). Suggestive associations were found at five other loci. Conclusions We have further interrogated the association between the HLA region and non-infectious non-anterior uveitis. In addition, we have identified a new non-HLA susceptibility factor and proposed additional risk loci with putative roles in this complex condition.

A restrictive use of oral glucocorticoids in systemic lupus erythematosus prevents damage without worsening long-term disease control: An observational study

To analyze the influence of 2 different treatment strategies on general and specific damage accrual in patients with systemic lupus erythematosus (SLE).

Predictors of peripheral arterial disease in SLE change with patient’s age

Objective To analyse the differential influence of risk factors of peripheral artery disease (PAD) according to age in patients with SLE. Methods 216 patients from the Lupus-Cruces cohort were divided in three age groups: ≤34 years, 35–49 years and ≥50 years. A low ankle–brachial index defined PAD. Significant variables were identified by univariant and multivariant analysis in each age group. Results Different factors were identified in different age groups: antiphospholipid antibodies/antiphospholipid syndrome and glucocorticoids in patients ≤34 years; in patients 35–49 years old, hypertension was the only statistically significant predictor, although a trend was observed for fibrinogen levels; a trend was observed for hypercholesterolaemia in those ≥50 years. Conclusions Age may modulate the influence of risk factors for PAD in patients with SLE.

Specific association of IL17A genetic variants with panuveitis

Background/aims A pathogenic role of Th17 cells in uveitis has become clear in recent years. Therefore, in the present study, we aimed to evaluate the possible influence of the IL17A locus on susceptibility to non-anterior uveitis and its main clinical subgroups. Methods Five IL17A polymorphisms (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909), selected by tagging, were genotyped using TaqMan assays in 353 Spanish patients with non-anterior uveitis and 1851 ethnically matched controls. Results The case/control analysis yielded a consistent association between two of the analysed genetic variants, rs8193036 and rs2275913, and the presence of panuveitis under a dominant model (pFDR=2.86E-03, OR=2.26, 95% CI 1.42 to 3.59 and pFDR=0.033, OR=1.83, 95% CI 1.13 to 2.97, respectively). Subsequently, a specific association of both polymorphisms with the diffuse form of the disease was evident in the subphenotype analysis when considering this same genetic model (panuveitis vs posterior and intermediate uveitis: rs8193036, p=0.020; rs2275913, p=0.038). Independent effects of rs8193036 and rs2275913 were observed by conditional regression analysis. Conclusions Polymorphisms within the IL17A locus show a novel association with panuveitis. Our data agree with the elevated levels of this cytokine that are found in patients with uveitis, supporting a crucial role of Th17 cells in this pathology. Subtitle Our results clearly evidenced the role of IL17A as a novel genetic risk factor for panuveitis, thus suggesting the implication of Th17 cells in the extensive inflammation of the uveal tract that occurs in this subtype of uveitis.