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Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data

Adverse effects of glucocorticoids have been abundantly reported. Published reports on low dose glucocorticoid treatment show that few of the commonly held beliefs about their incidence, prevalence, and impact are supported by clear scientific evidence. Safety data from recent randomised controlled clinical trials of low dose glucocorticoid treatment in RA suggest that adverse effects associated with this drug are modest, and often not statistically different from those of placebo.

Undifferentiated connective tissue disease: a seven-center cross-sectional study of 184 patients

The purpose of this study was to characterize the clinical and serological features of a large cohort of patients with antinuclear antibody (ANA) positive undifferentiated connective tissue disease (UCTD). Consecutive patients with UCTD, followed up at the Rheumatology Clinic of the participating centers, were included. Data from these patients were obtained by clinical evaluation and chart review. All patients were diagnosed as having UCTD on basis of the following criteria: positive ANA plus at least one clinical feature of connective tissue disease, but not fulfilling classification criteria for any differentiated connective tissue disease. One hundred eighty-four patients were studied (female patients—94.5%; mean age at time of evaluation—47xa0years). The most prevalent manifestations were arthralgia (66%), arthritis (32%), Raynaud’s phenomenon (30%), sicca symptoms (30%), and leukopenia (19%). The prevalence of ANA was 100%, anti-SSA 20%, anti-dsDNA 14%, and anti-SSB 7%. Patients with anti-dsDNA/anti-Sm, anticentromere/anti-Scl70, or anti-SSA/anti-SSB antibodies more frequently presented a set of manifestations close to systemic lupus erythematosus (SLE), systemic sclerosis, or Sjögren syndrome, respectively. We analyze a large cohort of UCTD. Seventy-two percent of these UCTD patients present lupus-, scleroderma-, or Sjögren-like features but do not fulfill classification criteria and mostly present a mild disease.

NK cells dysfunction in systemic lupus erythematosus: relation to disease activity.

Through their cytotoxic capacities and cytokine production, natural killer (NK) cells modulate autoimmune diseases. However, their role in the pathogenesis of systemic lupus erythematosus (SLE) has not been extensively studied. The aim of this study was to analyse the immunophenotypic and functional characteristics of the two major NK cell subsets in SLE and relate them with disease activity. Peripheral blood samples from 44 patients with active (nu2009=u200918) and inactive SLE (nu2009=u200926) and 30 controls were analysed by flow cytometry to evaluate NK cell subsets, according to: the differential expression of CXCR3 and CD57; expression of granzyme B and perforin; and production of interferon gamma (IFN-γ) and tumor necrosis alpha (TNF-α), after PMA/ionomycin activation. A clear decrease in absolute and relative numbers of circulating NK cells was found in SLE, particularly in active disease, while the proportions of the major NK cell subsets were unaffected. Active SLE was associated with a reduced CXCR3 expression on both NK cell subsets and a lower frequency of CD56dim NK cells expressing CXCR3. Furthermore, granzyme B expression was decreased in both SLE groups, but the percentage of NK cells expressing granzyme B and perforin was higher, particularly in active disease. We found a significant decrease in the percentage of CD56bright and CD56dim NK cells producing TNF-α and of its expression on CD56dim NK cells in active disease, while IFN-γ expression on CD56bright NK cells was increased in both SLE groups. Our findings suggest that NK cell subsets exhibit unique phenotypic and functional changes that are particularly evident in active SLE, and they may have the potential to affect the disease outcome.

Differential male and female adrenal cortical steroid hormone and cortisol responses to interleukin-6 in humans

Abstract: Evidence from experimental animal studies show that sex hormones influence the glucocorticoid response to a variety of inflammatory and noninflammatory stimuli. In this study we assessed gender differences in the response of ACTH and cortisol in normal young male and female humans following intravenous infusion of human IL‐6 in various dosages. Males presented a significantly stronger ACTH production in response to IL‐6 than females. Peak cortisol response, however, was similar in males and females. Cortisol/ACTH ratios were significantly higher in females than in males, both at baseline and after each of the IL‐6 dosages. These results suggest that an effective glucocorticoid response requires similar levels of IL‐6 in males and females. However, they also suggest that the adrenals of males and females have different sensitivities to ACTH (higher in females) and possibly also to direct IL‐6 stimulation.

CD38, CD81 and BAFFR combined expression by transitional B cells distinguishes active from inactive systemic lupus erythematosus.

AbstractnIn view of its heterogeneous presentation and unpredictable course, clinical management of systemic lupus erythematosus (SLE) is difficult. There is a need for biomarkers and diagnostic aids to monitor SLE disease activity and severity prior to, during and after treatment. We undertook this study to search for unique phenotypic patterns in each peripheral blood (PB) B cell subset, capable of distinguishing SLE patients with inactive disease versus SLE patients with active disease versus controls by using an automated population separator (APS) visualization strategy. PB was collected from 41 SLE patients and 28 age- and gender-matched controls. We analyzed the cell surface markers (in a tube CD20/CD27/CD19/CD45/CD38/CD81/BAFFR combination) expression on PB B cell subsets using principal component analysis, implemented in the APS software tool. Overall, our analysis indicates that active SLE can be distinguished from inactive SLE on the basis of a single tube analysis, focused on the decreased expression of CD38, CD81 and BAFFR in transitional B cells. The cluster analysis of immunophenotypic profiles of B cell subsets highlighted disease-specific abnormalities on transitional B cells that emerge as promising surrogate markers for disease activity. Further validation is needed with larger samples and prospective follow-up of patients.

Sera from patients with active systemic lupus erythematosus patients enhance the toll-like receptor 4 response in monocyte subsets

BackgroundSystemic Lupus Erythematosus (SLE) is an auto-immune disease whose complex pathogenesis remains unraveled. Here we aim to explore the inflammatory ability of SLE patients’ sera upon peripheral blood (PB) monocyte subsets and myeloid dendritic cells (mDCs) obtained from healthy donors.MethodsIn this study we included 11 SLE patients with active disease (ASLE), 11 with inactive disease (ISLE) and 10 healthy controls (HC). PB from healthy donors was stimulated with patients’ sera, toll-like receptor (TLR) 4 ligand – lipopolysaccharide or both. The intracellular production of TNF-α was evaluated in classical, non-classical monocytes and mDCs, using flow cytometry. TNF-α mRNA expression was assessed in all these purified cells, after sera treatment.ResultsWe found that sera of SLE patients did not change spontaneous TNF-α production by monocytes or dendritic cells. However, upon stimulation of TLR4, the presence of sera from ASLE patients, but not ISLE, significantly increased the intracellular expression of TNF-α in classical and non-classical monocytes. This ability was related to titers anti-double stranded DNA antibodies in the serum. High levels of anti-TNF-α in the patients’ sera were associated with increased TNF-α expression by co-cultured mDCs. No relationship was found with the levels of a wide variety of other pro-inflammatory cytokines. A slight increase of TNF-α mRNA expression was observed in these purified cells when they were cultured only in the presence of SLE serum.ConclusionsOur data suggest that SLE sera induce an abnormal in vitro TLR4 response in classical and non-classical monocytes, reflected by a higher TNF-α intracellular expression. These effects may be operative in the pathogenesis of SLE.

Multitarget therapy of mycophenolate mofetil and cyclosporine A for induction treatment of refractory lupus nephritis

Standard induction therapy for lupus nephritis (LN) with mycophenolate mofetil (MMF) or cyclophosphamide (CYC) is often ineffective. Evidence on rescue induction regimens is scarce. We analyzed efficacy and tolerability of multitarget immunosuppression with MMF and cyclosporine A (CsA) as induction treatment for LN (class III/IV/V) refractory to CYC and/or MMF. We included all six refractory LN patients (class IVu2009=u20093, class Vu2009=u20092, class IIIu2009=u20091) from our 400-patient tertiary Lupus Clinic observed between 2012 and 2015. Four patients had previously received pulse CYC. All six received MMF as first or second induction therapy and CsA was added once failure to reach remission was established. Daily dose of MMF was 2–3u2009g and CsA was dosed up to 2.6–3.7u2009mg/kg/day. Mean proteinuria was reduced from 2407u2009mg/24 hours at the start of the MMF+CsA regimen to 544u2009mg/day after six months. The mean prednisolone dose was reduced from 17.5 to 6u2009mg/day after six months of MMF+CsA. Four patients achieved a complete renal response, one patient had a partial renal response and one failed to respond. None of the patients presented with adverse events. These data suggest that adding CsA to MMF can induce complete remission of refractory LN and is well tolerated.

Risk of damage and mortality in SLE patients fulfilling the ACR or only the SLICC classification criteria. A 10-year, inception cohort study

Objective To compare damage and mortality, from inception up to 10-year follow-up, between SLE patients meeting at baseline the 1997 ACR criteria or only the 2012 SLICC classification criteria. Methods Patients fulfilling the ACR and/or the SLICC classification criteria for SLE were enrolled at inception and followed-up to 10 years at an academic lupus clinic. Damage was defined as SLICC Damage Index (SDI) score ≥1. We assessed with multivariate Cox models the damage and mortality outcomes, according to SLE classification status at inception, adjusting for potential baseline confounders. Results We recruited 192 patients (69.8% fulfilling at inception the ACR criteria and 30.2% only the SLICC criteria). During follow-up, 24.0% of patients accrued organ damage and 4.2% died. Patients meeting ACR criteria compared to those with SLICC criteria alone presented during follow-up with more cases of lupus nephritis (35.1% versus 13.8%, pu2009<u20090.01), but less thrombotic antiphospholipid syndrome (4.5% versus 17.2%, pu2009<u20090.01). The Cox models showed no significant differences in risk for damage [hazard ratio (HR) (95% CI) 0.991 (0.453–2.167)] or death [hazard ratio (HR) (95% CI) 0.694 (0.107–4.506)] between groups. Conclusion The SLE classification status at inception identified different patterns of clinical phenotype, but did not influence damage accrual or mortality up to 10-year follow-up.

OP0206 Performance of SLEDAI-2K to detect a clinically meaningful change in SLE disease activity: a 36-month prospective cohort study of 334 patients

Background The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) is the core determinant of response in the SLE Responder Index (SRI), a primary efficacy outcome in SLE clinical trials. However, SLEDAI is unable to discriminate partial improvement/worsening, as it scores each item categorically. Furthermore, potentially severe lupus manifestations, such as hemolytic anemia are not scored in SLEDAI. Objectives To evaluate the performance of SLEDAI-2K to detect a clinically meaningful change in SLE disease activity. Methods Prospective cohort study of SLE patients followed at a tertiary care lupus clinic from January 2014 to December 2016. Consecutive patients fulfilling the ACR97 and/or the SLICC12 classification criteria were included. At each outpatient visit, disease activity from the last 30 days was scored in the Physician Global Assessment (PGA) (0–3 cm scale) and in SLEDAI-2k. The association between PGA and SLEDAI-2K at each visit was tested with Spearmans Correlation. A clinically meaningful change in SLE disease activity was defined as difference in PGA ≥0.3 cm at follow-up compared to the baseline visit. Performance of change in SLEDAI-2K was tested in two models: against worsening and improvement in PGA ≥0.3 cm from baseline using Receiver Operating Characteristic (ROC) curve analysis. Sensitivity, specificity, positive and negative predictive values (PPV, NPV) of SLEDAI-2k to change in PGA was calculated. Statistical significance was set at 0.05. Results We included 334 patients (87.1% female, mean age at baseline - 44.8±14.5 years). At baseline, median PGA and SLEDAI-2k score was 0.2 points (range 0–2.5) and 2 points (range 0–19), respectively. Eighty-three patients (24.8%) had a PGA ≥0.4 points at baseline. During follow-up of 36 months, 2129 visits were performed. PGA and SLEDAI-2K scores presented a high correlation (rho=0.82, p<0.0001) (fig. 1). Reductions in SLEDAI-2K presented in ROC analysis an area under curve (AUC) of 0.697 [95% CI (0.628–0.766), p<0.0001] for an improvement in PGA≥0.3. For a worsening of PGA≥0.3 points, increase in SLEDAI-2K presented an AUC of 0.877 [95% CI (0.822–0.932), p<0.0001]. Estimated sensitivities, specificities, PPV and NPV are presented in table 1.Table 1. Performance of Sledai-2K to detect a clinically meaningful change in PGA, using cut-offs of decrease and increase (for a clinical improvement and worsening, respectively) in SLEDAI-2K ≥1 and ≥4 points Δ SLEDAI-2K≥1 Δ SLEDAI-2K≥4 Sens. Spec. PPV NPV Sens. Spec. PPV NPV Improvement PGA≥0.3 0.7 0.571 0.397 0.825 0.288 0.929 0.622 0.763 Worsening PGA≥0.3 0.725 0.903 0.627 0.936 0.353 0.996 0.947 0.873 Sens: Sensitivity; Spec: Specificity; PPV: Positive predictive value; NPV: Non predictive value. Conclusions SLEDAI-2K presents a limited performance in detecting a clinically meaningful change in SLE disease activity, failing to identify more than a quarter of cases with clinically meaningful improvement or worsening. There is a need to optimize SLE disease activity measures. Disclosure of Interest None declared

AB0608 Greater Organ Involvement and Disease Activity in Childhood-Onset than Adult-Onset With SLE (DATA from Reuma.Pt/Les)

Background Systemic lupus erythematosus (SLE) is a multi-organ immune-mediated disease that affects predominantly women at reproductive age but may present itself at any age. Age at disease onset has a strong modulating effect on clinical presentation and course of disease. Although young patients may have a more aggressive disease, controversies persist regarding the impact of age at disease onset on SLE outcome. Objectives Characterize childhood-onset, adult-onset and late-onset SLE and assess whether disease outcome differs in these three patient groups. Methods Patients with childhood-onset (diagnosis ≤18 years) SLE fulfilling ACR 1997 criteria were identified in the Portuguese registry Reuma.pt/SLE and compared with adult-onset (≥19y and ≤49 years) and late-onset (≥50 years) SLE patients paired for disease duration. Results Two hundred and sixty seven SLE patients with mean disease duration of 11.9±9.3 years were analyzed (Table 1). The number of fulfilled ACR criteria was significantly higher in childhood-onset SLE. A greater proportion of women, higher prevalence of arthritis and anti-SSA antibodies were noted in the adult-onset group. Hypertension, diabetes and thyroid disease were significantly more prevalent in late-onset SLE. Disease activity at last visit evaluated using the SLEDAI-2K was significantly higher in childhood-onset group than in the late-onset counterparts. SLICC/ACR damage index was numerically higher in late-onset SLE and significantly more patients in this group had irreversible damage. Cyclophosphamide and mycophenolate mophetil were used more frequently in childhood-onset SLE patients.Table 1. Demographic and clinical characteristics of childhood-onset, adult-onset and late-onset SLE Childhood-onset Adult-onset Late-onset P N=89 N=89 N=89 Female n (%) 77 (87) 85 (96) 78 (88) 0.039 Current mean age (years) 25.1±9.1 40.0±13.1 68.3±7.3 <0.001 Number of ACR criteria fulfilled 5.8±1.3 5.3±1.3 5.2±1.1 0.005 u2003Malar rash (%) 55 (62) 32 (36) 33 (37) <0.001 u2003Arthritis (%) 62 (70) 79 (89) 71 (80) 0.005 u2003Renal involvement (%) 52 (58) 28 (31) 14 (16) <0.001 u2003Neurologic disorder (%) 10 (11) 5 (6) 2 (2) 0.039 u2003Hematologic disorder (%) 68 (76) 53 (62) 67 (75) 0.029 Anti-SSA positivity (%) 13 (15) 30 (34) 19 (21) 0.006 Low complement (%) 74 (83) 60 (67) 46 (52) <0.001 SLEDAI-2K at last visit 3.4±3.8 2.2±2.7 1.6±2.8 0.004 SLICC-DI 0.5±0.9 0.7±1.3 0.9±1.3 0.116 SLICC-DI ≥1 (%) 18 (20) 23 (26) 36 (40) <0.001 Hypertension (%) 17 (19) 16 (18) 43 (48) <0.001 Diabetes (%) 0 (0) 7 (8) 15 (17) 0.008 Thyroid disease (%) 3 (3) 13 (26) 20 (23) 0.004 Conclusions The skin, kidney and neurological involvement are most common in childhood-onset, as well as the use of immunosuppressants, supporting the concept of a more severe disease. In contrast, patients with late-onset SLE have more comorbidities and irreversible damage. The age of SLE onset has a significant impact not only on the clinical characteristics and disease activity, but is also important for disease outcome. Disclosure of Interest None declared