Eva Tomero

Multicenter longitudinal study of B-lymphocyte depletion in refractory systemic lupus erythematosus: the LESIMAB study

Objective: This study aimed to investigate the effectiveness and safety of single and repeated courses of rituximab in patients with refractory lupus. Methods: LESIMAB is a multicenter, retrospective, longitudinal study of lupus patients who have not responded to standard therapy and have been treated with rituximab. Response rates at six months and at follow-up were defined as efficacy outcomes. Complete response was defined as a SELENA-SLEDAI score ≤ two and a SELENA-SLEDAI Flare Index of zero. Partial response was defined as a reduction in the SELENA-SLEDAI score of ≥four points with no new or worsening of symptoms. Adverse events were collected. Results: Seventy-three (62.9%) of 116 patients achieved a response at six months (complete in 22 and partial in 51). Ninety-seven (77.6%) of 128 patients achieved a response after a mean follow-up of 20.0 ± 15.2 months (complete in 50 and partial in 47). High baseline SLEDAI score, previous treatment with ≥100 mg/day prednisone, and no history of severe hematologic flare were associated with response after the first treatment course. The median time to response was 6.5 months (95% CI, 5.0–8.0). Thirty-seven patients (38.1%) relapsed after the first infusion. The flare was severe in seven cases and mild to moderate in 29 cases. Serious infection rate was 12.6/100 patient-years. A schedule of four weekly doses was associated with more serious infections. Six patients died: two of infection and four of lupus complications. Conclusion: Rituximab can be an effective treatment option for patients who have refractory lupus with severe or life-threatening disease with an acceptable tolerance profile.

Baseline serum RANKL levels may serve to predict remission in rheumatoid arthritis patients treated with TNF antagonists

Aims: The objective of this study was to investigate whether baseline receptor activator for nuclear factor kappaB ligand (RANKL) and osteoprotegerin (OPG) serum (s) levels can predict the therapeutic response to TNF antagonists (a-TNF). Methods: We studied 75 rheumatoid arthritis patients (81% female) with a longstanding refractory disease. The variables of disease activity, physical function and sRANKL and sOPG levels were determined before and after both 12–14 and 28–30 weeks of a-TNF therapy (65 adalimumab, 10 infliximab). Remission was defined by a 28 joint count disease activity score (DAS28) ⩽2.6 and clinical response by a reduction in DAS28⩾1.2 at both 3- and 7-month follow-up visits. Results: In most patients, disease activity was severe, as reflected by a baseline DAS28 score of 5.9±1 (mean±SD), an HAQ of 1.6 (1.1 to 2.1) (median (interquartile range (IQR))) and a CRP 15 mg/l (IQR: 9 to 24). The sRANKL levels and RANKL/OPG ratio in patients that achieved remission were significantly lower at baseline than in the remaining patients at both 3 and 7 months of follow-up. The sOPG levels correlated with the HAQ and the physician’s disease assessment and diminished significantly after a-TNF treatment. However, no significant association was detected between the therapeutic response profile and sOPG levels. Conclusions: These data suggest that in patients receiving a-TNF treatment, lower serum levels of RANKL and RANKL/OPG ratio may serve to predict remission.

Interleukin 15 Levels in Serum May Predict a Severe Disease Course in Patients with Early Arthritis

Background Interleukin-15 (IL-15) is thought to be involved in the physiopathological mechanisms of RA and it can be detected in the serum and the synovial fluid of inflamed joints in patients with RA but not in patients with osteoarthritis or other inflammatory joint diseases. Therefore, the objective of this work is to analyse whether serum IL-15 (sIL-15) levels serve as a biomarker of disease severity in patients with early arthritis (EA). Methodology and Results Data from 190 patients in an EA register were analysed (77.2% female; median age 53 years; 6-month median disease duration at entry). Clinical and treatment information was recorded systematically, especially the prescription of disease modifying anti-rheumatic drugs. Two multivariate longitudinal analyses were performed with different dependent variables: 1) DAS28 and 2) a variable reflecting intensive treatment. Both included sIL-15 as predictive variable and other variables associated with disease severity, including rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (ACPA). Of the 171 patients (638 visits analysed) completing the follow-up, 71% suffered rheumatoid arthritis and 29% were considered as undifferentiated arthritis. Elevated sIL-15 was detected in 29% of this population and this biomarker did not overlap extensively with RF or ACPA. High sIL-15 levels (β Coefficient [95% confidence interval]: 0.12 [0.06–0.18]; p<0.001) or ACPA (0.34 [0.01–0.67]; p = 0.044) were significantly and independently associated with a higher DAS28 during follow-up, after adjusting for confounding variables such as gender, age and treatment. In addition, those patients with elevated sIL-15 had a significantly higher risk of receiving intensive treatment (RR 1.78, 95% confidence interval 1.18–2.7; p = 0.007). Conclusions Patients with EA displaying high baseline sIL-15 suffered a more severe disease and received more intensive treatment. Thus, sIL-15 may be a biomarker for patients that are candidates for early and more intensive treatment.

Validity of the Ankylosing Spondylitis Disease Activity Score (ASDAS) in patients with early spondyloarthritis from the Esperanza programme

Objectives To evaluate the validity of the Ankylosing Spondylitis Disease Activity Score (ASDAS) in early spondyloarthritis (SpA) in comparison with conventional clinical measures of disease activity. Methods Six hundred and seventy-six incident cases of early SpA from the Esperanza programme were included. Patients were categorised into high and low disease activity states based on patient and physician global assessment scores and on the physicians decision to start treatment with a disease-modifying antirheumatic drug or tumour necrosis factor blocker. The discriminant ability of ASDAS-C-reactive protein (CRP) and ASDAS-erythrocyte sedimentation rate (ESR) was tested using standardised mean differences between patients with high and low disease activity. Convergent validity was tested by Pearson correlation between ASDAS versions and other measures of disease activity. Results ASDAS-ESR and ASDAS-CRP showed good correlation with BASDAI (r=0.79 and 0.74, respectively). Both indices correlated well with the patient global assessment (r=0.70 in both indices) and moderately with the physician global score (r=0.46 and 0.47, respectively). CRP and ESR showed poor correlation with patient- and physician-derived measures. ASDAS performed similarly across the global SpA sample, ankylosing spondylitis (AS), non-radiographic axial SpA and peripheral SpA. Conclusions ASDAS performed as a valid activity score even being slightly better than the Bath Ankylosing Spondylitis Disease Activity Index in its ability to discriminate between high and low disease activity in early SpA. ASDAS performed similarly in AS, early forms of SpA, non-radiographic axial SpA and peripheral SpA.

Age at treatment predicts reason for discontinuation of TNF antagonists: data from the BIOBADASER 2.0 registry

OBJECTIVES To assess the retention rate of TNF antagonists in elderly patients suffering from chronic arthropathies and to identify predictive variables of discontinuation by inefficacy or by adverse events (AEs). METHODS All patients treated with TNF antagonists in BIOBADASER 2.0, with a diagnosis of either RA or spondyloarthritis (SpA: AS and PsA) were included and classified as <65 (younger) or ≥65 years of age (older) at start of the treatment. Cumulative incidence function for discontinuation (inefficacy or AE) was estimated as being the alternative reason for a competing risk. Competing-risks regression models were used to measure the association between study groups, covariates and reason for discontinuation. RESULTS A total of 4851 patients were studied; 2957 RA (2291 in the younger group and 666 in the older group) and 1894 SpA (1795 in the younger group and 99 in the older group). Retention curves were statistically differently stratified by age groups, with the SpA younger group having the largest retention rate. Competing-risks regression models showed that in the older group, AEs were the most common reason for discontinuation regardless of the diagnosis of the patient and TNF antagonist molecule, whereas in the younger group, the most common cause of discontinuation was inefficacy. CONCLUSION In conclusion, factors predicting discontinuation of TNF antagonists due to AEs are older age and diagnosis of RA. On the other hand, younger age predicts discontinuation due to lack of efficacy.

Performance of the Assessment of Spondyloarthritis International Society criteria for the classification of spondyloarthritis in early spondyloarthritis clinics participating in the ESPERANZA programme

OBJECTIVE The objective of this study was to analyse the performance of the Assessment of SpondyloArthritis International Society (ASAS) criteria for the classification of SpA in early SpA clinics. METHODS We used a cross-sectional study of patients referred to early SpA units within the ESPERANZA programme (a Spanish nationwide health management programme designed to provide excellence in diagnosis and care for early SpA). Patients were eligible if they were <45 years of age and had any of the following: (i) a 2-year history of inflammatory back pain; (ii) back or joint pain with psoriasis, anterior uveitis, radiographic sacroiliitis, family history of SpA or positive HLA-B27; or (iii) asymmetric arthritis. We excluded patients for whom imaging (X-rays/MRI) or HLA-B27 results were not available. We analysed the performance (sensitivity and specificity) of different classification criteria sets, taking the rheumatologists opinion as the gold standard. RESULTS The analysis included 775 patients [mean age 33 (s.d. 7) years; 55% men; mean duration of symptoms 11 (s.d. 6) months]; SpA was diagnosed in 538 patients (69.5%). A total of 274 (67.9%) patients with chronic back pain met the ASAS axial criteria, 76 (56.3%) patients with arthritis but not chronic back pain fulfilled the ASAS criteria for peripheral SpA and 350 (65.1%) fulfilled all the ASAS criteria. The sensitivity and specificity of the ASAS criteria set were 65% and 93%, respectively (axial criteria: sensitivity 68%, specificity 95%). The sensitivity and specificity for the ESSG and Amor criteria were 58% and 90% and 59% and 86%, respectively. CONCLUSION Despite performing better than the Amor or ESSG criteria, the ASAS criteria may be limited to detection of early forms, particularly in populations in which MRI is not extensively available or in populations with a low prevalence of HLA-B27.

Comprehensive Description of Clinical Characteristics of a Large Systemic Lupus Erythematosus Cohort from the Spanish Rheumatology Society Lupus Registry (RELESSER) With Emphasis on Complete Versus Incomplete Lupus Differences

AbstractSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ involvement and pronounced racial and ethnic heterogeneity. The aims of the present work were (1) to describe the cumulative clinical characteristics of those patients included in the Spanish Rheumatology Society SLE Registry (RELESSER), focusing on the differences between patients who fulfilled the 1997 ACR-SLE criteria versus those with less than 4 criteria (hereafter designated as incomplete SLE (iSLE)) and (2) to compare SLE patient characteristics with those documented in other multicentric SLE registries.RELESSER is a multicenter hospital-based registry, with a collection of data from a large, representative sample of adult patients with SLE (1997 ACR criteria) seen at Spanish rheumatology departments. The registry includes demographic data, comprehensive descriptions of clinical manifestations, as well as information about disease activity and severity, cumulative damage, comorbidities, treatments and mortality, using variables with highly standardized definitions.A total of 4.024 SLE patients (91% with ≥4 ACR criteria) were included. Ninety percent were women with a mean age at diagnosis of 35.4 years and a median duration of disease of 11.0 years. As expected, most SLE manifestations were more frequent in SLE patients than in iSLE ones and every one of the ACR criteria was also associated with SLE condition; this was particularly true of malar rash, oral ulcers and renal disorder. The analysis—adjusted by gender, age at diagnosis, and disease duration—revealed that higher disease activity, damage and SLE severity index are associated with SLE [OR: 1.14; 95% CI: 1.08–1.20 (P < 0.001); 1.29; 95% CI: 1.15–1.44 (P < 0.001); and 2.10; 95% CI: 1.83–2.42 (P < 0.001), respectively]. These results support the hypothesis that iSLE behaves as a relative stable and mild disease. SLE patients from the RELESSER register do not appear to differ substantially from other Caucasian populations and although activity [median SELENA-SLEDA: 2 (IQ: 0–4)], damage [median SLICC/ACR/DI: 1 (IQ: 0–2)], and severity [median KATZ index: 2 (IQ: 1–3)] scores were low, 1 of every 4 deaths was due to SLE activity.RELESSER represents the largest European SLE registry established to date, providing comprehensive, reliable and updated information on SLE in the southern European population.

Independent Candidate Serum Protein Biomarkers of Response to Adalimumab and to Infliximab in Rheumatoid Arthritis: An Exploratory Study

Response to treatment of rheumatoid arthritis shows large inter-individual variability. This heterogeneity is observed with all the anti-rheumatic drugs, including the commonly used TNF inhibitors. It seems that drug-specific and target-specific factors lead individual patients to respond or not to a given drug, although this point has been challenged. The search of biomarkers distinguishing responders from non-responders has included shotgun proteomics of serum, as a previous study of response to infliximab, an anti-TNF antibody. Here, we have used the same study design and technology to search biomarkers of response to a different anti-TNF antibody, adalimumab, and we have compared the results obtained for the two anti-TNF drugs. Search of biomarkers of response to adalimumab included depletion of the most abundant serum proteins, 8-plex isobaric tag for relative and absolute quantitation (iTRAQ) labeling, two-dimensional liquid chromatography fractionation and relative quantification with a hybrid Orbitrap mass spectrometer. With this approach, 264 proteins were identified in all the samples with at least 2 peptides and 95% confidence. Nine proteins showed differences between non-responders and responders (P < 0.05), representing putative biomarkers of response to adalimumab. These results were compared with the previous study of infliximab. Surprisingly, the non-responder/responder differences in the two studies were not correlated (rs = 0.07; P = 0.40). This overall independence with all the proteins showed two identifiable components. On one side, the putative biomarkers of response to either adalimumab or infliximab, which were not shared and showed an inverse correlation (rs = -0.69; P = 0.0023). On the other, eight proteins showing significant non-responder/responder differences in the analysis combining data of response to the two drugs. These results identify new putative biomarkers of response to treatment of rheumatoid arthritis and indicate that they are notably drug-specific.

Characterization of Patients With Lupus Nephritis Included in a Large Cohort From the Spanish Society of Rheumatology Registry of Patients With Systemic Lupus Erythematosus (RELESSER).

AbstractThe aim of the study was to profile those patients included in the RELESSER registry with histologically proven renal involvement in order to better understand the current state of lupus nephritis (LN) in Spain.RELESSER-TRANS is a multicenter cross-sectional registry with an analytical component. Information was collected from the medical records of patients with systemic lupus erythematosus who were followed at participating rheumatology units. A total of 359 variables including demographic data, clinical manifestations, disease activity, severity, comorbidities, LN outcome, treatments, and mortality were recorded. Only patients with a histological confirmation of LN were included. We performed a descriptive analysis, chi-square or Students t tests according to the type of variable and its relationship with LN. Odds ratio and confidence intervals were calculated by using simple logistic regression.LN was histologically confirmed in 1092/3575 patients (30.5%). Most patients were female (85.7%), Caucasian (90.2%), and the mean age at LN diagnosis was 28.4 ± 12.7 years. The risk for LN development was higher in men (M/F:47.85/30.91%, P < 0.001), in younger individuals (P < 0.001), and in Hispanics (P = 0.03). Complete response to treatment was achieved in 68.3% of patients; 10.35% developed ESRD, which required a kidney transplant in 45% of such cases. The older the patient, the greater was the likelihood of complete response (P < 0.001). Recurrences were associated with persistent lupus activity at the time of the last visit (P < 0.001) and with ESRD (P < 0.001). Thrombotic microangiopathy was a risk factor for ESRD (P = 0.04), as for the necessity of dialysis (P = 0.01) or renal transplantation (P = 0.03). LN itself was a poor prognostic risk factor of mortality (OR 2.4 [1.81–3.22], P < 0.001). Patients receiving antimalarials had a significantly lower risk of developing LN (P < 0.001) and ESRD (P < 0.001), and responded better to specific treatments for LN (P = 0.014).More than two-thirds of the patients with LN from a wide European cohort achieved a complete response to treatment. The presence of positive anti-Sm antibodies was associated with a higher frequency of LN and a decreased rate of complete response to treatment. The use of antimalarials reduced both the risk of developing renal disease and its severity, and contributed to attaining a complete renal response.

Incidence, associated factors and clinical impact of severe infections in a large, multicentric cohort of patients with systemic lupus erythematosus

OBJECTIVES To estimate the incidence of severe infection and investigate the associated factors and clinical impact in a large systemic lupus erythematosus (SLE) retrospective cohort. METHODS All patients in the Spanish Rheumatology Society Lupus Registry (RELESSER) who meet ≥4 ACR-97 SLE criteria were retrospectively investigated for severe infections. Patients with and without infections were compared in terms of SLE severity, damage, comorbidities, and demographic characteristics. A multivariable Cox regression model was built to calculate hazard ratios (HRs) for the first infection. RESULTS A total of 3658 SLE patients were included: 90% female, median age 32.9 years (DQ 9.7), and mean follow-up (months) 120.2 (±87.6). A total of 705 (19.3%) patients suffered ≥1 severe infection. Total severe infections recorded in these patients numbered 1227. The incidence rate was 29.2 (95% CI: 27.6-30.9) infections per 1000 patient years. Time from first infection to second infection was significantly shorter than time from diagnosis to first infection (p < 0.000). Although respiratory infections were the most common (35.5%), bloodstream infections were the most frequent cause of mortality by infection (42.0%). In the Cox regression analysis, the following were all associated with infection: age at diagnosis (HR = 1.016, 95% CI: 1.009-1.023), Latin-American (Amerindian-Mestizo) ethnicity (HR = 2.151, 95% CI: 1.539-3.005), corticosteroids (≥10mg/day) (HR = 1.271, 95% CI: 1.034-1.561), immunosuppressors (HR = 1.348, 95% CI: 1.079-1.684), hospitalization by SLE (HR = 2.567, 95% CI: 1.905-3.459), Katz severity index (HR = 1.160, 95% CI: 1.105-1.217), SLICC/ACR damage index (HR = 1.069, 95% CI: 1.031-1.108), and smoking (HR = 1.332, 95% CI: 1.121-1.583). Duration of antimalarial use (months) proved protective (HR = 0.998, 95% CI: 0.997-0.999). CONCLUSIONS Severe infection constitutes a predictor of poor prognosis in SLE patients, is more common in Latin-Americans and is associated with age, previous infection, and smoking. Antimalarials exerted a protective effect.