J.M. Pego-Reigosa

Interstitial lung disease induced or exacerbated by TNF-targeted therapies: analysis of 122 cases.

OBJECTIVESnTo analyze the clinical characteristics, outcomes, and patterns of association with the different biologic agents used in all reported cases of adult patients developing interstitial lung disease (ILD) after biologic therapy.nnnMETHODSnIn 2006, the Study Group on Autoimmune Diseases of the Spanish Society of Internal Medicine created the BIOGEAS project. One objective was to collect data on autoimmune diseases secondary to the use of biologic agents by quarterly Medline search surveillance of reported cases. For this study, the baseline included articles published between January 1990 and March 2010, including the MeSH term lung diseases, interstitial as the key research term. In addition, we report an unpublished case of ILD secondary to biologic therapy.nnnRESULTSnThere are 122 reported cases of new-onset or exacerbation of ILD secondary to administration of biologic therapies. Biologic agents associated with ILD were overwhelmingly anti-tumor necrosis factor agents (etanercept in 58 cases and infliximab in 56) and were administered for rheumatoid arthritis in 108 (89%) patients. ILD appeared a mean of 26 weeks after initiation of biologic agents. ILD was confirmed by pulmonary biopsy in 26 cases, although a specific histopathologic description was detailed in only 20: 7 patients were classified as usual interstitial pneumonia, 6 as nonspecific interstitial pneumonia, 5 as organizing pneumonia, 1 as diffuse alveolar damage, and 1 as lymphoid interstitial pneumonia. Treatment of ILD included withdrawal of biologic agents in all cases but 1. The outcome of ILD was detailed in 52 cases. Complete resolution was reported in 21 (40%) cases, improvement or partial resolution in 13 (25%), and no resolution in 18 (35%). Fifteen (29%) patients died during the follow-up, the majority (70%) during the first 5 weeks after initiating biologic therapy. In comparison with survivors, patients who died were aged >65 years (67% vs 33%, P = 0.036), with later onset of ILD (46 weeks vs 15 weeks, P = 0.006), received immunosuppressive drugs more frequently (33% vs 8%, P = 0.036), and more often had a previous diagnosis of ILD (67% vs 29%, P = 0.025).nnnCONCLUSIONSnWe found that 97% of cases of ILD associated with biologic agents were associated with agents blocking tumor necrosis factor-α, a cytokine that has been implicated in the pathophysiology of pulmonary fibrosis. Strikingly, drug-induced ILD had a poor prognosis, with an overall mortality rate of around one third, rising to two thirds in patients with preexisting ILD.

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 scoreu2009≤u2009two 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 20.0u2009±u200915.2 months (complete in 50 and partial in 47). High baseline SLEDAI score, previous treatment with ≥100u2009mg/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.

Analysis of disease activity and response to treatment in a large Spanish cohort of patients with systemic lupus erythematosus

Objectives The objectives of this paper are to study the impact of disease activity in a large cohort of patients with systemic lupus erythematosus (SLE) and estimate the rate of response to therapies. Methods We conducted a nationwide, retrospective, multicenter, cross-sectional cohort study of 3658 SLE patients. Data on demographics, disease characteristics: activity (SELENA-SLEDAI), damage, severity, hospitalizations and therapies were collected. Factors associated with refractory disease were identified by logistic regression. Results A total of 3658 patients (90% female; median SLE duration (interquartile range): 10.4 years (5.3–17.1)) were included. At the time of their last evaluation, 14.7% of the patients had moderate-severe SLE (SELENA-SLEDAI score ≥6). There were 1954 (53.4%) patients who were hospitalized for activity at least once over the course of the disease. At some stage, 84.6% and 78.8% of the patients received glucocorticoids and antimalarials, respectively, and 51.3% of the patients received at least one immunosuppressant. Owing to either toxicity or ineffectiveness, cyclophosphamide was withdrawn in 21.5% of the cases, mycophenolate mofetil in 24.9%, azathioprine in 40.2% and methotrexate in 46.8%. At some stage, 7.3% of the patients received at least one biologic. A total of 898 (24.5%) patients had refractory SLE at some stage. Renal, neuropsychiatric, vasculitic, hematological and musculoskeletal involvement, a younger age at diagnosis and male gender were associated with refractory disease. Conclusions A significant percentage of patients have moderately-to-severely active SLE at some stage. Disease activity has a big impact in terms of need for treatment and cause of hospitalization. The effectiveness of the standard therapies for reducing disease activity is clearly insufficient. Some clinical features are associated with refractory SLE.

Systemic lupus erythematosus in Spanish males: a study of the Spanish Rheumatology Society Lupus Registry (RELESSER) cohort

Objective The objective of this study was to describe the demographic, clinical, and immunological manifestations of systemic lupus erythematosus (SLE) in male patients. Methods A cross-sectional, multicenter study was carried out of 3651 patients (353 men, 9.7%, and 3298 women, 90.2%) diagnosed with SLE, included in the Spanish Rheumatology Society SLE Registry (RELESSER). Results Mean ages (18–92 years) of symptom onset were 37 (SD 17) years (men) and 32 (SD 14) years (women). Male/female ratio was 1/9. Age of onset of symptoms and age at diagnosis were higher in men than in women (pu2009<u20090.001). Males were diagnosed earlier than females (pu2009=u20090.04) and had more cardiovascular comorbidities (pu2009<u20090.001). Two hundred and thirty-six males (68%) with SLE required hospitalization in comparison with 1713 females (53%) (pu2009<u20090.001). During follow-up, 208 patients died: 30 men (9.3%) and 178 women (5.9%) (pu2009=u20090.02). As regards clinical manifestations, loss of weight (pu2009=u20090.01), lymphadenopathies (pu2009=u20090.02), and splenomegaly (pu2009=u20090.02) were more common in male patients. Female patients were more likely to have inflammatory rash, alopecia, and arthritis (pu2009<u20090.05). As for lung involvement, men with SLE had more pleural fibrosis (pu2009<u20090.001) and pulmonary embolism (pu2009=u20090.01). However, Raynaud’s phenomenon was more common in women (35%) than in men (23.7%) (pu2009<u20090.001); lupus nephritis was more common in men, being present in 155 (44.8%) of males versus 933 (29%) of females (pu2009<u20090.001). Multivariate analysis showed that SLE patients with a high Charlson index (more than 3 points) and ageu2009>u200950 years had a higher mortality (odds ratios 3.6 and 2.1, respectively). Furthermore, SLE patients who developed pulmonary hemorrhage, pulmonary hypertension, psychiatric involvement, complement deficiency, and hemophagocytic syndrome also had higher mortality, regardless of gender. Conclusion Patients with SLE over the age of 50 years have an increased risk of mortality. In Caucasians, age at diagnosis and symptom onset is higher in men than in women. The diagnostic delay is shorter in men. Male SLE patients present more cardiovascular comorbidities, and also more serositis, adenopathies, splenomegaly, renal involvement, convulsion, thrombosis, and lupus anticoagulant positivity than women.

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

OBJECTIVESnTo estimate the incidence of severe infection and investigate the associated factors and clinical impact in a large systemic lupus erythematosus (SLE) retrospective cohort.nnnMETHODSnAll 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.nnnRESULTSnA 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).nnnCONCLUSIONSnSevere 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.

The effects of rituximab on the lipid profile of patients with active systemic lupus erythematosus: results from a nationwide cohort in Spain (LESIMAB)

Introduction Patients with systemic lupus erythematosus (SLE) have increased cardiovascular risk related to lipid changes induced by inflammatory activity, proteinuria and treatments. Our objective was to analyse lipid changes in a cohort of patients with SLE resistant to standard treatments who were treated with rituximab. Methods The study population comprised a retrospective multicentre, national cohort of patients with SLE resistant to standard treatments who were treated with rituximab. The basic lipid profile, concomitant treatment and disease activity were analysed at the start of the treatment, 24 weeks later, and at the end of the follow-up period. The effects of the main lupus variables and therapy on the lipid changes were analysed. Results Seventy-nine patients with active lupus treated with rituximab were assessed during 149.3 patient-years. Prior to the treatment, 69% had dyslipidaemia. The most frequent abnormalities were a low-density lipoprotein (LDL) level of ≥100u2009mg/dl (34%) and a high-density lipoprotein (HDL) level of <50u2009mg/dl (27%). Baseline total cholesterol (TC) and LDL levels correlated with the degree of proteinuria, while the concentration of triglycerides (TGs) correlated with the SLE Disease Activity Index (SLEDAI). TGs were reduced at short- and long-term follow-up after rituximab treatment. A multiple linear regression analysis identified that the reduction of the lupus inflammatory activity, particularly changes in proteinuria, was the only independent variable that was positively associated with the reduction in TGs after 24 weeks (pu2009=u20090.001) and with TC (pu2009=u20090.005) and TGs (pu2009<u20090.001) at the end of the follow-up period. Conclusion Our results suggest that rituximab may improve the long-term lipid profile of patients with SLE refractory to standard treatment, mainly by reducing inflammatory activity.

Relationship between damage clustering and mortality in systemic lupus erythematosus in early and late stages of the disease: cluster analyses in a large cohort from the Spanish Society of Rheumatology Lupus Registry

OBJECTIVESnTo identify patterns (clusters) of damage manifestations within a large cohort of SLE patients and evaluate the potential association of these clusters with a higher risk of mortality.nnnMETHODSnThis is a multicentre, descriptive, cross-sectional study of a cohort of 3656 SLE patients from the Spanish Society of Rheumatology Lupus Registry. Organ damage was ascertained using the Systemic Lupus International Collaborating Clinics Damage Index. Using cluster analysis, groups of patients with similar patterns of damage manifestations were identified. Then, overall clusters were compared as well as the subgroup of patients within every cluster with disease duration shorter than 5 years.nnnRESULTSnThree damage clusters were identified. Cluster 1 (80.6% of patients) presented a lower amount of individuals with damage (23.2 vs 100% in clusters 2 and 3, P < 0.001). Cluster 2 (11.4% of patients) was characterized by musculoskeletal damage in all patients. Cluster 3 (8.0% of patients) was the only group with cardiovascular damage, and this was present in all patients. The overall mortality rate of patients in clusters 2 and 3 was higher than that in cluster 1 (P < 0.001 for both comparisons) and in patients with disease duration shorter than 5 years as well.nnnCONCLUSIONnIn a large cohort of SLE patients, cardiovascular and musculoskeletal damage manifestations were the two dominant forms of damage to sort patients into clinically meaningful clusters. Both in early and late stages of the disease, there was a significant association of these clusters with an increased risk of mortality. Physicians should pay special attention to the early prevention of damage in these two systems.

Anti-CD26 autoantibodies are involved in rheumatoid arthritis and show potential clinical interest

OBJECTIVESnRheumatoid arthritis (RA) patients show low serum levels of the Ag dipeptidyl peptidase IV (DPP-IV/CD26), both soluble CD26 (sCD26) concentration and its DPP-IV activity. The aim of this study was to test if anti-DPP-IV/CD26 Abs (Anti-CD26) cleared sCD26.nnnDESIGN & METHODSnSerum Anti-CD26 and Total titers (as comparison) of isotypes IgA, IgM and IgG as well as sCD26 concentration and DPP-IV activity were measured in a cohort of RA patients undergoing different biological and non-biological therapies (n=105) and controls (n=50).nnnRESULTSnAnti-CD26 levels were increased approximately two-fold for each isotype in RA, were not related to the sCD26 clearance, showed several correlations with disease activity parameters, were significantly higher in smokers and they were not ACPA. Anti-CD26 Igs showed high diagnostic power (82% sensitivity and 96% specificity) and their levels differed amongst the different groups of patients stratified by the type of therapy.nnnCONCLUSIONSnAs DPP-IV/CD26 is associated to factors triggering RA in the lung and periodontal tissue, these results suggest that Anti-CD26 isotypes may participate in pathogenesis and may be useful as biomarkers for earlier diagnosis and/or precision medicine.

Relationship between damage and mortality in juvenile-onset systemic lupus erythematosus: Cluster analyses in a large cohort from the Spanish Society of Rheumatology Lupus Registry (RELESSER)

OBJECTIVESnTo identify patterns (clusters) of damage manifestation within a large cohort of juvenile SLE (jSLE) patients and evaluate their possible association with mortality.nnnMETHODSnThis is a multicentre, descriptive, cross-sectional study of a cohort of 345 jSLE patients from the Spanish Society of Rheumatology Lupus Registry. Organ damage was ascertained using the Systemic Lupus International Collaborating Clinics Damage Index. Using cluster analysis, groups of patients with similar patterns of damage manifestation were identified and compared.nnnRESULTSnMean age (years)u202f±u202fS.D. at diagnosis was 14.2u202f±u202f2.89; 88.7% were female and 93.4% were Caucasian. Mean SLICC/ACR DIu202f±u202fS.D. was 1.27u202f±u202f1.63. A total of 12 (3.5%) patients died. Three damage clusters were identified: Cluster 1 (72.7% of patients) presented a lower number of individuals with damage (22.3% vs. 100% in Clusters 2 and 3, Pu202f<u202f0.001); Cluster 2 (14.5% of patients) was characterized by renal damage in 60% of patients, significantly more than Clusters 1 and 3 (Pu202f<u202f0.001), in addition to increased more ocular, cardiovascular and gonadal damage; Cluster 3 (12.7%) was the only group with musculoskeletal damage (100%), significantly higher than in Clusters 1 and 2 (Pu202f<u202f0.001). The overall mortality rate in Cluster 2 was 2.2 times higher than that in Cluster 3 and 5 times higher than that in Cluster 1 (Pu202f<u202f0.017 for both comparisons).nnnCONCLUSIONSnIn a large cohort of jSLE patients, renal and musculoskeletal damage manifestations were the two dominant forms of damage by which patients were sorted into clinically meaningful clusters. We found two clusters of jSLE with important clinical damage that were associated with higher rates of mortality, especially for the cluster of patients with predominant renal damage. Physicians should be particularly vigilant to the early prevention of damage in this subset of jSLE patients with kidney involvement.

S2A:5 Development and validation of a score to predict the risk of severe infection in sle

Purpose To develop a predictive risk score that assesses the probability of severe infection in SLE patients and to test it in an independent cohort. Methods The SLE severe infection score (SLESIS) was developed using data from the RELESSER (Spanish Society of Rheumatology Lupus Registry) cohort of 3658 SLE patients using a Cox regression model for repeated events (Andersen-Gill) The results were expressed as hazard ratio (HR) of developing one serious infection/1000 patient-years for patients with the risk factor compared to those without that factor. SLESIS for an individual patient is the sum of the HR values of all factors present at that time. SLESIS was validated using retrospective data from the UCLH (University College London Hospital) cohort including 699 SLE patients. Results The risk factors included in SCORE and their HR calculated from RELESSER data are shown in table 1. From 699 SLE UCLH patients, 98 (14%) developed serious infection. We compared these patients with 111 SLE controls who never suffered serious infection. The characteristics of the SLE infection and SLE non-infection groups are summarised in table 2. Median SLESIS at diagnosis in patients with infection was 4.27 (IQR 3.18) which was significantly higher than in the control group (Median 2.55, IQR 3.79) (z=3.341; p=0.0008). Median SLESIS just before infection was 5.3 (IQR 3.68) which was significantly higher compared to SLESIS at diagnosis (z=−5.733; p≤0.001) in those patients or SLESIS measured at the same time post-diagnosis in the non-infected group (Median 3.73 RI 3.7) (z=−4.765, p≤0.001). By Receiver Operator Characteristic analysis, we defined three possible cut-offs to distinguish patients with and without infection. For SLESIS just before infection, the area under the ROC curve was 0.75 (CI: 0.66 to 0.84) and the three selected cut offs (3.67, 3.79, 4.24) reached a sensitivity of 90% and specificity of 50%. Conclusion We have developed a score for predicting risk of serious infection in SLE and validated it in an independent cohort. Given the potential mortality from such infections, SLESIS could be clinically useful though the moderate sensitivity and specificity necessitate caution and further prospective studies.Abstract S2A:5 Table 1Abstract S2A:5 Table 2