Diana Castillo-Martínez

Self-reactivity against stress-induced cell molecules: The missing link between Takayasu’s arteritis and tuberculosis?

Takayasus arteritis (TA) is a chronic, occlusive, inflammatory disease of the aorta, its major branches and the pulmonary arteries. Its etiology remains unclear, although it has been suggested that a variety of antigens from Mycobacterium tuberculosis and probably other mycobacteria may trigger inflammatory pathology either directly in the arterial wall or remote from the actual location of mycobacterial infection, possibly through molecular mimicry mechanisms. However, recent evidence showing absence of both mycobacteria directly into arterial tissue as well as latent M. tuberculosis infection is challenging this notion. The hypothesis offered in this manuscript postulates that the lost of tolerance against self stress proteins is a primal pathogenic event in TA with the innate immune system as key culprit in the initiation and amplification of inflammatory response, while the extensive sequence homology between mycobacterial and human stress proteins leads to epiphenomenal cross-reactions mediated by adaptive immune system. If it is so, this postulate reconciles epidemiological, immunological and genetic linkage between TA and mycobacteria, while supporting the widespread Bacille Calmette-Guérin (BCG) vaccination worldwide and giving rationale to a safety use of anti-tumor necrosis factor (TNF) therapy in patients with TA.

Levels of uric acid may predict the future development of pulmonary hypertension in systemic lupus erythematosus: a seven-year follow-up study

Objective The objective of this paper is to assess whether pulmonary hypertension (PH) may be detected at one point in time or longitudinally predicted by serum uric acid (sUA) levels in systemic lupus erythematosus (SLE). Methods We conducted a post-hoc analysis of a long-term followed cohort of Mexican SLE patients. Echocardiography-based definitions of PH by the ESC/ERS/ISHLT and its associations with clinical and laboratory data on enrollment were studied. Especially, the impact that sUA levels at baseline may have on the future development of PH in patients with normal pulmonary artery systolic pressure (PASP) was explored. Results Out of the 156 SLE patients originally enrolled in the cohort, 44 met the inclusion criteria for the present study and were grouped as having (n = 10) or not having (n = 34) PH. At baseline, sUA levels of 5.83 ± 1.79 and 5.82 ± 1.97 mg/dl (p = ns) were found in patients with and without PH, respectively. No association between PASP and other markers was found. In patients with normal PASP, the presence of sUA ≥ 7 mg/dl at baseline predicted future development of PH (relative risk 8.5, 1.0009 to 72; p = 0.04). Conclusion In SLE, sUA levels at one point in time are useless to detect PH. However, steady hyperuricemia may predict the future development of PH in patients with normal PASP at baseline.

Pulmonary hypertension in systemic lupus erythematosus: echocardiography-based definitions predict 6-year survival

OBJECTIVE The aim of this study was to investigate whether a core of echocardiography-based definitions of pulmonary hypertension (PH), as proposed by the European Society of Cardiology, European Respiratory Society and International Society of Heart and Lung Transplantation (ESC/ERS/ISHLT), may predict long-term survival in patients with SLE. METHODS A post hoc analysis from a cohort of SLE patients followed over 6 years was performed. Clinical associations, serum biomarkers, autoantibody profile, length of survival and all-cause mortality were assessed. RESULTS Out of 115 patients from the original cohort, 55 satisfied our inclusion criteria and were grouped according to echocardiography as unlikely (n = 26), possible (n = 16) or likely (n = 13) to have PH. Likely PH was associated with a history of pulmonary thromboembolism, higher cumulated organ damage and active arthritis. The 6-year survival rate was 88% in the unlikely PH group, 87% in the possible PH group and 68% in the likely PH group (P < 0.05). Serum levels of endothelin-1, monocyte chemotactic protein-1, IL-17, and IFN-γ as well as a number of autoantibodies were no different between groups. CONCLUSION The ESC/ERS/ISHLT echocardiography-based definitions of PH are useful to predict 6-year mortality in SLE patients. A history of pulmonary thromboembolism and lung vasculitis/haemorrhage, cumulated organ damage and long-lasting disease are associated with PH in SLE.

Neutropenia and the risk of infections in ambulatory patients with systemic lupus erythematosus: a three-year prospective study cohort

Sir, Infections are leading causes of morbidity and mortality in SLE, often in association with intrinsic (disease activity) or exogenous (immunosuppressants and corticosteroids) disease factors. Neutropenia is an undeniable predisposing factor to infection in different clinical settings, but its role in SLE is unclear. Previous studies have addressed this issue through retrospective reviews of hospitalized patients or have focused on major infections, thus hampering any extrapolation to ambulatory patients, a subset of SLE in which the information is scarce. We analyze the role of neutropenia on the incidence of infections in an ambulatory SLE cohort followed over three years. One hundred and one outpatients fulfilling the ACR criteria, and with no evidence of infection were recruited between February 2006 and April 2007. On enrollment, demographics, clinical data, disease activity (SLEDAI-2K) and chronic damage (SLICC/ ACR-DI) were assessed. Patients were grouped within neutropenic (<1.5 10/L) and non-neutropenic ( 1.5 10/L) cohorts and followed (visits 2–3 month intervals) up to November 2009. Attention was focused on any clinically apparent infection (most of the suspected infections were corroborated) and its occurrence was set as the primary endpoint. Patients with less than six months’ follow-up were excluded. Statistics included descriptive data, Fisher’s exact test, Mann–Whitney or Wilcoxon matchedpairs tests, and Kaplan–Meier survival analyses with log-rank test. Significance was set at p< 0.05, two-sided. Sixteen patients were eliminated because of less than six months’ follow-up (14), change in diagnosis (1), and receiving a kidney transplant (1). Of the remaining 85 patients, seven showed neutropenia (median 1.3, range 1.1–1.4 10/L) for 8% prevalence. The most frequent causes of secondary neutropenia were excluded and the patients were thus classified as having SLE-associated neutropenia. Baseline characteristics are shown in Table 1. On follow-up, 5/7 neutropenic patients had at least one infectious event, compared with 53/78 in non-neutropenic (cumulative incidence 71% and 68% over 39 months; p1⁄4 0.7). Incidence rates of infection were 57 cases/100 patients per year in neutropenic and 45 cases/100 patients per year in non-neutropenic cohorts (p1⁄4 0.11), while the proportion of patients that remain uninfected through the follow-up was similar (Figure 1). Although the frequency and severity of infections were similar (see Table 1), seven episodes of vulvovaginitis were seen in three patients with neutropenia in contrast to eight episodes in six non-neutropenic patients (43% vs. 8% of patients in each cohort; p1⁄4 0.02); these figures represent 35% and 6% from all infections, respectively (p1⁄4 0.0009). Leukocyte count remained unchanged between baseline and the occurrence of infection in neutropenic patients (median 3, range 2.5–4 vs. 2.4, 1.8–4.2 10/L; p1⁄4 0.3), while significantly increased in non-neutropenic (4.95, 2.5–8.2 vs. 5.55, 2.6–16.7 10/L; p1⁄4 0.01). Neutrophil count rose in non-neutropenic patients (3, 1.6–6.1 vs. 3.8, 1.7–15.6 10/L; p1⁄4 0.007) and it was unchanged in those with neutropenia (1.3, 1.1–1.4 vs. 1, 0.6–1.5 10/L; p1⁄4 0.1). After adjustment, concurrent use of corticosteroids in any dose was the only variable associated with the frequency of infections, conferring a relative risk of 1.92 (95% confidence interval (CI), 1.05–3.49; p1⁄4 0.04); while the use of >10mg/day of prednisone (or equivalent) increased the risk up to 3.1 (0.8 to 11.9). Of note, high doses of corticosteroids were not associated with the severity of infections. The small number of SLE patients with neutropenia included in this study precludes the reaching of robust conclusions; however, this is a first approach to assess the impact of the neutrophils count and the risk of infections in a real-life scenario, ambulatory SLE patients followed and monitored over long periods of time. Awaiting confirmation, our results suggest that mild neutropenia is frequent among ambulatory SLE patients and is associated with less chronic SLE damage. Even when 1–1.5 10/L neutrophils count seems not to increase the risk of infection in Correspondence to: Dr Luis M Amezcua-Guerra, Department of Immunology, Instituto Nacional de Cardiologı́a Ignacio Chavez, LaSalle University School of Medicine, Juan Badiano #1, Sección XVI, Tlalpan 14080, Mexico City, Mexico Email: lmamezcuag@gmail.com

Joint involvement in primary Sjögren's syndrome: an ultrasound "target area approach to arthritis".

Objective. To characterize the ultrasound (US) pattern of joint involvement in primary Sjögrens syndrome (pSS). Methods. Seventeen patients with pSS, 18 with secondary Sjögrens syndrome (sSS), and 17 healthy controls underwent US examinations of various articular regions. Synovitis (synovial hypertrophy/joint effusion), power Doppler (PD) signals, and erosions were assessed. Results. In patients with pSS, synovitis was found in the metacarpophalangeal joints (MCP, 76%), wrists (76%), and knees (76%), while the proximal interphalangeal joints, elbows, and ankles were mostly unscathed. Intra-articular PD signals were occasionally detected in wrists (12%), elbows (6%), and knees (6%). Erosions were evident in the wrists of three (18%) patients with pSS, one of these also having anti-cyclic citrullinated peptide (anti-CCP) antibodies. While US synovitis does not discriminate between sSS and pSS, demonstration of bone erosions in the 2nd MCP joints showed 28.8% sensitivity and 100% specificity for diagnosing sSS; in comparison, these figures were 72.2 and 94.1% for circulating anti-CCP antibodies. Conclusions. In pSS, the pattern of joint involvement by US is polyarticular, bilateral, and symmetrical. Synovitis is the US sign most commonly found in patients with pSS, especially in MCP joints, wrists, and knees, and bone erosions also may occur.

Anti-Ro/SSA antibodies are associated with severe mitral valve regurgitation in patients with systemic lupus erythematosus.

Abstract Objective: To assess whether anti-Ro/SSA antibodies are associated with cardiac valve disease in lupus. Methods: A single-center, medical chart review was performed. Lupus patients were divided according to its anti-Ro/SSA status and subgroups were compared for valvular abnormalities and other characteristics. Dependence of anti-Ro/SSA reactivity to anti-Ro52/TRIM21 antibodies was also evaluated. Results: Eighty-nine lupus patients were analyzed. The most common valvular abnormalities were tricuspid (60%), mitral (41%) and pulmonary (14%) regurgitation. Thirty-six patients were positive and 53 negative for anti-Ro/SSA antibodies. In patients positive to anti-Ro/SSA, a difference was noted for anti-dsDNA (67 versus 45%; p = 0.04) and anti-La/SSB (19 versus 2%; p = 0.004) antibodies. An association between anti-Ro/SSA antibodies and severe mitral regurgitation was observed; indeed, 4/15 patients with anti-Ro/SSA and mitral regurgitation had severe forms of valvulopathy as compared to only 1/22 patients with mitral regurgitation but negative to such antibody (27 versus 5%; p = 0.02). Anti-Ro/SSA antibodies significantly elevated the risk of severe mitral regurgitation (OR = 5). Anti-Ro52/TRIM21 levels (103 ± 29 versus 42 ± 43 U/mL; p = 0.03) and anti-Ro52/TRIM21: anti-Ro/SSA ratios (0.88 ± 0.02 versus 0.35 ± 0.37; p = 0.03) were higher in patients with mitral valve regurgitation than in those with no valvulopathy. Conclusion: Anti-Ro/SSA antibodies, mainly against Ro52/TRIM21 antigens, may be pathologically involved in lupus-associated mitral valve regurgitation.

The Story Behind the Acute-phase Reactants

Physicians usually try to quantify complex biological phenomena through simple laboratory assays. So several tests have been developed to assess the inflammatory response, a nonspecific intricate system of response against different aggressors that includes multiple mechanisms of innate and adaptive immunity. These tests are often used interchangeably or redundantly, on the assumption that all evaluate the same processes. In this vein Crowson and colleagues1 compared the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) to assess inflammation in patients with rheumatoid arthritis (RA). The authors conclude that it is not necessary to obtain both measures and that, where available, the CRP alone may be preferred for disease activity assessment. In the accompanying editorial2, … Address correspondence to Dr. Bojalil; E-mail: bojraf{at}yahoo.com

Type Iii Interferons in Systemic Lupus Erythematosus: Association Between Interferon λ3, Disease Activity, and Anti-ro/ssa Antibodies

Objective The aim of this study was to assess associations between serum type III (&lgr;) interferons (IFN-&lgr;) and disease activity in systemic lupus erythematosus (SLE). Methods Serum levels of IFN-&lgr;1, IFN-&lgr;2, and IFN-&lgr;3 were measured in 93 SLE patients and 67 healthy individuals. The associations with overall disease activity, organ-specific damage, and SLE-related antibodies were assessed. Results Median IFN-&lgr;1 levels were 0 pg/mL (range, 0–510 pg/mL) and 0 pg/mL (0–171 pg/mL; P = 0.814) in SLE patients and control subjects, respectively. These figures were 0 pg/mL (0–28 pg/mL) and 0 pg/mL (0–43 pg/mL; P = 0.659) for IFN-&lgr;2, as well as 83 pg/mL (0–965 pg/mL) and 42 pg/mL (0–520 pg/mL; P = 0.002) for IFN-&lgr;3, respectively. According to the Systemic Lupus Erythematosus Disease Activity Index categories, IFN-&lgr;3 levels were 44 pg/mL (0–158 pg/mL) in quiescent, 117 pg/mL (0–344 pg/mL) in mild, 79 pg/mL (0–965 pg/mL) in moderate, and 78 pg/mL (0–329 pg/mL) in severe disease, with the highest levels found in patients with serosal or cutaneous involvement. In line with this, IFN-&lgr;3 levels were inversely correlated with C3 (&rgr; = −0.44; 95% confidence interval, −0.62 to −0.20; P = 0.0003) and C4 (&rgr; = −0.40; 95% confidence interval, −0.59 to −0.15; P = 0.0001) complement proteins. In addition, higher IFN-&lgr;3 levels were found in patients positive for anti-Ro/SSA antibodies than in those negative for that antibody (122 pg/mL [0–965 pg/mL] vs. 0 pg/mL [0–165 pg/mL]; P = 0.001). The concentration of IFN-&lgr;3 also was higher in patients receiving glucocorticoids (104 pg/mL [0–965 pg/mL] vs. 30 pg/mL [0–165 pg/mL]; P = 0.009), and a dose-related effect was observed. Conclusions Interferon &lgr;3, a subtype of type III IFNs, is associated with the extent of lupus activity, in particular with active serosal and cutaneous disease. This association could be mechanistically related to anti-Ro/SSA antibodies.OBJECTIVE The aim of this study was to assess associations between serum type III (λ) interferons (IFN-λ) and disease activity in systemic lupus erythematosus (SLE). METHODS Serum levels of IFN-λ1, IFN-λ2, and IFN-λ3 were measured in 93 SLE patients and 67 healthy individuals. The associations with overall disease activity, organ-specific damage, and SLE-related antibodies were assessed. RESULTS Median IFN-λ1 levels were 0 pg/mL (range, 0-510 pg/mL) and 0 pg/mL (0-171 pg/mL; P = 0.814) in SLE patients and control subjects, respectively. These figures were 0 pg/mL (0-28 pg/mL) and 0 pg/mL (0-43 pg/mL; P = 0.659) for IFN-λ2, as well as 83 pg/mL (0-965 pg/mL) and 42 pg/mL (0-520 pg/mL; P = 0.002) for IFN-λ3, respectively. According to the Systemic Lupus Erythematosus Disease Activity Index categories, IFN-λ3 levels were 44 pg/mL (0-158 pg/mL) in quiescent, 117 pg/mL (0-344 pg/mL) in mild, 79 pg/mL (0-965 pg/mL) in moderate, and 78 pg/mL (0-329 pg/mL) in severe disease, with the highest levels found in patients with serosal or cutaneous involvement. In line with this, IFN-λ3 levels were inversely correlated with C3 (ρ = -0.44; 95% confidence interval, -0.62 to -0.20; P = 0.0003) and C4 (ρ = -0.40; 95% confidence interval, -0.59 to -0.15; P = 0.0001) complement proteins. In addition, higher IFN-λ3 levels were found in patients positive for anti-Ro/SSA antibodies than in those negative for that antibody (122 pg/mL [0-965 pg/mL] vs. 0 pg/mL [0-165 pg/mL]; P = 0.001). The concentration of IFN-λ3 also was higher in patients receiving glucocorticoids (104 pg/mL [0-965 pg/mL] vs. 30 pg/mL [0-165 pg/mL]; P = 0.009), and a dose-related effect was observed. CONCLUSIONS Interferon λ3, a subtype of type III IFNs, is associated with the extent of lupus activity, in particular with active serosal and cutaneous disease. This association could be mechanistically related to anti-Ro/SSA antibodies.

Type-III interferons and rheumatoid arthritis: Correlation between interferon lambda 1 (interleukin 29) and antimutated citrullinated vimentin antibody levels

Abstract Aim: To assess serum type III or lambda (λ) interferons (IFN) levels and its clinical and laboratory associations in rheumatoid arthritis (RA). Methods: A cross-sectional study including 43 patients with RA (86% females; age 45.3 ± 10.3 years) and 43 healthy individuals was performed. Clinical data including disease activity, acute-phase reactants, rheumatoid factor and anticyclic citrullinated peptide (anti-CCP) antibodies were collected. Serum IFNλ1, IFNλ2, IFNλ3, CXCL8 and anti-mutated citrullinated vimentin (anti-MCV) antibody levels were measured. Results: Patients with RA had higher IFNλ1 (113.5 ± 118.6 pg/mL versus 55.9 ± 122.3 pg/mL; p < 0.0001) and IFNλ2 (245.4 ± 327.7 pg/mL versus 5.1 ± 11.0 pg/mL; p = 0.009) levels than controls, but not IFNλ3 levels. Notably, IFNλ1 levels were found to be higher in both patients with active disease (124.9 ± 135.9 pg/mL; p < 0.001) and quiescent disease (99.0 ± 93.7 pg/mL; p < 0.01), while IFNλ2 levels were higher only in patients with active disease (264.0 ± 356.1 pg/mL; p = 0.02). A noteworthy association between serum IFNλ1 levels and anti-MCV antibody titers (Spearmans rho coefficient 0.36, 95% CI 0.36 to 0.61; p = 0.02) was observed. Conclusion: Serum IFNλ1 and IFNλ2 levels are abnormally elevated in patients with RA and the former are linearly associated with circulating anti-MCV antibody levels. These results may place type-III IFN as an attractive new therapeutic target in RA.

An imbalance in the T-helper phenotypes displayed by senescent CD4+CD28null T cells is associated with erosive arthritis (rhupus syndrome) in systemic lupus erythematosus.

Objective The objective was to assess the proportion of Th1, Th2 and Th17 phenotypes in senescent CD4+CD28null cells from patients with systemic lupus erythematosus (SLE) and its association with the pattern of joint involvement. Methods This cross-sectional study was performed in SLE patients with erosive arthritis (rhupus) or nondeforming, nonerosive arthritis. Total CD4+CD28null cells as well as the proportion of these cells expressing T-bet, GATA3 or RORγt were analyzed by color-flow cytometry. Serum osteopontin levels were measured by ELISA. Results Eighteen SLE patients (nine with rhupus and nine with nonerosive arthritis) were studied. The percentage of CD4+CD28null/CD4+ cells (17.7%, 10.3–25.0% versus 9.4%, 8.1–22.4%; P = 0.386) as well as the osteopontin levels (5800, 5,134–5995 pg/ml versus 5578, 5171–5717 pg/ml; P > 0.05) were similar in both groups. A higher percentage of CD4+CD28nullT-bet+ cells (42.8%, 33.5–53.4% versus 30.0%, 23.3–34.2%) but a lower percentage of CD4+CD28nullGATA3+ cells (3.1%, 1.7–5.6% versus 6.2%, 2.6–18.4%) was observed in patients with rhupus than in their counterparts (P = 0.016). The frequency of CD4+CD28nullRORγt+ cells was similar between groups. Conclusions In patients with rhupus, senescent CD4+CD28null cells are preferentially polarized to a Th1 phenotype, whereas this is partial towards Th2 in lupus patients with a nonerosive arthritis pattern.