M. Ramos-Casals

Systemic lupus erythematosus (SLE) in childhood: analysis of clinical and immunological findings in 34 patients and comparison with SLE characteristics in adults

OBJECTIVE To define the pattern of disease expression in patients with childhood onset systemic lupus erythematosus (SLE). METHODS Prospective analysis of clinical manifestations and immunological features of 34 patients in whom the first manifestations appeared in childhood from a series of 430 unselected patients with SLE. RESULTS Thirty one (91%) patients from the childhood onset group were female and three male (9%) (ratio female/male, 10/1, with no difference compared with the adult onset group). Mean age of this group at disease onset was 11 years (range 5–14) compared with 32 years (15–48) for the remaining patients. The childhood onset patients more often had nephropathy (20%v 9% in adult onset SLE, p=0.04; OR:2.7; 95%CI:1.1, 7), fever (41% v 21%, p=0.006; OR:2.6, 95%CI:1.2, 5.7), and lymphadenopathy (6%v 0.5%, p=0.03, OR: 12.3, 95%CI: 1.2, 127.6), as presenting clinical manifestations. During the evolution of the disease, the childhood onset patients had an increased prevalence of malar rash (79% v 51%, p=0.002; OR:3.7; 95%CI:1.5, 9.5) and chorea (9% v 0%, p<0.0001). This group exhibited a higher prevalence of anticardiolipin antibodies (aCL) of the IgG isotype when compared with the remaining patients (29% v 13%, p=0.017; OR:2.9, 95%CI:1.2, 6.8). No significant differences were found among the other antibodies between the two groups. Childhood onset patients more often received azathioprine (15% v 6%, p=0.00004; OR:11.2; 95%CI:2.8, 44.9) but no differences were detected between the groups concerning side effects or drug toxicity. CONCLUSIONS The presentation and the clinical course of SLE varied in this series of 430 patients depending on their age at disease onset. Nephropathy, fever, and lymphadenopathy were more common in childhood onset patients as presenting clinical manifestations, while malar rash, chorea, and detection of IgG aCL were more common during the evolution of the disease.

Cryoglobulinemia in primary Sjögren's syndrome: Prevalence and clinical characteristics in a series of 115 patients

OBJECTIVES To determine the prevalence and nature of cryoglobulins in a large series of patients with primary Sjögrens syndrome (SS) and identify the clinical and immunologic features related to their presence. METHODS In a cross-sectional study, we investigated 115 consecutive patients (107 women and eight men) with primary SS. All patients fulfilled four or more of the preliminary diagnostic criteria for SS proposed by the European Community Study Group in 1993. Serum cryoglobulinemia was measured in all patients. Serum samples were obtained at 37 degrees C, and cryoglobulinemia was estimated by centrifugation after incubation at 4 degrees C for 7 days. The type of cryoglobulinemia was identified by agarose gel electrophoresis and immunofixation. RESULTS Cryoglobulins were detected in the sera of 18 (16%) of our patients with primary SS; most were IgMkappa monoclonal/IgG polyclonal. When compared with patients without cryoglobulins, those with cryoglobulins presented a higher prevalence of leukocytoclastic cutaneous vasculitis (56% v8%, P < .001), hypocomplementemia (75% v 2%; P < 0.001) and antibodies to hepatitis C virus (HCV) (47% v8%, P < .001). Liver involvement (clinical signs, biochemical features, or ultrasound/histological data of liver disease) was present in all patients (100%) with cryoglobulins and HCV infection but in only 11% of patients with cryoglobulins without HCV infection (P < .001). CONCLUSIONS Leukocytoclastic cutaneous vasculitis, hypocomplementemia, and HCV infection are associated with the presence of cryoglobulins in the sera of patients with primary SS. Testing for HCV infection is recommended for patients with SS and cryoglobulinemia because of its high prevalence and its strong association with liver disease.

Validation of EULAR primary Sjögren's syndrome disease activity (ESSDAI) and patient indexes (ESSPRI)

Objectives To validate the two recently developed disease activity indexes for assessment of primary Sjögrens syndrome (SS): the European League Against Rheumatism (EULAR) SS Patient Reported Index (ESSPRI) and the EULAR SS Disease Activity Index (ESSDAI). Methods A prospective international 6-month duration validation study was conducted in 15 countries. At each visit, physicians completed ESSDAI, SS disease activity index (SSDAI), Sjögrens Systemic Clinical Activity Index (SCAI) and physician global assessment (PhGA); and patients completed ESSPRI, Sicca Symptoms Inventory (SSI), Profile of Fatigue and Discomfort (PROFAD) and patient global assessment (PGA). Psychometric properties (construct validity, responsiveness and reliability) were evaluated and compared between scores. Results Of the 395 patients included, 145 (37%) and 251 (64%) had currently active or current or past systemic manifestations, respectively. EULAR scores had higher correlation with the gold standard than other scores (ESSDAI with PhGA: r=0.59; ESSRPI with PGA: r=0.70). Correlations between patient and systemic scores were very low (ranging from 0.07 to 0.29). All systemic scores had similar large responsiveness in improved patients. Responsiveness of patient scores was low but was significantly higher for ESSPRI compared with SSI and PROFAD. Reliability was very good for all scores. Conclusions ESSDAI and ESSPRI had good construct validity. All scores were reliable. Systemic scores had a large sensitivity to change in patients whose disease activity improves. Patient scores had a small sensitivity to change, however, significantly better for ESSPRI. Systemic and patient scores poorly correlated, suggesting that they are 2 complementary components that should be both evaluated, but separately.

Association of antiphospholipid antibodies with retinalvascular disease in systemic lupus erythematosus

OBJECTIVES To study the prevalence and characteristics of retinal vascular disease in patients with systemic lupus erythematosus (SLE) and to analyze their relationship with antiphospholipid antibodies (aPL) and other serological markers. PATIENTS AND METHODS Eighty-two consecutive patients (77 women and 5 men; mean age, 36 years) were studied. All patients fulfilled the 1982 revised criteria of the American College of Rheumatology for the classification of SLE. Ophthalmologic examination included assessment of best corrected visual acuity, tonometry, slit-lamp biomicroscopy, and fundus examination. Serologic studies included determination of anticardiolipin antibodies (aCL) (ELISA), lupus anticoagulant (LA) (coagulation tests), antinuclear antibodies (indirect immunofluorescence), anti-DNA (Farrs test), and anti-ENA antibodies (counterimmunoelectrophoresis). RESULTS Retinal vascular disease was detected in 13 (15%) of 82 SLE patients. The retinal lesions consisted of retinal vascular occlusions in six patients (five arterial and one venous), cotton-wool spots in three, optic disc edema in three, retinal hemorrhages in three, and ischemic optic neuropathy in one. Antiphospholipid antibodies were detected in 10 (77%) of these 13 patients: nine had aCL and two had the LA. When compared with patients without retinal vascular disease, patients with retinopathy had a higher prevalence of aPL (77% v. 29%, P = .005). CONCLUSIONS Retinal vascular disease is frequent in patients with SLE. The presence of aPL is associated with a higher prevalence of retinal abnormalities in SLE patients.

Defining disease activity states and clinically meaningful improvement in primary Sjögren's syndrome with EULAR primary Sjögren's syndrome disease activity (ESSDAI) and patient-reported indexes (ESSPRI)

Objectives To define disease activity levels, minimal clinically important improvement (MCII) and patient-acceptable symptom state (PASS) with the primary Sjögrens syndrome (SS) disease activity indexes: European League Against Rheumatism (EULAR) SS disease activity index (ESSDAI) and EULAR SS patient-reported index (ESSPRI). Methods For 790 patients from two large prospective cohorts, ESSDAI, physician evaluation of disease activity, ESSPRI and patients’ satisfaction with their current health status were recorded. Receiver operating characteristic curve analyses and anchoring methods were used to estimate disease activity levels of ESSDAI and the PASS of ESSPRI. At follow-up visit, patients and physicians assessed, respectively, whether symptoms and disease activity have improved or not. An anchoring method based on this evaluation was used to estimate MCII of ESSDAI and ESSPRI. Results Low-activity (ESSDAI<5), moderate-activity (5≤ESSDAI≤13) and high-activity (ESSDAI≥14) levels were defined. MCII of ESSDAI was defined as an improvement of at least three points. The PASS estimate was defined as an ESSPRI<5 points and MCII as a decrease of at least one point or 15%. Conclusions This study determined disease activity levels, PASS and MCII of ESSDAI and ESSPRI. These results will help designing future clinical trials in SS. For evaluating systemic complications, the proposal is to include patients with moderate activity (ESSDAI≥5) and define response to treatment as an improvement of ESSDAI at least three points. For addressing patient-reported outcomes, inclusion of patients with unsatisfactory symptom state (ESSPRI≥5) and defining response as an improvement of ESSPRI at least one point or 15% seems reasonable.

Outcome measures for primary Sjogren's syndrome

Lymphocytic infiltration of different exocrine and non-exocrine epithelia is the pathological hallmark of primary Sjögrens syndrome, whereas involvement of salivary and lachrymal glands with the clinical counterpart of dry eye and dry mouth are the predominant features of the disease, together with fatigue and musculoskeletal pain. In addition, systemic manifestations, like arthritis, skin vasculitis, peripheral neuropathy, glomerulonephritis, may also be present in a consistent number of patients. As result, clinical features in SS can be divided into two facets: the benign subjective but disabling manifestations such as dryness, pain and fatigue, and the systemic manifestations. In the past decades, a core set of domains, which included sicca symptoms, objective measurements of tear and saliva production, fatigue, quality of life, disease activity and damage was indicated as essential for outcome assessment in this disorder. Afterwards, great efforts have been made to develop valid tools for the assessment of different domains. Specific questionnaires such as the Profile of Fatigue and Discomfort (PROFAD) and Sicca Symptoms Inventory (SSI) have been proposed as dedicated tools for the evaluation of patients symptoms, whereas different composite indexes have been suggested for the assessment of disease activity and damage. Some of these preliminary studies served as bases of an international project supported by EULAR, aimed at developing two consensus disease activity indexes: the EULAR Sjögrens Syndrome Patients Reported Index (ESSPRI), and the EULAR Sjögrens Syndrome Disease Activity Index (ESSDAI), a systemic activity index to assess systemic manifestations. A detailed and critical review of all these indexes is provided in this article. Both EULAR indexes showed, in recent studies, to be feasible, valid, and reliable instruments. After their final validation, which is currently in process, they could be used as consensus outcome criteria in therapeutic trials and in clinical practice.

Systemic activity and mortality in primary Sjögren syndrome: predicting survival using the EULAR-SS Disease Activity Index (ESSDAI) in 1045 patients

Objective To score systemic activity at diagnosis and correlate baseline activity with survival in a large cohort of patients with primary Sjögren syndrome (SS). Patients and methods We include 1045 consecutive patients who fulfilled the 2002 classification criteria for primary SS. The clinical and immunological characteristics and level of activity (EULAR-SS Disease Activity Index (ESSDAI) scores) were assessed at diagnosis as predictors of death using Cox proportional hazards regression analysis adjusted for age at diagnosis. The risk of death was calculated at diagnosis according to four different predictive models. Results After a mean follow-up of 117 months, 115 (11%) patients died. The adjusted standardised mortality ratio for the total cohort was 4.66 (95% CI 3.85 to 5.60), and survival rates at 5, 10, 20 and 30 years were 96%, 90%, 81% and 60%, respectively. The main baseline factors associated with overall mortality in the multivariate analysis were male gender, cryoglobulins and low C4 levels. Baseline activity in the constitutional, pulmonary and biological domains was associated with a higher risk of death. High activity in at least one ESSDAI domain (HR 2.14), a baseline ESSDAI score ≥14 (HR 1.85) and more than one laboratory predictive marker (lymphopenia, anti-La, monoclonal gammopathy, low C3, low C4 and/or cryoglobulins) (HR 2.82) were associated with overall mortality; these HRs increased threefold to 10-fold when the analysis was restricted to mortality associated with systemic disease. Conclusions Patients with primary SS, who present at diagnosis with high systemic activity (ESSDAI ≥14) and/or predictive immunological markers (especially those with more than one), are at higher risk of death.

EULAR Sjögren's syndrome disease activity index (ESSDAI): a user guide

The EULAR Sjögrens syndrome (SS) disease activity index (ESSDAI) is a systemic disease activity index that was designed to measure disease activity in patients with primary SS. With the growing use of the ESSDAI, some domains appear to be more challenging to rate than others. The ESSDAI is now in use as a gold standard to measure disease activity in clinical studies, and as an outcome measure, even a primary outcome measure, in current randomised clinical trials. Therefore, ensuring an accurate and reproducible rating of each domain, by providing a more detailed definition of each domain, has emerged as an urgent need. The purpose of the present article is to provide a user guide for the ESSDAI. This guide provides definitions and precisions on the rating of each domain. It also includes some minor improvement of the score to integrate advance in knowledge of disease manifestations. This user guide may help clinicians to use the ESSDAI, and increase the reliability of rating and consequently of the ability to detect true changes over time. This better appraisal of ESSDAI items, along with the recent definition of disease activity levels and minimal clinically important change, will improve the assessment of patients with primary SS and facilitate the demonstration of effectiveness of treatment for patients with primary SS.

Registry of the Spanish Network for Systemic Sclerosis: Survival, Prognostic Factors, and Causes of Death.

AbstractSystemic sclerosis (SSc) is a rare, multisystem disease showing a large individual variability in disease progression and prognosis. In the present study, we assess survival, causes of death, and risk factors of mortality in a large series of Spanish SSc patients. Consecutive SSc patients fulfilling criteria of the classification by LeRoy were recruited in the survey. Kaplan–Meier and Cox proportional-hazards models were used to analyze survival and to identify predictors of mortality. Among 879 consecutive patients, 138 (15.7%) deaths were registered. Seventy-six out of 138 (55%) deceased patients were due to causes attributed to SSc, and pulmonary hypertension (PH) was the leading cause in 23 (16.6%) patients. Survival rates were 96%, 93%, 83%, and 73% at 5, 10, 20, and 30 years after the first symptom, respectively. Survival rates for diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc were 91%, 86%, 64%, and 39%; and 97%, 95%, 85%, and 81% at 5, 10, 20, and 30 years, respectively (log-rank: 67.63, P < 0.0001). The dcSSc subset, male sex, age at disease onset older than 65 years, digital ulcers, interstitial lung disease (ILD), PH, heart involvement, scleroderma renal crisis (SRC), presence of antitopoisomerase I and absence of anticentromere antibodies, and active capillaroscopic pattern showed reduced survival rate. In a multivariate analysis, older age at disease onset, dcSSc, ILD, PH, and SRC were independent risk factors for mortality. In the present study involving a large cohort of SSc patients, a high prevalence of disease-related causes of death was demonstrated. Older age at disease onset, dcSSc, ILD, PH, and SRC were identified as independent prognostic factors.

Hepatitis G virus infection in primary Sjögren’s syndrome: analysis in a series of 100 patients

OBJECTIVE To determine the prevalence and clinical significance of hepatitis G virus (HGV) infection in a large cohort of patients with primary Sjögren’s syndrome (SS). PATIENTS AND METHODS The study included 100 consecutive patients (92 female and eight male), with a mean age of 62 years (range 31–80) that were prospectively visited in our unit. All patients fulfilled the European Community criteria for SS and underwent a complete history, physical examination, as well as biochemical and immunological evaluation for liver disease. Two hundred volunteer blood donors were also studied. The presence of HGV-RNA was investigated in the serum of all patients and donors. Aditionally, HBsAg and antibodies to hepatitis C virus were determined. RESULTS Four patients (4%) and six volunteer blood donors (3%) presented HGV-RNA sequences in serum. HGV infection was associated with biochemical signs of liver involvement in two (50%) patients. When compared with primary SS patients without HGV infection, no significant differences were found in terms of clinical or immunological features. HCV coinfection occurs in one (25%) of the four patients with HGV infection. CONCLUSION The prevalence of HGV infection in patients with primary SS is low in the geographical area of the study and HCV coinfection is very uncommon. HGV infection alone does not seen to be an important cause of chronic liver injury in the patients with primary SS in this area.