Susanne Ullman

Mortality and Causes of Death of 513 Danish Patients with Systemic Lupus Erythematosus

A multicentre cohort of 513 clinic attenders with systemic lupus erythematosus (SLE) was retrospectively identified, representing 4185 patient-years of follow-up. Expected numbers of death were calculated by means of age- and sex-specific mortality rates of the general Danish population. The observed number of deaths was 122. The survival rates were 97%, 91%, 76%, 64% and 53% after 1, 5, 10, 15, and 20 years respectively. The overall mortality rate was 2.9% per year (95% CI 2.4-3.5), and the standardized mortality rate (SMR) was 4.6 (95% CI 3.8-5.5). The causes of death included active SLE (n = 19), end stage organ failure due to SLE (n = 16), infections (n = 25), malignancy (n = 9), cardiovascular disease (n = 32), and other causes (n = 21). SLE was directly related to one third of the excess mortality. In conclusion, SLE patients in the present cohort had a 4.6-fold increased mortality compared with the general population and half of the deaths were caused by SLE manifestations or infections, especially in young patients during the early period of the disease.

Clinical prediction of 5-year survival in systemic sclerosis: validation of a simple prognostic model in EUSTAR centres

Objective Systemic sclerosis (SSc) is associated with a significant reduction in life expectancy. A simple prognostic model to predict 5-year survival in SSc was developed in 1999 in 280 patients, but it has not been validated in other patients. The predictions of a prognostic model are usually less accurate in other patients, especially from other centres or countries. A study was undertaken to validate the prognostic model to predict 5-year survival in SSc in other centres throughout Europe. Methods A European multicentre cohort of patients with SSc diagnosed before 2002 was established. Patients with SSc according to the preliminary American College of Rheumatology classification criteria were eligible for the study when they were followed for at least 5 years or shorter if they died. The primary outcome was 5-year survival after diagnosis of SSc. The predefined prognostic model uses the following baseline variables: age, gender, presence of urine protein, erythrocyte sedimentation rate (ESR) and carbon monoxide diffusing capacity (DLCO). Results Data were available for 1049 patients, 119 (11%) of whom died within 5 years after diagnosis. Of the patients, 85% were female, the mean (SD) age at diagnosis was 50 (14) years and 30% were classified as having diffuse cutaneous SSc. The prognostic model with age (OR 1.03), male gender (OR 1.93), urine protein (OR 2.29), elevated ESR (1.89) and low DLCO (OR 1.94) had an area under the receiver operating characteristic curve of 0.78. Death occurred in 12 (2.2%) of 509 patients with no risk factors, 45 (13%) of 349 patients with one risk factor, 55 (33%) of 168 patients with two risk factors and 7 (30%) of 23 patients with three risk factors. Conclusion A simple prognostic model using three disease factors to predict 5-year survival at diagnosis in SSc showed reasonable performance upon validation in a European multicentre study.

Prognostic value of renal biopsy and clinical variables in patients with lupus nephritis and normal serum creatinine.

OBJECTIVE To evaluate factors with possible influence on the renal outcome in patients with lupus nephritis but without chronic renal insufficiency (CRI). METHODS Renal biopsies from 94 patients were re-assessed with regard to WHO class, activity, chronicity and tubulointerstitial indices without knowledge of clinical features. The outcome parameters were CRI defined as irreversibly increased serum creatinine and renal end stage disease. RESULTS The risk ratios (RR) of developing CRI were 2.6 for active urinary sediment, 3.1 for hyaline thrombi and 7.3 for glomerular leukocyte exudation. The RR of renal end stage disease was 5.0 when the duration of renal disease exceeded one year at the time of biopsy and 4.3 when biopsy disclosed a class IV lesion. Glomerular sclerosis was also associated to renal end stage disease. CONCLUSION Early renal biopsy and the abovementioned signs of active renal disease carry prognostic information that may have significant therapeutic implications.

A Randomized Trial of Etretinate (Tigason®) in Palmoplantar Pustulosis

5 patients with palmoplantar pustulosis (PPP) were randomized to 8 weeks of daily treatment with either oral etretinate, 1 mg/kg b.w. or placebo. Good or moderate effect was obtained in 18 or 20 patients on etretinate compared o 6 of 21 patients on placebo (p less than 0.001). Etretinate proved to be significantly superior to placebo with regard to influence on the individual symptoms and signs of pustulosis. All patients on etretinate experienced some side effects from the mucous membranes, but they were generally mild. Treatment was discontinued after 4 weeks in 3 patients for reasons unrelated to treatment, in 4 for lack of effect (all on placebo) and in 2 for side effects (both or etretinate). Etretinate is a good alternative to other systemic treatments of PPP.

Mapping and predicting mortality from systemic sclerosis

Objectives To determine the causes of death and risk factors in systemic sclerosis (SSc). Methods Between 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation. Results We identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile. Conclusion Combining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients’ survival.

Xeroderma pigmentosum lesions related to ultraviolet transmittance by clothes

Xeroderma pigmentosum is associated with severe actinic degeneration of the skin. Our patient with xeroderma pigmentosum showed increasing actinic damage in some areas covered by clothes. We therefore performed a complete evaluation of the patients exposure to ultraviolet radiation. This included transmission measurements of the patients clothes, glasses, and car windows. The transmission of UVB (280 to 320 nm) by the clothes varied from none to 17.8%. The transmitted UVB radiation was proportional to the clinical manifestations of xeroderma pigmentosum. The patients wardrobe was changed, and UVA-blocking film was applied to the windows of the car and house. A decline in manifestations was seen after 18 months of improved ultraviolet protection.

Follow-up of 151 patients with high-titer U1RNP antibodies

SummaryWe performed a longitudinal follow-up study of clinical findings in 151 patients with high-titer antibodies against U1 ribonucleoprotein (U1RNP) as measured by haemagglutination. Formal connective tissue disease (CTD) diagnoses were assigned and diagnostic transitions analysed.One-hundred eighteen females and 33 males entered the study; the mean duration of follow-up was 7.1 years. Mean age at entry was 34.7 years; 73% of the patients had early disease (duration <2 years). Fifty-six patients (37%) presented with a definite diagnosis, most often mixed connective tissue disease (MCTD, n=40), followed by systemic lupus erythematosus (SLE, n=11) and systemic sclerosis (SSc, n=5). Of 84 patients (56%) presenting with nonspecific symptoms of possible, “undifferentiated” CTD, 58 developed MCTD, 4 SSc and 2 SLE. By the end of the follow-up period, 127 patients had developed a well-defined CTD; final diagnoses were: MCTD (n=97), SLE (n=18), SSc (n=12).We conclude that CTD in the context of high-titer anti-U1RNP antibodies may be transitive and sequential in nature, although the diagnostic criteria for MCTD previously proposed by our group seem to delimit a clinically stable condition in most patients in this subgroup.

Skin signs in Ehlers–Danlos syndrome: clinical tests and para-clinical methods

Objective: The criteria for Ehlers–Danlos syndrome (EDS) and the hypermobility syndrome (HMS) should be reliable. Examination for general joint hypermobility has high reliability but there is only sparse information on the reliability of skin tests, and no information on the level of normal skin extensibility. The present study aimed to assess skin signs by means of clinical and para-clinical methods. Methods: A total of 31 EDS patients and 28 healthy controls were examined blinded and in random order. Inter-examiner analysis of clinical tests for skin extensibility, consistency, scarring, and bruising was performed, followed by analyses of extensibility with the suction cup (SC), consistency with a soft tissue stiffness meter (STSM), and thickness with ultrasonography (US). Semi-quantitative assessment of skin extensibility in healthy controls was incorporated in the tests. Results: The clinical analyses demonstrated kappa values of: 0.72 for extensibility, 0.23 for consistency, 0.53 for scarring, and 0.63 for bruising. Skin extensibility measurements in healthy controls (n = 28) were 2.79 and 2.93 cm (mean + 2 SD), respectively, by the two examiners. There were significant differences between patients with classical-type EDS and controls with respect to skin extensibility by SC (4.91 vs. 12.52 kPa/mm) and skin consistency by STSM (0.59 vs. 0.76 N). We found no difference in skin thickness. Conclusion: The reproducibility of the clinical skin tests was substantial to good, apart from the consistency measurements. We suggest that skin consistency is withdrawn as a diagnostic criterion. The upper level for normal skin extensibility should be 3 cm. SC and STSM are promising para-clinical methods, but their diagnostic sensitivity and specificity need to be determined.

Value of systolic pulmonary arterial pressure as a prognostic factor of death in the systemic sclerosis EUSTAR population.

Objective. The aim of this study was to assess the prognostic value of systolic pulmonary artery pressure (sPAP) estimated by echocardiography in the multinational European League Against Rheumatism Scleroderma Trial and Research (EUSTAR) cohort. Methods. Data for patients with echocardiography documented between 1 January 2005 and 31 December 2011 were extracted from the EUSTAR database. Stepwise forward multivariable statistical Cox pulmonary hypertension analysis was used to examine the independent effect on survival of selected variables. Results. Based on our selection criteria, 1476 patients were included in the analysis; 87% of patients were female, with a mean age of 56.3 years (s.d. 13.5) and 31% had diffuse SSc. The mean duration of follow-up was 2.0 years (s.d. 1.2, median 1.9). Taking index sPAP of <30 mmHg as reference, the hazard ratio (HR) for death was 1.67 (95% CI 0.92, 2.96) if the index sPAP was between 30 and 36 mmHg, 2.37 (95% CI 1.14, 4.93) for sPAP between 36 and 40 mmHg, 3.72 (95% CI 1.61, 8.60) for sPAP between 40 and 50 mmHg and 9.75 (95% CI 4.98, 19.09) if sPAP was >50 mmHg. In a multivariable Cox model, sPAP and the diffusing capacity for carbon monoxide (DLCO) were independently associated with the risk of death [HR 1.833 (95% CI 1.035, 3.247) and HR 0.973 (95% CI 0.955, 0.991), respectively]. sPAP was an independent risk factor for death with a HR of 3.02 (95% CI 1.91, 4.78) for sPAP ≥36 mmHg. Conclusion. An estimated sPAP >36 mmHg at baseline echocardiography was significantly and independently associated with reduced survival, regardless of the presence of pulmonary hypertension based on right heart catheterization.

The Immunological and Clinical Outcome of HIV Infection: 31 Months of Follow-up in a Cohort of Homosexual Men

T-cell subsets, antibodies (Ab) against human immunodeficiency virus (HIV) and clinical status were evaluated during a 31 (24-35) month follow-up study of homosexual men. The study group included 50 homosexual men, with many sexual partners, who by 1982-83 were without symptoms and had a prevalence of HIV Ab of 38%. Among the men who were seropositive on the initial investigation a significant decrease occurred in the absolute number of CD4+ lymphocytes (p less than 0.01). 88% of these men experienced a decrease, and by follow-up 59% had CD4+ lymphocytes below the normal range. Also the men who seroconverted during the study had a significant decrease in CD4+ lymphocytes, while no changes were observed in the seronegative group. None of the subgroups had significant changes in CD8+ lymphocyte number. AIDS or AIDS related complex developed in 33% of the men seropositive at inclusion. None of these clinical syndromes developed in the seroconverting or the seronegative group. The men who eventually developed clinical symptoms did not differ significantly from the healthy HIV Ab positive persons, with respect to lifestyle parameters, presence of lymphadenopathy and isolation of cytomegalovirus. However, they had significantly lower CD4+ cells and CD4/CD8 ratio (p less than 0.01) at inclusion. It is concluded that in the majority of persons infected with HIV, phenotypic T-cell alterations will occur with a latency of years, but it remains to be seen if the alterations necessarily will result in clinical manifestations. Further, T-cell subset determination among healthy HIV Ab positive persons will provide prognostic information.