Jens Møller Rasmussen

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.

A multicentre study of 513 Danish patients with systemic lupus erythematosus. I. Disease manifestations and analyses of clinical subsets

A Danish multicentre study was undertaken of the manifestations, infections, thrombotic events, survival and predictive factors of survival in 513 Danish patients with systemic lupus erythematosus (SLE) according to the 1982 classification criteria of the American College of Rheumatology. The mean duration of follow-up was 8.2 years from diagnosis and 12.8 years from first symptom. This paper describes the most common clinical and laboratory manifestations and their relationship to sex and age at the time of onset and diagnosis. Cluster analysis revealed three clinically defined clusters at the time of disease onset. Cluster 1 (57% of patients) consisted of relatively elderly patients without nephropathy or malar rash, but with a high prevalence of discoid lesions. Cluster 2 (18%) consisted of patients with nephropathy, a third of whom also developed serositis and lymphopenia. The patients of the third cluster (25%) all had malar rash and half were photosensitive. Follow-up showed that the patients of cluster 2 developed azotaemia, large proteinuria, arterial hypertension and myositis significantly more often than did the rest of the patients, but the mortality was not increased. The risk of developing renal end-stage disease was highest in men with early-onset disease.

A multicentre study of 513 Danish patients with systemic lupus erythematosus. II. Disease mortality and clinical factors of prognostic value.

In this Danish multicentre study, predictive clinical factors of mortality and survival were calculated for 513 patients with systemic lupus erythematosus (SLE), 122 of whom died within a mean observation period of 8.2 years equalling a mortality rate of 2.9% per year. Survival rates were 97%, 91%, 76% and 64% after 1, 5, 10 and 15 years, respectively. The direct causes of death included SLE (n=35_, infections (n=25), malignancy (n=9), cardiovascular disease (n=32) and other causes (n=21). Uni-and multivariate analyses of survival and mortality were performed for all deaths and for SLE-related deaths. Azotaemia (one-fifth of the patients) was a strong predictor of increased overall and SLE-related mortality, but nephropathy per se (one-half of the patients) and large proteinuria (one-sixth of the patients) were unrelated to survival. Haemolytic anaemia had a significant negative influence on survival related to mortality caused by infections. Diffuse central nervous system disease and myocarditis were related to increased SLE-related mortality, whereas photosensitivity predicted a decreased mortality. Non-fatal infections and thrombotic events predicted a decreased overall survival. Since 1980 the mortality caused by SLE manifestations has decreased significantly.

Complement receptor expression and activation of the complement cascade on B lymphocytes from patients with systemic lupus erythematosus (SLE).

It has previously been reported that the expression of the complement receptors, CR1 on erythrocytes and blood leucocytes and CR2 on B cells, is reduced in patients with SLE, and that the reduced expression of CR1 on erythrocytes is related to disease activity. We have earlier demonstrated that normal B cells are capable of activating the alternative pathway (AP) of complement in a CR2‐dependent fashion. In this study we have investigated whether disturbances in this activity may be related to the altered phenotype of SLE B cells. Flow cytometry was used to measure expression of complement receptors and regulatory proteins on B cells from SLE patients, as well as the deposition of C3 fragments occurring in vivo or after in vitro AP activation. We have confirmed, for a proportion of the patients studied, reduced expression of CR1 and CR2 on B cells, and shown a consistency between low CR2 expression and reduced in vitro AP activation in the presence of homologous, normal serum. In addition, the B cells, like erythrocytes, bear raised levels of in vivo‐deposited C3dg, but not C3b fragments, compared with normal B cells. The erythrocytes from SLE patients were unable to inhibit in vitro AP activation by B cells in homologous serum. Finally, we demonstrated an inverse relationship between SLE disease activity index (SLEDAI) and the expression of complement receptor 2 (CR2) on SLE B cells. Thus, determination of CR2 on B cells may emerge as an additional laboratory tool in the assessment of SLE activity.

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.

Factor I Deficiency and C3 Nephritic Factor: Immunochemical Findings and Association with Neisseria meningitidis Infection in Two Patients

The complement system was examined in two patients with systemic Neisseria meningitidis infections, both of whom had reduced or nondeteclable CH50 as analysed by both pathways. C3 measured by conventional technique revealed 19% anti‐C3c‐reactive protein in the plasma of patient 1 and 3% in patient 2. Patient 1 had circulating C3b but no detectable C3c, C3d, or C4d, whereas patient 2 had normal levels of C3c and C4d and strongly elevated levels of C3d. Factor B analysis revealed no demonstrable native factor B and small amounts of Bb in patient 1 and normal concentration of native factor B plus trace amounts of Bb in patient 2. The depletion of C3 in both patients was due to uncontrolled activation caused by complete factor I deficiency (patient 1) and circulating C3 nephritic factor (patient 2). Both parents of patient 1 had factor I concentrations below (mean‐2 SD) that seen in normal healthy individuals (n= 20). Circulating immune complexes (IC) were demonstrated in patient 1 only, whereas serum from both patients had strongly reduced capacity to solubilize preformed IC.

Separation of human peripheral blood monocytes on continuous density gradients of polyvinylpyrrolidone-coated silica gel (Percoll®)

A standardized, reproducible two-step method for separation of human peripheral blood monocytes on continuous Percoll gradients has been developed. The first step involves separation of mononuclear cell on Percoll of density 1.075 g/ml and the second step separation of monocytes from lymphocytes on a continuous Percoll gradient with a starting density of 1.075 g/ml for the formation of the gradient. The average yield during a 10 month period of daily routine use has been 74 +/- 17% (mean +/- 1 S.D.), and the average purity 63 +/- 10%. Ninety to 95% of the monocytes are viable after separation as judged from trypan blue exclusion and by ingestion of latex particles and sensitized sheep erythrocytes. The separation takes about 3 h and the total number of monocytes obtained from 40 ml of blood is in the range of 10-15 x 106. The procedure has been reliable with 3-4% separation failures, mainly due to bacterial or fungal growth in Percoll suspension or media. The contaminating cells are exclusively lymphocytes, predominantly T-lymphocytes (90-95%), when citrate is used as anticoagulant. Heparin can not be used as anticoagulant, as there appears to be a dose-dependent formation of thrombocyte aggregates which contaminate the monocytes, and result in poor separation.

A family with complement factor I deficiency.

A family with inherited factor I deficiency is described. The proband was a 19‐year‐old Caucasian female with one episode of meningococcal meningitis and one episode of suspected septicaemia of unknown cause. Two obligate and two probable heterozyotes with factor I levels below the lower limit of the reference range were identified. None of these exhibited increased susceptibility to infectious diseases. The inheritance was autosomal codominant. In addition, molecular heterogeneity of factor H in plasma from the proband but not from any other family members was demonstrated by crossed Immunoelectrophoresis. The migration of factor H component of fast electrophoretic mobility was retarded by antibodies to C3eand C3d. suggesting the presence of a fluid‐phase complex between factor H and excess C3h generated by the uncontrolled activity of the amplification loop.

Interaction between tramadol and phenprocoumon

We report an interaction between phenprocoumon (Marcoumar) and tramadol which led to an increase in International Normalised Ratio (INR) in two patients. A 54-year-old woman, otherwise healthy, with a suspected deep venous thrombosis in the left lower leg, was begun on heparin (10 000 IU twice daily) and phenprocoumon monitored by INR (therapeutic target range 2–3). Treatment was stopped after 2 days, because the diagnosis of deep venous thrombosis was not confirmed by ultrasonography. Tramadol (Nobligan, Grunenthal, Grunenthal GmbH, Aachen, Germany) 50–100 mg four times daily was given from day 3 for low back pain (figure). Her only other medication was paracetamol 1 g four times daily. As the INR kept rising despite withdrawal of phenprocoumon, phytomenadione (vitamin K1) 2 mg (day 5) and 5 mg (days 9–11) was given orally and the INR gradually fell to 0·9 (figure). On day 6, she had a nosebleed (INR 4·0). A 66-year-old woman with idiopathic lung fibrosis was admitted after a fall that resulted in fracture of a lumbar vertebra. Tramadol (Dolol, Nocomed Christianes, Chausee de Gand, Brussels, Belgium) 100 mg four times daily was prescribed for pain. Her other medication included estazolam 250 mg four times daily, diflunisal 50 mg three times daily, oxazepam 30 mg daily, calcium (400 mg) and vitamin D (5 g) twice daily, and paracetamol 1 g four times daily. 1 month later, she had a pulmonary embolism after an endoscopic retrograde cholangiopancreaticography, and treatment with heparin (12 500 IU twice daily) and phenprocoumon was begun. A rise in INR was seen and on day 6 phytomenadione 2 mg was given intramuscularly. Tramadol was stopped on day 8 and 3 days later, INR was stable at about 2 (figure). Albumin concentration, prothrombin time, and plasma transaminases were normal in both patients. Apart from tramadol, none of the prescribed drugs was suspected of affecting the anticoagulant effect of phenprocoumon. A pharmacodynamic interaction in which tramadol potentiated the action of phenprocoumon on vitamin K epoxide reductase may have caused the prolonged rise in INR. Several pharmacokinetic mechanisms are also possible. Increased absorption of phenprocoumon is unlikely because phenprocoumon is almost completely absorbed. An interaction caused by protein displacement of phenprocoumon (plasma protein binding 98–99%) and tramadol (plasma protein binding 20%) is unlikely because of the low protein binding of tramadol. A change in apparent volume of distribution is unlikely too, as none of the patients were oedematous at any time and both had normal serum creatinine. Tramadol is metabolised by CYP2D6, and phenprocoumon is probably metabolised by CYP2C9 but even so, we think the most likely mechanism for this interaction is inhibition of phenprocoumon metabolism in the liver by tramadol or one of its metabolites, as described for the drug interaction between warfarin and phenylbutazone. If tramadol is widely prescribed to older people taking anticoagulants this interaction should be monitored by frequent INR measurements. This advice also applies to warfarin, because adverse reports to the Danish Medicines Agency’s Committee on Adverse Drug Reactions suggest that tramadol increases the effect of both warfarin (three reports) and phenprocoumon (two reports).

An Epidemic Outbreak of Group B Meningococcal Disease on the Faroe Islands

An epidemic of group B meningococcal disease on the Faroe Islands is described. A peak annual incidence of 95 cases/100,000 was reached in 1981. The time at which the epidemic commenced cannot be determined due to inadequate diagnostic facilities, but was presumably around the end of the 1970s. The incidence fell to 29 cases/100,000 in 1985, which indicates that the Faroe Islands are still a high incidence area. A total of 203 cases of meningococcal disease were recorded during the period 1978-1985 with 11 deaths (lethality rate 5.4%). After rifampicin was introduced in 1981 as prophylactic treatment against secondary cases, 1,892 persons were treated with this agent and none of these appeared in the study population. Before rifampicin prophylaxis was introduced, the number of cases were distributed with an evenly increasing incidence in the capital and in the provinces. Following the introduction of rifampicin as prophylactic agent, a fall in the incidence in both areas was observed. This fall was more pronounced in the capital, where the number of prescribed prophylactic doses per case of meningococcal disease was higher than in the province.