Da Isenberg

Analysis of the relationship between disease activity and damage in patients with systemic lupus erythematosus—a 5-yr prospective study

OBJECTIVE To determine whether initial damage, disease duration, age, initial health status, average disease activity over the 5 yr or an average medication score covering the follow-up period would predict an increase in damage in patients with systemic lupus erythematosus (SLE) within the next 5 yr. METHODS A 5-yr prospective longitudinal study of a cohort of 141 consecutive patients with SLE attending a specialist lupus out-patient clinic in London from their first assessment between July 1994 and February 1995. Disease activity was assessed using the BILAG system, initial health status by the Medical Outcome Survey Short Form 20 with an extra question about fatigue (SF-20+) and damage by the SLICC/ACR Damage Index (SDI). Damage was reassessed 5 yr later. Statistical analysis was carried out using multiple logistic regression analysis (logXact). RESULTS One hundred and thirty-three female and eight male SLE patients (97 Caucasians, 16 Afro-Caribbeans, 22 Asians and 6 others) were included, their age at inclusion was 41.1 +/- 12.5 yr and their disease duration 10.2 +/- 6.3 yr. The mean measures at inclusion were: total BILAG 5.2 (range 0-17), total SDI 1.2 (0-7) and medication score 1.2 (0-3). Six patients were lost to follow-up because they had moved. Of the remaining 135 patients total damage had increased in 40 patients and 10 patients had died. At the end of the study, at 4.63 +/- 0.19 yr, the total SDI had increased to 1.6 +/- 1.7. Multiple logistic regression analysis revealed that death and increase in damage were strongly predicted by a high total disease activity over the entire study period (P<0.001) as we had hypothesized. When the total BILAG score was replaced by the average number of A-flares the prediction of accrual of damage during the study period was again highly significant (P = 0.004). CONCLUSIONS In this first prospective study of its type a highly significant impact of total disease activity, as measured over 5 yr using the BILAG system, on the development of total damage was revealed. Moreover, these results provide further proof of the validity of the SDI and support the BILAG concept of the A-flares.

Autoantibodies in systemic lupus erythematosus: comparison of historical and current assessment of seropositivity

Systemic lupus erythematosus (SLE) is characterized by multiple autoantibodies and complement activation. Recent studies have suggested that anti-nuclear antibody (ANA) positivity may disappear over time in some SLE patients. Anti-double-stranded DNA (dsDNA) antibody titers and complement levels may vary with time and immunosuppressive treatment, while the behavior of anti-extractable nuclear antigen (ENA) over time is less well understood. This study sought to determine the correlation between historical autoantibody tests and current testing in patients with SLE. Three hundred and two SLE patients from the ACR Reclassification of SLE (AROSE) database with both historical and current laboratory data were selected for analysis. The historical laboratory data were compared with the current autoantibody tests done at the reference laboratory and tested for agreement using percent agreement and Kappa statistic. Serologic tests included ANA, anti-dsDNA, anti-Smith, anti-ribonucleoprotein (RNP), anti-Ro, anti-La, rheumatoid factor (RF), C3 and C4. Among those historically negative for immunologic markers, a current assessment of the markers by the reference laboratory generally yielded a low percentage of additional positives (3–13%). However, 6/11 (55%) of those historically negative for ANA were positive by the reference laboratory, and the reference laboratory test also identified 20% more patients with anti-RNP and 18% more with RF. Among those historically positive for immunologic markers, the reference laboratory results were generally positive on the same laboratory test (range 57% to 97%). However, among those with a history of low C3 or C4, the current reference laboratory results indicated low C3 or C4 a low percentage of the time (18% and 39%, respectively). ANA positivity remained positive over time, in contrast to previous studies. Anti-Ro, La, RNP, Smith and anti-dsDNA antibodies had substantial agreement over time, while complement had less agreement. This variation could partially be explained by variability of the historical assays, which were done by local laboratories over varying periods of time. Variation in the results for complement, however, is more likely to be explained by response to treatment. These findings deserve consideration in the context of diagnosis and enrolment in clinical trials.

Anti-C1q antibodies in systemic lupus erythematosus

Objective Anti-C1q has been associated with systemic lupus erythematosus (SLE) and lupus nephritis in previous studies. We studied anti-C1q specificity for SLE (vs rheumatic disease controls) and the association with SLE manifestations in an international multicenter study. Methods Information and blood samples were obtained in a cross-sectional study from patients with SLE (n = 308) and other rheumatologic diseases (n = 389) from 25 clinical sites (84% female, 68% Caucasian, 17% African descent, 8% Asian, 7% other). IgG anti-C1q against the collagen-like region was measured by ELISA. Results Prevalence of anti-C1q was 28% (86/308) in patients with SLE and 13% (49/389) in controls (OR = 2.7, 95% CI: 1.8–4, p < 0.001). Anti-C1q was associated with proteinuria (OR = 3.0, 95% CI: 1.7–5.1, p < 0.001), red cell casts (OR = 2.6, 95% CI: 1.2–5.4, p = 0.015), anti-dsDNA (OR = 3.4, 95% CI: 1.9–6.1, p < 0.001) and anti-Smith (OR = 2.8, 95% CI: 1.5–5.0, p = 0.01). Anti-C1q was independently associated with renal involvement after adjustment for demographics, ANA, anti-dsDNA and low complement (OR = 2.3, 95% CI: 1.3–4.2, p < 0.01). Simultaneously positive anti-C1q, anti-dsDNA and low complement was strongly associated with renal involvement (OR = 14.9, 95% CI: 5.8–38.4, p < 0.01). Conclusions Anti-C1q was more common in patients with SLE and those of Asian race/ethnicity. We confirmed a significant association of anti-C1q with renal involvement, independent of demographics and other serologies. Anti-C1q in combination with anti-dsDNA and low complement was the strongest serological association with renal involvement. These data support the usefulness of anti-C1q in SLE, especially in lupus nephritis.

Cardiovascular events prior to or early after diagnosis of systemic lupus erythematosus in the systemic lupus international collaborating clinics cohort

Objective To describe the frequency of myocardial infarction (MI) prior to the diagnosis of systemic lupus erythematosus (SLE) and within the first 2 years of follow-up. Methods The systemic lupus international collaborating clinics (SLICC) atherosclerosis inception cohort enters patients within 15 months of SLE diagnosis. MIs were reported and attributed on a specialised vascular event form. MIs were confirmed by one or more of the following: abnormal ECG, typical or atypical symptoms with ECG abnormalities and elevated enzymes (≥2 times upper limit of normal), or abnormal stress test, echocardiogram, nuclear scan or angiogram. Descriptive statistics were used. Results 31 of 1848 patients who entered the cohort had an MI. Of those, 23 patients had an MI prior to SLE diagnosis or within the first 2 years of disease. Of the 23 patients studied, 60.9% were female, 78.3% were Caucasian, 8.7% black, 8.7% Hispanic and 4.3% other. The mean age at SLE diagnosis was 52.5±15.0 years. Of the 23 MIs that occurred, 16 MIs occurred at a mean of 6.1±7.0 years prior to diagnosis and 7 occurred within the first 2 years of follow-up. Risk factors associated with early MI in univariate analysis are male sex, Caucasian, older age at diagnosis, hypertension, hypercholesterolaemia, family history of MI and smoking. In multivariate analysis only age (OR=1.06 95% CI 1.03 to 1.09), hypertension (OR=5.01, 95% CI 1.38 to 18.23), hypercholesterolaemia (OR=4.43, 95% CI 1.51 to 12.99) and smoking (OR=7.50, 95% CI 2.38 to 23.57) remained significant risk factors. Conclusions In some patients with lupus, MI may develop even before the diagnosis of SLE or shortly thereafter, suggesting that there may be a link between autoimmune inflammation and atherosclerosis.

Changes in Quality of Life in the First 5 Years of Disease in a Multicenter Cohort of Patients With Systemic Lupus Erythematosus

The Medical Outcomes Study Short Form 36 (SF‐36) is recommended to assess quality of life (QOL) in systemic lupus erythematosus (SLE). The aim of the current study was to assess QOL over time in the first 5 years of a multicenter inception cohort of patients with SLE.

New therapies in systemic lupus erythematosus – trials, troubles and tribulations…. working towards a solution

As rheumatologists, we are living in an exciting and a remarkable time. After several decades of introducing, in a very ad hoc fashion, general immunosuppressive drugs (e.g. azathioprine, methotrexate, cyclosporine) for the treatment of autoimmune rheumatic diseases, the era of targeted therapies is upon us. There is much intellectual and, we hope, therapeutically advantageous satisfaction to be gained from knowing that blocking key molecules or cells is appropriate because there is clear evidence that they are integral to the development of the disorders that we treat. The classical example of TNF-α blockade in patients with rheumatoid arthritis1–3 and more recently psoriatic arthritis4 and ankylosing spondylitis5 is a genuine ‘big leap forward’ in the therapies we offer our patients. It has proved relatively straight forward to demonstrate the benefit of TNF-α blockade and more recently, rituximab6,7 in large double-blind control trials in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. In contrast, several recent studies exploring the use of mycophenolate, and more targeted approaches in patients with systemic lupus erythematosus have reported disappointing results. Encouraging results from relatively small open label studies of mycophenolate in lupus nephritis8,9 had encouraged the view that this drug was better and safer than intravenous cyclophosphamide. However, a double-blind controlled trial comparing mycophenolate vs. cyclophosphamide as agents for induction of remission in patients with lupus nephritis, showed no advantage in the use of mycophenolate,10 although encouraging improvements11 in disease activity of non-renal manifestations were recorded using the British Isles Lupus Assessment Group (BILAG) disease activity assessment tool.12 A trial of edratide, a novel tolerogenic peptide which is thought to alter T-cell function,13 did not meet its primary end point which was based on the use of the systemic lupus erythematosus disease activity index (SLEDAI).14 Likewise, it has recently been announced that the Explorer trial comparing use of rituximab given intravenously with a placebo infusion failed to show any benefit using either the BILAG or SLEDAI activity in disease in lupus patients lacking renal disease. These disappointing results are of great concern to the lupus community (patients and physicians), because it encourages the view that lupus trials are simply too complex and costly to undertake and even the larger pharmaceutical companies may baulk at the prospect of undertaking further trials. Evidence of this has already emerged with the postponement by Roche of a trial of ocralizumab (a humanized anti-CD20 reagent) in patients with nonrenal lupus. The question, therefore, arises as to whether the therapeutic agents, so promising in case series, are truly ineffective or is it rather the design of the trials themselves that has contributed to the negative results. This could be the result of inappropriate case selection, inappropriate clinical trials centres, inadequate clinimetric tools and variable outcomes. These concerns stress the importance for us in the lupus research community to collaborate and address each of these issues to ensure the maximum chance for our new therapies to be fairly tested in double-blind control trials.

American College of Rheumatology Criteria at Inception, and Accrual over 5 Years in the SLICC Inception Cohort.

Objective. To determine the frequency of each American College of Rheumatology (ACR) criterion met at time of enrollment, and the increase in each of the criteria over 5 years. Methods. In 2000 the Systemic Lupus International Collaborating Clinics (SLICC) recruited an international inception cohort of patients with systemic lupus erythematosus (SLE; ≥ 4 ACR criteria) who were followed at yearly intervals according to a standard protocol. Descriptive statistics were used to assess the total and cumulative number of ACR criteria met at each visit. Regression models were done to compare the increase of individual and cumulative criteria as a function of race/ethnicity group, and sex. Results In all, 768 patients have been followed for a minimum of 5 years. Overall, 59.1% of the patients had an increase in the number of ACR criteria they met over the 5-year period. The mean number of ACR criteria met at enrollment was 5.04 ± 1.13 and at year 5 was 6.03 ± 1.42. At enrollment, nonwhite patients had a higher number of ACR criteria (5.19 ± 1.23) than white patients. The total number of criteria increased in both white and nonwhite ethnicities, but increased more among whites. Males had a slightly lower number of criteria at enrollment compared to females and males accrued fewer criteria at 5 years. Conclusion. In this international inception cohort of SLE patients with at least 4 ACR criteria at entry, there was an accumulation of ACR criteria over the following 5 years. The distribution of criteria both at inception and over 5 years is affected by sex and ethnicity.

Autoantibodies and neuropsychiatric events at the time of systemic lupus erythematosus diagnosis

OBJECTIVE To examine, in an inception cohort of systemic lupus erythematosus (SLE) patients, the association between neuropsychiatric (NP) events and anti-ribosomal P (anti-P), antiphospholipid (lupus anticoagulant [LAC], anticardiolipin), anti-beta2-glycoprotein I, and anti-NR2 glutamate receptor antibodies. METHODS NP events were identified using the American College of Rheumatology case definitions and clustered into central/peripheral and diffuse/focal events. Attribution of NP events to SLE was determined using decision rules of differing stringency. Autoantibodies were measured without knowledge of NP events or their attribution. RESULTS Four hundred twelve patients were studied (87.4% female; mean +/- SD age 34.9 +/- 13.5 years, mean +/- SD disease duration 5.0 +/- 4.2 months). There were 214 NP events in 133 patients (32.3%). The proportion of NP events attributed to SLE varied from 15% to 36%. There was no association between autoantibodies and NP events overall. However, the frequency of anti-P antibodies in patients with central NP events attributed to SLE was 4 of 20 (20%), versus 3 of 107 (2.8%) in patients with other NP events and 24 of 279 (8.6%) in those with no NP events (P = 0.04). Among patients with diffuse NP events, 3 of 11 had anti-P antibodies (27%), compared with 4 of 111 patients with other NP events (3.6%) and 24 of 279 of those with no NP events (8.6%) (P = 0.02). Specific clinical-serologic associations were found between anti-P and psychosis attributed to SLE (P = 0.02) and between LAC and cerebrovascular disease attributed to SLE (P = 0.038). There was no significant association between other autoantibodies and NP events. CONCLUSION Clinically distinct NP events attributed to SLE and occurring around the time of diagnosis were found to be associated with anti-P antibodies and LAC. This suggests that there are different autoimmune pathogenetic mechanisms, although low sensitivity limits the clinical application of testing for these antibodies.

Autoantibodies and Neuropsychiatric events at diagnosis of SLE: Results from an international inception cohort study

OBJECTIVE To examine, in an inception cohort of systemic lupus erythematosus (SLE) patients, the association between neuropsychiatric (NP) events and anti-ribosomal P (anti-P), antiphospholipid (lupus anticoagulant [LAC], anticardiolipin), anti-beta2-glycoprotein I, and anti-NR2 glutamate receptor antibodies. METHODS NP events were identified using the American College of Rheumatology case definitions and clustered into central/peripheral and diffuse/focal events. Attribution of NP events to SLE was determined using decision rules of differing stringency. Autoantibodies were measured without knowledge of NP events or their attribution. RESULTS Four hundred twelve patients were studied (87.4% female; mean +/- SD age 34.9 +/- 13.5 years, mean +/- SD disease duration 5.0 +/- 4.2 months). There were 214 NP events in 133 patients (32.3%). The proportion of NP events attributed to SLE varied from 15% to 36%. There was no association between autoantibodies and NP events overall. However, the frequency of anti-P antibodies in patients with central NP events attributed to SLE was 4 of 20 (20%), versus 3 of 107 (2.8%) in patients with other NP events and 24 of 279 (8.6%) in those with no NP events (P = 0.04). Among patients with diffuse NP events, 3 of 11 had anti-P antibodies (27%), compared with 4 of 111 patients with other NP events (3.6%) and 24 of 279 of those with no NP events (8.6%) (P = 0.02). Specific clinical-serologic associations were found between anti-P and psychosis attributed to SLE (P = 0.02) and between LAC and cerebrovascular disease attributed to SLE (P = 0.038). There was no significant association between other autoantibodies and NP events. CONCLUSION Clinically distinct NP events attributed to SLE and occurring around the time of diagnosis were found to be associated with anti-P antibodies and LAC. This suggests that there are different autoimmune pathogenetic mechanisms, although low sensitivity limits the clinical application of testing for these antibodies.

Grand Rounds from International Lupus Centres A young woman with SLE: diagnostic and therapeutic challenges

The presence of antiphospholipid antibodies, especially of the IgG isotype and in high titre, is associated with additional complications in patients with SLE. The thrombocytopaenia and cerebral events in the patient described are likely to have been linked to her lupus anticoagulant. However, the antibody and anticardiolipin antibodies are not necessarily synonymous and indeed we did not detect anticardiolipin antibodies in the patient, although her sister had them. It is likely that they represent overlapping sets of immunoglobulins. The production and analysis of further such antibodies, as described in this review, is awaited urgently. Much effort is also being expanded on identifying the precise targets for these antibodies. In a very recent report Horkko et al have shown that these antibodies may be directed against epitopes of oxidized phospholipids. The management of patients with complex disorders such as described here remain a challenge, although in the short term the patients major locomotor, neurological, dermatological and haematological problems have been controlled. Long-term problems including impaired fertility and osteoporosis remain to be faced.