The Systemic Lupus International Collaborating Clinics (SLICC) group – It was 20 years ago today

Introduction/History

Fans of the Beatles will know the next line of the popular song referred to in the title of this review. However, this is not an attempt to introduce you to the history of a band, but rather to reflect on two decades of the Systemic Lupus International Collaborating Clinics (SLICC) group. The group was formed by rheumatologists interested in lupus at a meeting organized by Matt Liang following the American College of Rheumatology (ACR) meeting in Boston in October 1991. Details of our origins have already been published,^1,2 but in brief, members of the British Isles Lupus Assessment Group (BILAG) had already linked with colleagues from the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) group from Toronto and Matt Liang and his colleagues from Boston to undertake the initial comparison of disease activity indices in a series of studies supported by NATO (presumably standing for the New Arthritis Treatment Organization!). The establishment of the SLICC incorporated the enthusiasm, experience and talents of several other rheumatologists. At this meeting we began to develop the SLICC/ACR damage index.

The group currently has a full membership of 37 (the full list is shown in Appendix 1) representing some 30 centres from 11 different countries. Various levels of membership have evolved including Full member, Emeritus (for those former full members now retired or whose careers have moved in different directions but who wished to retain a connection with SLICC), Associate members (mainly for those with particular skills that the group might wish to call upon periodically) and Provisional (a recent category, designed primarily with the idea of ‘taking over the reins’ in due course from a full member). Full members are expected to have a strong publication record in lupus research, to be associated with a cohort of well-established lupus patients and a willingness to participate in most of the ongoing projects within SLICC.

In 1998, the group developed a strategy for the next decade. The key objectives were to establish a prospective cohort of newly diagnosed patients with lupus, collecting clinical information, serum and plasma on an annual basis and DNA at enrolment; to look in great detail at the challenging issue of why patients with lupus are predisposed to atherosclerosis; to use the same cohort of patients to explore the manifestations, outcomes and autoantibody associations of nervous system involvement and to complete studies with the damage index. ³ Other initiatives were to undertake a major study of malignancy in lupus and to explore the role of the physicians’ global assessment in determining the level of activity experienced by patients with systemic lupus erythematosus (SLE).

Review of recent/ongoing projects

These projects have come to fruition in full, or remain ongoing. The SLICC inception cohort led by Murray Urowitz has identified over 1600 newly diagnosed patients enrolled within 15 months of diagnosis with annual follow-up (clinical assessment and serum collection) of up to 10 years in some patients. In an initial report ⁴ of 278 patients from this cohort followed for 3 years, several risk factors for coronary artery disease, both classic and other, were identified. Among the classic coronary artery disease risk factors, percentage increases from enrolment were seen in hypertension (48.6%), hypercholesterolaemia (65.3%), smoking (36.7%), diabetes (55.6%, though the numbers involved here were small) and being post-menopausal (37.2%). Amongst the non-traditional risk factors, similar or enhanced increases were observed for body mass index (54.3%), waist:hip ratio (79.5%), low physical activity (71.6%), family history with coronary heart disease (40.8%) and nephritic syndrome (81.8%). During this 3-year period, there was a 12.2% increase in the use of corticosteroids treatment, 29.5% in anti-malarials and 56.6% in immunosuppressive drugs. In an analysis of 1249 patients entered into the cohort since 2000 ⁵ 97 vascular events in 72 patients were recorded. Amongst these congestive heart failure (n = 24) stroke (n = 23), angina (n = 15) and myocardial infarction (n = 13) were reported. The mean ± SD time from diagnosis to the first atherosclerosis event was 2 ± 1.5 years.

A major study of neuropsychiatric (NP) events in patients with lupus (led by John Hanly) has also been conducted. In an assessment of the first 572 patients enrolled into the cohort, ⁶ 28% experienced at least one neuropsychiatric event over a period from 6 months prior to the diagnosis of SLE up to the time of enrolment (maximum duration of 21 months, but mean was approximately 12 months). Of these events, headache (38.8%), mood disorders (12.4%), cerebrovascular disease and seizure disorders (both 7.9%) were the commonest. Decision rules of graded stringency were derived to determine the attribution of NP events to SLE and non-SLE causes, and the application of these rules indicated that the proportion of NP events attributed to lupus varied from 19–38% using alternate attribution models, and occurred in 6.1–11.7% of patients. The SF-36, and in particular the mental component summary score, was validated as a reliable outcome for the assessment of NP events in SLE.^7,8 Those patients with NP events, regardless of attribution, had lower scores on the SF-36 summary and subscale scores compared with patients without NP events indicating a reduced self-report health-related quality of life.

In a short-term (mean of 3.7 ± 3.1 months) follow-up study of an expanded cohort of 890 patients due to additional recruitment, the outcome of NP events was significantly better when the event was attributed directly to lupus rather than to some concomitant cause. ⁷ This detailed analysis showed clearly that at least the short-term outcome of NP events is determined both by the nature of the event itself and its attribution. These findings were supported in a further analysis of an expanded cohort of 1206 patients followed over a mean of 1.9 ± 1.2 years. ⁹

Clearly, it would be of great interest to know whether any of the autoantibodies associated with lupus might be linked to NP events, either at the time of lupus diagnosis or subsequently. The SLICC group thus carried out a study of 412 newly diagnosed patients focussing on antibodies to ribosomal P, antiphospholipid and anti-NR2 glutamate receptor antibodies. ¹⁰ There was no association between autoantibodies and NP events from all causes. However, there was an association between the frequency of anti-ribosomal P antibodies with central NP events attributed to SLE (odds ratio (95% confidence interval (CI)) 8.4 (1.7, 46.5); p = 0.04). Specific clinical–serologic associations were found between anti-ribosomal P and psychosis (odds ratio (95% CI) 20.8 (1.6, 620.5); p = 0.02) and between lupus anticoagulant and cerebrovascular disease (odds ratio (95% CI) 3.3 (1.1,10.2); p = 0.04) attributed to SLE. This suggests different autoimmune pathogenetic mechanisms, although the low sensitivity of the tests limits their clinical application. Additional studies will examine the association between the presence of these autoantibodies at enrolment and over time with subsequent NP events attributed to SLE using the previously mentioned attribution models.

In a project led by Sasha Bernatsky and Rosalind Ramsey-Goldman, the largest ever study of cancer in SLE has been undertaken. ¹¹ Some 9547 patients from 23 centres with an average follow-up of 8 years were assessed. During the period of observation, 431 cancers were identified with a standardized incidence ratio (SIR) estimate of 1.15 (95% CI, 1.05–1.27 noted). This indicated a slightly increased risk of cancer among patients with lupus, though this was principally to be found amongst haematological malignancies where the SIR was 2.75 (95% CI 2.13–3.49) and for non-Hodgkin lymphoma, where it was 3.64 (95% CI 2.63–4.93). Weaker links to lung cancer and hepatobiliary cancer were also noted in a follow-up study ¹² exploring the possible clinical associations and medication exposures. Results were presented from 246 cancer cases and 538 controls without cancer. The adjusted HR for overall cancer risk after any immunosuppressive drug was 0.82 (95% CI 0.50–1.36). Age ≥65 years, and the presence of non-malignancy damage were associated with overall cancer risk. For lung cancer (n = 35 cases), smoking was also a prominent risk factor. When looking specifically at haematological cancers (n = 46 cases), there was a suggestion of an increased risk after immunosuppressive drug exposures, particularly when these were lagged by a period of 5 years (adjusted HR 2.29, 95% CI 1.02–5.15). These studies were performed by means of collaboration between the SLICC group and the Canadian network for improved outcomes in systemic lupus erythematosus (CaNIOS).

Many members of the SLICC group have helped to optimize the way clinical response is defined in patients with lupus. This is particularly important given the introduction of biological therapies inpatients with lupus. In a study of 80 paper patients ¹³ using the BILAG and SLEDAI, and physicians’ global assessment of activity scores, disease activity was captured at baseline, and at 3 and 6 months following the initiation of therapy. Whereas the BILAG and SLEDAI scores correlated well over time, we concluded that the physician visual activity score (VAS) is likely to be too blunt an instrument to assess response adequately in SLE. A key problem in using the VAS is thateven experienced ‘Lupologists’ clearly rate improvement (or deterioration) in various organs and systems involved rather differently. In addition, obtaining agreement about overall disease activity in a patient in whom some systems are improving whilst others are deteriorating continues to remain a challenge. Although the physician VAS is problematic, it is interesting that recent trials of biological agents have attempted, when assessing disease activity, to use composite measures utilizing BILAG, SLEDAI and a Physician VAS.

Extending this study, David Isenberg recently organized a lupus flare assessment in which 16 patients with active disease were reviewed by 16 ‘lupologists’, using the BILAG 2004, the flare version of SELENA and a physician's global assessment. Severe flare was associated with good agreement between the indices but mild/moderate flare was much less consistent. ¹⁴

Although we have yet to publish in detail on the subject, the SLICC group, in a major project led by Michelle Petri, has been looking in detail at the classification criteria for SLE. At present the 1997 updating of the ACR criteria for lupus classification, albeit published as a letter with no formal validation,^11,15 remain the most widely quoted criteria. We thought it timely to determine whether these revised criteria or a modification of them, are indeed, optimal. Our data will be published in due course.

Changes in administration

In November 2005, SLICC began an initiative to formalize our administrative structure in order to address real and potential obstacles to ongoing work. It was recognized that SLICC membership needed to increase to assist the recruitment of patients to our projects. Furthermore, the projects themselves were becoming increasingly complex and costly to support, and fundraising was an ongoing challenge. The revised administrative structure was enunciated in the SLICC bylaws and formalized the number of SLICC members, categories of membership, qualifications, expectations, and oversight; the bylaws also included the establishment of new officers, committees and terms of reference. In 2008 SLICC was established as a 501(c)3 organization (registered in the state of Illinois) which facilitated our ability to act as a fundraising organization to support ongoing research initiatives. The SLICC group continues to meet on a twice-yearly basis, once at the ACR's Annual meeting and once during the springtime.