Department of Rheumatology, Division of Immunity and Infection, The Medical School, University of Birmingham, Edgbaston, Birmingham, B15 2TT, 1The University College London Hospitals, Centre for Rheumatology, Arthur Stanley House, 4050 Tottenham Street, London W1P 9PG, UK and 2Fachklinik fur Rehabilitation Rheumatologie Osteoporose, aarReha Schinznach, Badstrasse 55, CH-5116 Schinznach-Bad, Switzerland.
Correspondence to:
C. Gordon. E-mail: p.c.gordon{at}bham.ac.uk
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Abstract |
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Methods. Over a 12-month period, 250 patients regularly attending lupus clinics in Birmingham and London were assessed using the BILAG index at each visit.
Results. A new A or B score was observed in 154 (61.6%) patients. An A flare was observed in 26 (10.4%) patients. A B flare (in which the B score was preceded by a D or E score) was observed in 65 (26.0%) patients. There were 63 (25.2%) patients in whom there was a B score in a system in which a C score was previously recorded. Steroids were started or increased in 20 (77%) patients with an A flare. Almost all (92%) patients with a new A score had some increase in therapy. For the patients with new B scores, 53 (41%) had some increase in therapy, but multiple reasons were found for no change in therapy in 75 (59%) of these patients. There was no difference in the treatment of new B scores arising after a previous C score compared with previous D or E scores. Non-Caucasians were more likely to have a lupus flare than Caucasians.
Conclusions. These results are consistent with the principles upon which the BILAG index was devised and suggest that a moderate disease flare can be defined as a new B score following a C, D or E score according to the BILAG index.
KEY WORDS: Lupus, SLE, BILAG, Disease activity index, Flare, Ethnic.
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Introduction |
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The most severe features in each system, which are deemed to require high dose steroids (prednisolone >20 mg daily or equivalent) and/or cytotoxic agents, characterize an A score. One or more features may have to be present to score an A, depending on the system [3]. More moderate disease items that would be considered appropriate to treat with lower dose steroids, antimalarials or non-steroidal anti-inflammatory drugs (NSAIDs) contribute to a B score. Mild symptomatic features that require just symptomatic therapy, for example with analgesics and NSAIDs, can only contribute to a C score. If there are no current symptoms but the system has previously been involved then a D is recorded. If the system has never been involved, it is scored E [3]. A severe flare of lupus has been defined as a new score of A in any system and a moderate flare has been defined as a score of B in any system which previously scored D or E [8].
The aim of this study was to determine whether or not, in routine clinical practice, treatment was different for A and B flares at two sites which were involved in the original validation of version 3 of the BILAG index [3]. We also wanted to determine whether the treatment of patients scoring a B after a previous D or E score in that system was different to those in whom the previous system score was a C, as the latter were not included in the definition of moderate flare [8]. Finally we were interested to assess whether there were any ethnic differences in the incidence of A and B flares as previous work has suggested that non-Caucasian patients have more severe disease.
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Patients and methods |
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At each clinic visit, clinical features covered by the BILAG index of lupus disease activity were recorded by doctors in the clinic in a standardized way on forms devised specifically for this purpose [3]. The data were subsequently entered on to the BILAG index computer program by a research assistant and the BILAG score was calculated using version 3 of the BILAG index [3]. Details were also recorded about the clinician's advice to the patient at each visit concerning changes in therapy with antimalarial drugs, NSAIDs, steroids (including dose and route of adminstration), cytotoxic agents (azathioprine, cyclophosphamide, methotrexate or cyclosporin A) and anticoagulants. For the purposes of this analysis, treatment options were divided into four groups: (i) starting or increasing a cytotoxic agent and/or prednisolone above 20 mg daily (or equivalent steroid, including intravenous methylprednisolone 500 mg bolus); (ii) starting or increasing lower dose prednisolone (20 mg daily) or equivalent steroid (including intramuscular or intra-articular methylprednisolone at a dose below 500 mg); (iii) starting or increasing NSAIDs, antimalarials or anticoagulants (without change in steroids or cytotoxic agents); and (iv) no change in any specific therapy for lupus (simple analgesics, antihypertensive agents, etc. were not assessed).
Demographic details are recorded at entry to the lupus cohorts. These include date of birth and ethnic group. Four ethnic groups were considered in this study: (i) Caucasian, (ii) Afro-Caribbean, (iii) South Asian (from India and Pakistan), and (iv) others (Chinese and those from all other backgrounds including those of mixed origin).
An A flare was recorded when a patient recorded an A score in any of the eight organs/systems having previously been a lower activity score (i.e. B/C/D/E). A B flare was noted if a B score preceded by a C/D/E score had occurred.
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Results |
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Treatment of lupus flares
The treatment given to patients with BILAG A or B scores is summarized in Tables 1 and 2. The management of patients with A flares was significantly different to that given to patients with a new B score (Table 1). Some increase in therapy for lupus disease occurred in 24 out of 26 (92%) patients with an A flare, but only 53 (41%) of new B scores (2 = 20.41, P < 0.001). High dose steroids and/or cytotoxic therapy was started or increased in 13 (50%) patients with an A flare compared with only 10 (8%) of new B scores (
2 = 27.05, P < 0.001). Any dose of steroids was started or increased in 20 (77%) of A flares and 41 (32%) of new B scores (
2 = 16.38, P < 0.001). However, there was no significant difference in the treatment of patients with B scores preceded by D or E scores (B flare) and those with previous C scores (Table 2), whether any change in therapy was considered or specific types of therapy.
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Treatment of B flares
A new B score occurred in 128 patients of whom 53 (41%) had some increase in therapy and 41 (32%) of 128 patients received some increase in steroid and/or cytotoxic therapy (Table 1). The many reasons for not giving additional therapy to 75 (59%) patients with a new B score are shown in Table 4.
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Discussion |
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We do not think that the doctors in the clinic were influenced significantly in their decisions about how to treat the patients based on the principles on which the BILAG index was devised. The doctors were not aware that we would be doing the specific analyses described in this paper at some point in the future, although the patients had consented to have their data on disease activity and therapy analysed. If the doctors in the clinic were treating lupus manifestations based on the BILAG index score, we would have expected much better agreement between the therapy given and that predicted from the BILAG score than we actually observed.
The present study did show significant differences in the frequency and management of A flares (new, very active lupus disease) compared with B flares (new moderate disease activity). However, the use of immunosuppression was less than expected from the paper on the validation of the BILAG index by Hay et al. [3] in which 87% of patients with A flares started or increased disease-modifying therapy. For A flares in this study, high dose steroid and/or cytotoxic therapy was started or increased in 13 out of 26 (50%) cases (Table 1). Steroids were started or increased in 20 (77%) patients and almost all, 24 out of 26 (92% patients), had some increase in therapy (Table 1). For the B flares, 53 (41%) had some increase in therapy with 41 (32%) of 128 patients receiving some increase in steroid and/or cytotoxic therapy. However, 75 (59%) had no change in therapy at all. Overall, 77 out of 154 (50%) patients with an A or B flare had some increase in therapy, which is comparable with Petri's [10] observations in the Hopkins Lupus cohort in which 44.8% of flares prompted a change in therapy. In that study, a disease flare was defined as a change of 1.0 in the physician's global assessment of disease activity (measured on a 03 scale) from the previous visit or from a visit within the last 93 days.
This study did not support differentiating a B (moderate activity) score following a previous D or E (no activity) score from a B score following a C (mild activity) score. The two types of B flare occurred about as frequently as each other (both in about 25% of patients) and were treated similarly (Table 2) with 53 out of 128 patients receiving some change in therapy. The observation that 75 out of 128 patients with new B scores were not given new or increased therapy was unexpected, but the initial validation of the BILAG index study only discussed the treatment given to A flares [3] and the subsequent paper by Stoll et al. [4] did not address therapy. The system involved by a B flare did not influence whether or not the therapy was changed, so there is no indication to weight individual BILAG systems differently to each other (Table 5). Seven out of eight patients with two systems recording B flares simultaneously (new activity having previously scored D or E) did have their immunosuppressive therapy increased. However, the total number of B scores did not influence the decision to increase therapy in about 40% of patients including four patients with multiple new B scores, which was very surprising and hard to explain unless the treatment change at the last clinic visit was considered. As some drug therapies including some forms of cytotoxic therapy can take up to several months to take effect, physicians will not necessarily change therapy in a patient with stable albeit active disease if they are not deteriorating severelyfor example, changing from clinical features that would score B to an A score on the BILAG index.
In contrast to the previous validation studies, the analysis in this longitudinal study was performed on data collected at every patient encounter at two centres which have been using the BILAG index for many years. The data were collected in routine SLE clinics where patients were seen by consultants, specialist registrars or research fellows. All doctors were given training in the use of the BILAG index when they started working in the lupus clinics at each centre. Most of them will not have been familiar with the calculation of BILAG scores, which is done by a research assistant at each centre using a computer after the clinic, and they were not aware that this analysis would be done. However, they will have been very familiar with the patients in the clinic, many of whom have been attending for some years. Previous studies involved doctors who were more involved in the derivation and plans for testing the BILAG index and will have known (consciously or subconsciously) how to calculate a BILAG index score manually. This may have biased their choice of therapy and the patients may not have been such established clinical attenders and therefore may have been more likely to have been started on new therapy. Many of the patients in this study were already on steroids and/or hydroxychloroquine and/or azathioprine or had previously tried these agents.
There were 2 out of 26 patients with A flares whose therapy was not changed at all at the time of assessment. In one case, the patient had recently been started on intravenous methylprednisolone and cyclophosphamide pulses and so the decision was to wait for another cycle of therapy before changing therapy as the response to the cyclophosphamide may be delayed. In the other patient, the pathological cause of the neurological deterioration was not clear and so therapy was deferred until further investigations had been performed. The initial validation of the BILAG index version 3 had also shown poor association between neurological A scores and treatment with immunosuppression [3]. This is an area of lupus that is widely acknowledged to be particularly challenging to understand and treat appropriately [11].
There were a variety of reasons why about half the patients with new B scores following a C, D or E were not given increased therapy. In all cases the physician did attribute the features to lupus or they would not have been scored on the BILAG index. However, there was uncertainty sometimes as to whether the symptoms and/or signs were just due to lupus or were partly due to a viral infection. In other cases, the history suggested that an infection (viral or bacterial) had contributed to triggering the lupus flare. Either way, if the features had been improving in the last few days, the decision was often to wait and see if these clinical features resolved spontaneously.
When the area of rash was relatively small, particularly if sun induced, the physicians often decided to continue local treatment with steroid cream, existing immunosuppressive therapy, re-emphasize the importance of avoiding the sun and using sunblock and would wait to review in a few weeks before increasing immunosuppressive therapy. These patients were usually already on antimalarials, and/or steroids and azathioprine. On some occasions, if patients had already started or increased therapy with one of these agents recently, no specific therapy would be advised. Interestingly, in the further validation of the BILAG index [4], the mucocutaneous system correlated least well of all the systems with global assessments of disease by patient and doctor, health status measured by SF-20, erythrocyte sedimentation rate and C3 level. Thus the lack of change in oral therapy is not so surprising, as we have previously suggested that mucocutaneous features are not perceived to be as worrying to physicians as changes in disease activity in other systems [4]. Nevertheless, patients with B flares in the mucocutaneous system were no more likely to have their oral therapy left unchanged than those with flares in other systems (Table 5).
Some patients with arthritis or pleurisy had already started NSAIDs at the time that they were seen in the clinic. Consequently, these were often continued if the patients were not actively deteriorating on these agents at the time of their BILAG assessments (which record features present over the previous 4 weeks). Similarly, some patients had already started symptomatic therapy with analgesics, antipsychotic agents, proton pump inhibitors for nausea, or iron therapy for anaemia that might be contributing to fatigue. In these cases, no additional therapy was prescribed if the patient had stabilized or was starting to improve (although they had deteriorated overall in the preceding 4 weeks, hence the BILAG index B score). It should also be noted that sometimes the decision was not to continue reducing therapy according to a previous plan but, as this was not always recorded clearly, it was hard to analyse. This concept should be considered a change in therapy in future studies.
Many patients were reluctant to increase oral steroids and would encourage physicians to recommend or continue other forms of treatment, or to just wait and see what happened. Some patients and physicians were well aware that previous episodes of disease had settled spontaneously or after treatment for an infection, and those patients with intermittent symptoms would prefer not to increase therapy unless the features became more severe and/or persistent. Although the BILAG index has built-in some variation in scoring based on severity or extent of clinical features, there is no time requirement for features to be present to score. Thus a patient with two joints with new signs of synovitis for the last 3 days will score the same (musculoskeletal B) as a patient with synovitis in six joints for all 4 weeks, as long as there is no impairment of function (which scores an A) and it is not just arthralgia (which scores a C). If the physician was recorded as having recommended increased steroids (orally or by injection), the patients would not be in the no change in therapy group. However, if the physician did not recommend steroids but chose another therapy or to wait and see because they knew the patient would not accept steroids, then the episode appears in one of the non-increase in steroid groups. Four patients with increased proteinuria but no symptoms of increased lupus activity and no cells or casts in the urine did not have increased therapy and are in this category. A further reason for this may be that the results of 24-h urine collections are usually not available in the clinic. Thus the physician would wait to discuss the results or retest the patient at the next clinic visit, which was often within 4 weeks for patients with renal disease.
Patients of non-Caucasian origin were found to have more flares of lupus than Caucasian patients (Table 6). This is consistent with previous observations by our own groups and others [8, 1216]. We did not observe any difference between Caucasians and non-Caucasians in the systems involved in the flares in this study, but the numbers of flares in each system were small (range 622). We did not find that age influenced the occurrence of flare in this cohort.
In conclusion, this study has confirmed that patients with new A scores (most active disease) according to the BILAG index usually receive new or increased therapy with steroids and cytotoxics. Patients with less severe disease (new B scores) are less often treated with new or increased doses of disease-modifying therapy, particularly if they are already on therapy, have had self-limiting disease previously or the physician is awaiting results of investigations before deciding on therapy. These results are consistent with the principle of the physician's intention to treat, the premise upon which the BILAG index scoring system was devised.
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Acknowledgments |
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Conflict of interest
The authors did not declare any conflicts of interest.
Key messages: A new BILAG A score is a severe lupus flare. Such flares are treated more aggressively than a moderate flare, defined as a B following a C, D or E score.
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References |
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