Assessing patients with lupus: towards a drug responder index

Transcription

1 Rheumatology 1999;38: Reviews Systemic Lupus Erythematosus Series Editors: D. Isenberg and C. Gordon Assessing patients with lupus: towards a drug responder index D. Isenberg and R. Ramsey-Goldman1 Centre for Rheumatology/Bloomsbury Rheumatology Unit, Middlesex Hospital, London and 1Division of Arthritis and Connective Tissue Diseases, Northwestern University, Chicago, IL , USA The remarkable diversity of clinical features that are better, the same, or worse than before? Next, the clinician evident in patients with systemic lupus erythematosus should estimate whether irreversible damage is (SLE) demands particular vigilance on the part of the present from the disease or its treatment. Monitoring clinician attempting to assess and treat this complex, for drug toxicity is essential to minimize the long-term but fascinating, disease. Although virtually any symp- morbidity from disease. Finally, an assessment of the tom one cares to think of may be due to active lupus patient s quality of life or current functional capabilities (particularly in the central nervous system), the physi- is needed because the patient s perceptions may not cian must also guard against the fallacy that every mirror their physician s. clinical problem experienced by a patient with lupus is Identification of disease and treatment of disease flares due to the disease. In this review, we will put forward (potentially reversible problems) while minimizing organ the view that in order to understand the totality of the damage (irreversible problems) and drug toxicity can be effect of a disease like lupus upon a patient, measures difficult in lupus for many reasons. Sometimes it is not are needed that distinguish disease activity (implying clear whether one can attribute symptom, sign or laboratory that the problems can be corrected), damage (meaning test to lupus. Symptoms from multiple organs can permanent change) and the patient s own perception of change simultaneously or sequentially over time. their health status. Semiquantitative measures of disease activity are being used increasingly in clinical research and improve our ability to compare studies to one another [1]. These Practical assessment of patients with lupus in measures are discussed in detail in subsequent sections the clinic or hospital ward of this review. They are currently being modified for use A comprehensive approach in a chronic disease characclinical practice is not clear. However, they can provide in clinical trials [2], but their utility and practicality in terized by exacerbations and remissions is needed in all settings in which clinicians assess lupus patients. a useful guide towards understanding the spectrum of Therefore, patients seen in the out-patient clinic or disease the clinician must assess in the patient with lupus. hospital, and those participating in a clinical drug trial, need a careful evaluation that assesses the current status What should be assessed? of the patient, but also looks to the future in order to The protean manifestations of lupus require a thorough prevent or minimize irreversible damage from the disease search for signs and symptoms of disease. The clinical or its treatment. review includes probing for constitutional symptoms What are the goals and challenges of (e.g. fatigue, fever, weight loss of >5% of body mass) and screening by history and examination for mucocutaneous, assessment in lupus patients? musculoskeletal, cardiopulmonary, gastroassessment intestinal, lymphoreticular, neuropsychiatric and ocular At the end of the patient s visit, the clinician should manifestations. have an assessment that includes current disease activity Laboratory monitoring includes a full blood count and attempts to answer the question: is the disease and differential white cell count ( lymphopenia is a common feature in lupus patients). Since renal disease Submitted 30 April 1999, accepted 14 May may be silent, a urinalysis looking for red cells, white Correspondence to: D. Isenberg, Centre for Rheumatology/ cells, protein and cellular casts should be performed on Bloomsbury Rheumatology Unit, Middlesex Hospital, Arthur Stanley a regular basis. If abnormalities are detected, a 24 h House, Tottenham Street, London W1P 9PG, UK. urine collection should be obtained to assess the total British Society for Rheumatology

2 1046 D. Isenberg and R. Ramsey-Goldman daily protein loss. The glomerular filtration rate is most would be expected to have differing levels of disease often assessed by measuring the creatine clearance. This activity (construct validity). is not entirely accurate as creatinine is secreted actively by the renal tubules. An alternative is 51Cr-labelled Two main types of activity measures have been evolved. EDTA, the clearance of which can be assessed from the The global score systems are aimed at providing a simple plasma radioactivity at one time point following an i.v. overall measure of activity. In contrast, individual dose (rather than collecting timed urine samples). organ/system assessment scales seek to emphasize the Autoantibody determinations including antinuclear antion the grounds that they are too reductionist. diverse nature of lupus and thus to avoid a single score body, anti-ro/ssa, anti-la/ssb, anti-rnp, anti-sm and anticardiolipin facilitate the diagnosis of lupus or The best known global disease activity measures are the its subsets. Only anti-double-stranded DNA antibodies SLAM (Systemic Lupus Activity Measure) [4], SLEDAI are thought to be helpful by some, but not all, investi- (Systemic Lupus Erythematosus Disease Activity Index) gators [1]. Similarly, changes in complement compon- [5] and ECLAM ( European Community Lupus Activity ents [notably C3, C4 or, if available, their breakdown Measure) [6]. Derived from a very different philosophical products (C3d or C4d)] may assist with prognosis and standpoint, the BILAG (British Isles Lupus Assessment monitoring of therapy in some patients [ 1]. Group) index was developed initially in 1984 in an attempt Organ damage can be assessed on a yearly basis with to move away from the global score approach. It is based the Systemic Lupus International Collaborative Clinics/ upon the intention-to-treat premise [7]. Each index has American College of Rheumatology (SLICC/ACR) been shown to have validity using the criteria set out in damage index, which is discussed in detail in a sub- the previous paragraph. sequent section. A strategy for monitoring drug toxicity The original SLEDAI index was developed from a in lupus patients was suggested in a recent review [1]. meeting in Toronto in 1985, through a nominal group Briefly, the authors suggested using the practice guidethought to be important by the participants in describing process, whereby a list of 24 variables was produced, lines for monitoring drug toxicity in rheumatoid arthritis developed by the American College of Rheumatology disease activity in SLE. These variables were then used to [3] as a guide for monitoring a patient with SLE. evaluate disease activity in a cohort of patient profiles Clearly, one must adapt the approach for the indi- selected from the database of the Toronto lupus clinic. vidual patient. The variables (or descriptors of disease activity) were Assessment of quality of life or the patient s perception grouped into nine organ systems. Multiple regression of disease is also important. In the last few years, various models were then used to derive weights for the selected indices have been utilized to assess this important perspectadopted included 24 items using weights ranging from 1 variables in predicting disease activity. The final scale ive. From the patient s standpoint, these instruments are easy to use and require little time to complete. Valuable to 8, with a total maximum possible score of 105. This information on the functional aspect of a patient s current index measures the disease activity in the 10 day period condition is available to the clinician. The scales and prior to the assessment, within which the manifestation domains measured in these instruments are described in must be recorded. It is a descriptive index and has been detail in a subsequent section. found to be reliable in naive observers [8], between coun- tries [9] and in routine use [10]. It is sensitive to change over time [11] and has been used in prognosis studies Formal assessment of disease activity in SLE [12]. The SLEDAI has been modified slightly for use in particular situations, e.g. the Mexican version of As Liang et al. [4] have pointed out, between the SLEDAI known as the MEXSLEDAI [13]. In an onmid-1950s and mid-1980s some 60 attempts were made going study in the USA, known as the SELENA (Safety to develop a disease activity index for patients with of Estrogens in Lupus Erythematosus, National SLE. None of these attempts were adequately validated Assessment) trial, another modification of SLEDAI is or even shown to be reliable. The situation has changed being used in which several of the descriptors have been radically in the last 15 yr, however, with the description changed. For example, vertigo has been added in cranial of genuinely validated clinical activity measures. Ideally, nerve disorder and for both pleurisy and pericarditis such measures should include the following components: classic and severe pain is sufficienttoberecordedinthe absence of objective data such as a pleural effusion $ Individual variables, ascertained in a generally acceptable (J. Buyon, personal communication). way (case validity). The SLAM index, in contrast, is designed to allow $ An adequate number of variables chosen in an appropriate some assessment of disease severity [4]. It was developed manner (content validity). in Boston with input from members of the Lupus $ Agreement with an external criterion considered to Council of the American College of Rheumatology. It be a superior measure of disease activity standard includes 32 items divided into 11 organ systems and (criterion validity). includes a scoring for severity as the variables are not $ Positive correlation with other clinical scales or with only scored as present, but graded on a scale of 1 3 laboratory markers of disease activity and the capacity based on severity, giving a possible total score of 86. to differentiate between patient groups who Although this index includes the concept of activity and

3 Assessing patients with SLE 1047 severity, some of the measures included, such as arthral- tures were due to lupus or simply coincidental findings, gia and fatigue, may not represent true disease activity, and also neurological disease may be treated with specific but rather the patient s perception of disease activity. therapy such as anticonvulsants in those with epileptic This index has been found to be reliable [13] and has attacks or anticoagulants following strokes, rather than been used as an outcome measure in therapeutic trials. by corticosteroids and immunosuppressants. A modified version of SLAM, SLAM-R, omits scoring Although it was not designed for this purpose, the for pneumonitis and truncates several scales. BILAG index can be converted into a global score The ECLAM index has been described following a system, thus A = 9, B = 3, C = 1, and D and E = 0, study in which 29 centres, from 14 European countries, resulting in a potential range of In a comparative evaluated and chose 15 items from an analysis of 704 study of 75 patients with SLE, a global score derived as patients [6 ]. These items were selected at a consensus above from BILAG was shown to correlate very highly meeting of representatives from several of the participat- with the genuine global score indices, SLAM, SLEDAI ing centres. It differs from the other activity indices as and ECLAM [15]. it was directly derived from a study of a large number of real patients and the analysis of a large amount of Assessment of damage in SLE data was collected in a standardized manner during the multicentre effort. Fifty years ago, when lupus had a 5 yr survival estimated In essence, each of these global indices scores a at ~50% [16], mortality was an important, and largely varying number of points for involvement in particular sufficient, measure of outcome in patients with lupus. organs or systems. By simply adding up the points With the substantially improved survival figures for scored, a global total is arrived at. These indices have patients with lupus, it has become necessary to develop shown sensitivity to change [10] and in a number of a more subtle method of assessing the overall cumulative studies (reviewed elsewhere [2]) have been shown to effect of the disease. The SLICC/ACR index was pub- compare well with each other. lished in 1996 after 5 yr of preparatory work [17]. The The BILAG index was derived following detailed index does not seek to attribute the cause of damage to discussions among a group of rheumatologists who the disease or its treatment. For example, it merely achieved a consensus about when to treat lupus patients records the number of items of permanent change that with disease-modifying therapy such as high doses of have affected an individual patient since the onset of corticosteroids or immunosuppressives [7]. The index the disease. The damage score can thus only remain the underwent relatively minor changes, but in its current same or increase with time. In order for a feature to be format has shown a high degree of between-rater varipersisted for at least 6 months. It is ascertained by regarded as due to damage, the change must have ability and validity [14]. The BILAG index now includes a total of 86 items clinical assessment or simple investigations such as urinin eight organs or systems, each item is scored as present alysis and plain radiographs, which are widely available. or absent within the previous month, with many of the Damage is distinguished in 12 organs or systems, items being identified as new, improved, the same, or including ocular, neuropsychiatric, renal, pulmonary, worse. For an item to be recorded in one of these cardiovascular, peripheral vascular, gastrointestinal, categories, the assumption is made that the problem is musculoskeletal, skin, gonadal and endocrine damage, due to lupus. Thus, a lupus patient with coincident and the occurrence of malignancies. Weighting was not asthma would not have shortness of breath recorded if shown to improve the ability of the index to record the clinician felt that it was due to the coincident disease. damage, but the index has been shown to discriminate As with the global score indices, laboratory tests make between changes in disease damage in patients with both up relatively little of the final score, apart from the active and inactive disease, and to have good interobser- haematological system, and to a lesser extent the renal ver reliability. system, for obvious reasons. In a 10 yr retrospective study of 80 patients with SLE Each organ or system is given a score of A E, where A using the damage index, it was shown that renal damage denotes disease thought to be sufficiently active to require at 1 yr was predictive of end-stage renal failure [18]. disease-modifying treatment, prednisolone <20 mg/day Pulmonary damage at 1 yr was predictive of death by or immunosuppressants, B refers to problems requiring 10 yr of follow-up. The study also demonstrated that only symptomatic therapy such as antimalarials or Afro-Caribbean and Asian patients had significantly non-steroidal anti-inflammatory drugs or prednisolone higher mean renal and total damage scores at 10 yr than <20 mg/day, C indicates stable, mild disease, D indicates the Caucasian population. A high neuropsychiatric a previous affected but currently inactive system and E damage score was also evident in the Asian group. indicates that the system/organ has never been involved Other studies [19, 20] have confirmed the usefulness previously. However, it must be emphasized that the and validity of this index. For example, Nossent [20] individual scores are determined on the basis of the prespatients undertook a case note review of 90 Afro-Caribbean ence/absence of the items referred to above. with lupus who had been followed for a mean BILAG has been shown to function well for each of period of 6 yr with periodic assessment of the these organs or systems, with the possible exception of the SLICC/ACR damage index. The mean damage score central nervous system. There has been particular difficulty 6 months after diagnosis was 0.6 and at last assessment amongst physicians in deciding whether neurological fea The damage score correlated with a weighted aver-

4 1048 D. Isenberg and R. Ramsey-Goldman age of SLEDAI disease activity scores and the number Both measures have been compared in a study of 150 of disease exacerbations, but not with age or steroid lupus patients [31], with significant associations between dose. the corresponding domains in each measure and with In contrast, Alarcon et al. [21], in a cross-sectional global disease activity measured by BILAG, although study of Hispanic, Afro-American and Caucasian this association is not strong, suggesting that quality of patients (70 80 patients in each group) whose disease life and disease activity measured by BILAG are distinct. duration did not exceed 5 yr, did not find a statistically In the SF-36 index, different disease activity levels were significant difference in the damage score between these significantly associated with different quality of life three groups. scores and showed an excellent ability to record the The SLICC/ACR damage index has won widespread continuum from good health to serious illness. Disease acceptance in the lupus research community. Thus, activity had a greater effect on quality of life than age, Bootsma et al. s [22] comment that the index appeared cumulative damage or disease duration. A previous useful in SLE because it has the capacity to measure study had shown that in the SF-20+, limitations in change over time; it offers the opportunity to compare physical functioning were associated with damage to the treatment arms in clinical trials and reflects cumulative musculoskeletal system, measured by the SLICC/ACR damage. It should be emphasized that long-term studies damage index, and renal disease was inversely associated are needed. In short-term studies (up to 3 yr), it is likely with fatigue, but there were no other significant associations that only 50% of patients with lupus will register any between this health questionnaire and the damage damage. index. In view of the comprehensiveness of the SF-36, its widespread use and international validation for a wide range of medical conditions, this is currently the Assessing health status in SLE optimal choice as the patient life-impact assessment, An important principle to remember is that the patients although the degree of change of an SF-36 score that is perceptions of their lupus, in particular its most trouble- clinically important is not yet known. some features, are frequently different from the clinician s. Although no lupus-specific measure has been designed Future developments to date, two measures have been used in a wide variety of studies. These measures were developed from the We stand on the brink of a revolution in the way in questionnaires devised initially by Ware and his colthis article, as well as the recent introduction of myco- which we treat patients with SLE. At the time of writing leagues at the Rand Corporation [23]. Over 200 items were initially selected for study, before the Medical phenolic acid to the immunosuppressive armamen- Outcome Survey Short Form-20 [ 24] ( literally 20 ques- tarium, we are aware of a major clinical study in the tions) and subsequently the Short Form-36 were USA assessing the effects of a B-cell collagen LJP394, a developed [25, 26]. The Short Form 20, however, lacks safety study of oestrogens given to post-menopausal a particular question about fatigue, which is most women, and two trials of monoclonal anti-cd40 ligand important in many patients with lupus. Thus, a number in the treatment of SLE. In addition, a double-blind of studies have been reported using the so-called SF-20+ placebo-controlled trial of the adrenal steroid hormone (i.e. the SF-20 questionnaire plus an additional question dehydroepiandrosterone (DHEA) has just been pubconcerning fatigue) [27, 28]. lished [32]. It appears to have a protective effect with Although the SF-20 appears to be a valid measure of respect to steroid-induced osteoporosis, but was of little quality of life, the instrument used most often and benefit in patients with severe disease. There is thus an internationally to assess health status is the SF-36. This urgent need to agree a format for assessing the response index may be more appropriate as it records the contherapy. of a patient with lupus to these exciting new forms of tinuum from healthy to severely ill very well [29, 30]. Intense discussions have been going on during The SF-36 is almost as quick and easy to complete as the past 2 yr among members of the SLICC and the SF-20. It has 36 questions concerning eight static OMERACT groups, and more recently the Food and domains predominantly occurring over the previous Drug Administration in the USA. We are hopeful that month, namely, physical function, role limitations: physthat consensus will be reached and consider it likely ical problems, role limitations: emotional problems, agreement requires recognition of the importance social function, mental health, general health perception, of recording a disease activity measure, a damage meas- vitality and pain. The SF-36 is broader than the SF-20, ure, a patient health perception index, and methods of asking questions about vitality and general health (over recording toxicity and economic costs. Only by assessing the previous year) not found in the SF-20. Other each of these factors will we be able to determine domains have a broader and deeper perspective, as, for whether new drugs provide overall benefit for a patient. example, physical function includes specific questions It seems logical to us that clinical researchers around about lifting groceries, climbing one or several flights of the world, who are interested in lupus, should compare stairs and walking different longer distances. It is scored in a similar way to the SF-20, with a score of ; higher values indicating better health. the outcome of their studies in the same way. The optimal way to do this is to ensure that everyone uses the same drug responder index.

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