Connective tissue diseases: evaluation of clinical response
Endokrinologie, Diabetologie und Rheumatologie, Heinrich-Heine-Universität Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
Correspondence to: Dr Rebecca Fischer-Betz, Endokrinologie, Diabetologie und Rheumatologie, Heinrich-Heine-Universität Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany. E-mail: Rebecca.Fischer{at}med.uni-duesseldorf.de
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Systemic connective tissue diseases (CTDs) are disease entities characterized by a systemic and heterogeneous spectrum of clinical symptoms. The treatment of CDTs has improved substantially, but with the developments of new and probably more expensive targeted therapies, there will be a need of rigorous evaluation in patient-oriented research. Proposed domains for outcome measurement of CTDs are activity, damage by disease and/or medications and quality of life. To evaluate the overall disease activity in CTDs, scores are developed that include typical signs and symptoms. For example, in systemic lupus erythematosus (SLE), various activity instruments have been developed and validated. Recently, a definition for significant reduction in activity based on these scores was proposed and has now to be validated in clinical trials. In addition, the American College of Rheumatology has framed recommendations for response criteria of major target organs. Besides, the rarity of CTDs other than SLE and the rare therapeutic options, especially the heterogeneous disease expression, has prevented development of instruments scoring the disease activity. In individual patients, there is need for a more organ-specific evaluation, and non-disease-specific and/or global health instruments may be used in evaluating the response of individual treatment regimen.
Systemic connective tissue diseases (CTDs) are all characterized by a systemic and heterogeneous array of clinical symptoms. Until today, patients with these diseases were predominantly treated with non-specific anti-inflammatory and immunosuppressive drugs. There have not been any newly approved drugs to treat systemic connective tissue diseases for more than 30 yrs, but remarkable advances in understanding of pathogenetic mechanisms of these diseases have facilitated targeted disease-related or disease-specific molecules. These developments and the discovery of other therapies, which may not be based on known mechanisms, require rigorous evaluation of new therapies especially in patient-oriented research. In addition, treatment in daily clinical practice will also improve by a prior setting of clinical goals including identification of a target organ or manifestation and definition of a treatment goal (e.g. improvement of an organ function) to be achieved in a certain time frame. This will at least become a prerequisite when new and probably more expensive drugs will be introduced into the market.
Proposed domains for outcome measurement of CTDs are activity, damage by disease and/or medications and quality of life [1]. The best outcome result would cure or induce a treatment-free remission, which are both unrealistic aims in CTDs at present. As demonstrated in rheumatoid arthritis (RA), clinical remissions under therapy are feasible when using modern drug therapies. Thereby, clinical remission is equivalent to a control of disease activity that prevents further damage followed by improved quality of life. The term ‘response’ describes also any reduction of disease activity, complete or partial, and is mostly used in CTDs, because the prevention of new damage is seldom precisely evaluable in complex diseases such as CTDs.
To evaluate the overall disease activity in CTDs, scores have been developed that include (weighted or un-weighted) typical signs and symptoms. For example, in systemic lupus erythematosus (SLE), various instruments have been published such as the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), the Systemic Lupus Activity Measure (SLAM) and the European Consensus Lupus Activity Measurement (ECLAM) [2–6]. The British Isles Lupus Assessment Group index (BILAG) reflects in a standardized way the physician's judgement for the necessity to treat different organ manifestations or clinical signs. Despite their differences in content, these instruments reflect overall disease activity and its changes in a larger number of SLE patients quite similar as shown by data from the process developing ACR response criteria. However, for evaluation of response in an individual, different instruments may not give conclusive information, and comparison with the ‘gold standard’, the physician's judgement, may be poor. Reasons for divergent judgements might be the heterogeneity of disease expression and the different weight of symptoms and signs in these scores. In addition, when searching the literature, it is obvious that there is no clear cut-off defined for low or high disease activity and inactivity by these scores. Only the BILAG, which is more complicated to use, allows to compare patients with different organ involvement.
Thus, for daily practice, all these instruments can be used to measure disease activity. This is the essential starting point to evaluate response. However, it remains to be defined what a significant reduction in disease activity or a good treatment response could be. To answer this question, we developed a proposal in an international effort on the basis of the validated activity scores for SLE [7]. All instruments are reflecting changes, both improvement and worsening, and significant differences for improvement are especially measured by BILAG-7, SLEDAI-6, SLAM-R-4 and ECLAM-3. These results have now to be validated in clinical trials, but may also be used to measure response in daily practice.
For CTDs other than SLE, instruments scoring the global disease activity are not yet available. This may be due to the low prevalence of CTDs such as mixed connective tissue disease (MCTD), systemic sclerosis (SSc) and poly-/dermatomyositis (P/DM) as well as the clinical problem that these entities predominantly involve one or two organs with lower general disease activity. This means that there is a need for a more organ specific evaluation, such as skin and lung in SSc or skin and muscle in P/DM. In clinical practice, first of all, a careful total evaluation of the patient is necessary to identify the organs involved. In most cases, this includes additional tests, e.g. laboratory parameters such as creatinine kinase (CK), and/or other functional organ analyses or imaging such as high-resolution CT scan. The results of these investigations will provide a picture of the actual status of the patient, but standardized disease-specific instruments allowing the physician to set such an individual patient in a broader range of disease severity (benchmarking) are rare in CTDs other than SLE. This results in a rather subjective evaluation with the exception of the Rodnan skin score, an instrument for evaluation of the skin manifestations in SSc [8].
In SLE, next to the BILAG, which is an organ-oriented activity instrument, novel organ-specific instruments are under development, e.g. the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) for skin [9] and others for kidney [10] and lung. The proposed kidney response criteria give also an idea how complex such an evaluation might be. Depending on the type of renal involvement, e.g. membranous or membranoproliferative glomerulonephritis (GN), the outcome has to focus more on proteinuria or more on renal function. Therefore, an initial histological evaluation of the renal involvement is mandatory for judgement of response, also to exclude non-classical manifestations. In GN, the tissue analysis also offers important information on a second domain that is important in evaluating response: damage. Damage is defined as irreversible change of an organ and the first aim of therapy is to prevent (further) damage. In case of kidney involvement, damage is clinically reflected by impaired kidney function and proteinuria according to the SLICC score, the validated instrument for damage in SLE. Both parameters may also reflect renal disease activity, which makes the assessment of any expected response more complicated. But, for the evaluation of response, separation of activity versus damage is mandatory, because only activity is responsive to immunosuppressive therapy. The use of angiotensin-converting enzyme (ACE) inhibitors may further complicate the analysis of response, as on one hand, e.g. in SLE nephritis, proteinuria may be improved and on the other hand renal function may further deteriorate. In GN, a re-biopsy may help to estimate therapeutic response if biomarkers are not predictive. In other organ manifestations, the evaluation of damage may be even more complex, e.g. in CNS, where the potential symptoms of the disease are even more diverse. The differentiation between activity and damage is also more complex, e.g. in the case of seizures.
It is the nature of CTDs that in most patients more than one organ is involved. Different organs may respond differentially to a given therapy, so every organ has to be carefully evaluated. In some cases, clinical symptoms might not be attributed to one single organ involvement, e.g. in the case of dyspnoea in pulmonary hypertension (PH) [11]. In this and other complex clinical situations, non-disease-specific and/or global health instruments may be helpful in evaluating a response. In PH, the 6 min walk distance could be one of the best predictors for response and outcome [12], but the musculo-skeletal involvement in CTDs may limit execution and/or interpretation.
In the long run, quality of life is crucial for patients. In case of lack of disease-specific instruments, global assessment tools can be helpful. General health instruments have been shown to be valid for measuring quality of life in SLE patients. Global health is most frequently measured by a visual analogue scale or the medical outcomes survey short form-36 (SF-36). Patient cohort data have demonstrated that the SF-36 reflected the effects of SLE better than other patient reported measures, and in addition, SF-36 also allows comparison with other diseases and chronic illnesses.
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