Fig. 21.5 Mean and 95% conÞdence intervals for ratings of discomfort at their worst over the last 2 weeks (7 = worst discomfort imaginable) for groups diagnosed with

PSS, SLE, RA, and healthy controls. • PSS (n = 78Ð112);SLE (n = 48Ð53); RA (n = 39Ð50); controls (n = 58Ð77)

[69Ð72] dryness, although this list is not exclusive. Data from the Sicca Symptoms Inventory (SSI) is presented in Fig. 21.5 demonstrating higher levels of oral, ocular, vaginal, and cutaneous dryness than controls. As with fatigue questionnaires, some of these sicca questionnaires are uni-dimensional [63, 64, 67] whereas others are multidimensional [65, 66, 68, 69, 71, 72] and some also include questions on vaginal, cutaneous, bronchial, and/or nasal dryness.

There have been relatively few studies directly comparing different sicca questionnaires. In our study developing the Sicca Symptoms Inventory (SSI) [69] we identiÞed similarities between the SSI and Xerostomia Inventory. The National Eye Institute Visual Function 25-item (NEI-VFQ-25) Questionnaire has also been shown to correlate with results using the ocular surface disease index (OSDI) [72]. It is likely, however, that as with the measurement of fatigue and pain, using a VAS of dryness as the primary outcome measure along with a dryness questionnaire as a conÞrmatory secondary outcome measure is the most

logical approach. This still leaves the question as to which component of dryness to choose? To some extent this will depend on the study medication and the research question. In a recent study, our patients demonstrated a close correlation between oral and global dryness VASs [45], and our preference at this time is to use oral rather than global dryness as the principal measure of sicca in a clinical trial, but this is by no means Þxed in stone.

21.8Data from Existing Clinical Studies Addressing Dryness in pSS

The largest trial of systemic therapy of oral and ocular dryness in SS was performed by Vivino et al. in 1999 [70]. They studied 373 patients with primary or secondary SS randomized to placebo or pilocarpine. Pilocarpine is a muscarinic agonist that stimulates exocrine glands. Pilocarpine was effective in stimulating salivary ßow at the

start and throughout the study, although with no increase in basal or stimulated ßow rates at the end of the study. Nevertheless, from a symptomatic perspective, patients on the 5 mg qds dose had a signiÞcantly higher likelihood of responding as assessed by symptomatic measures of global dryness of eyes and mouth and multiple individual dryness symptom items. Similar data are available from studies of cevimeline, another muscarinic agonist licensed in the USA and Japan for the treatment of dryness in pSS [73, 74].

Interferon-α lozenges have also been studied for improvement in salivary function in an openlabel study [75]. Salivary ßow and histological features improved but patient-related outcomes were not reported. In a combined report from two phase III double-blind randomized controlled studies by Cummins et al. [76] of 497 patients with pSS, improvement in unstimulated whole salivary ßow and 7 of 8 symptoms of oral dryness were observed although the chosen primary endpoints of an improvement in both stimulated whole salivary ßow and a VAS of oral dryness did not show statistically signiÞcant improvement.

Topical cyclosporine emulsion has also been studied in two large studies of ocular dryness [77, 78]. In the smaller study [77], the 0.1% dose was most consistent in improving some objective and some subjective endpoints and the 0.05% dose in improving patient symptoms including the OSDI. In the larger study of 877 patients by Sall et al. [78], SchirmerÕs tear test with anesthetic and corneal staining at 6 months improved signiÞcantly more in the active treatment groups compared with placebo, whereas SchirmerÕs test without anesthetic and the OSDI improved with both active drug and the placebo (vehicle alone) although other subjective measures (blurred vision, artiÞcial tear usage, and physician global assessment) did show greater beneÞt from the active drug. These studies suggest that both the vehicle and active drug have beneÞcial effects with some added beneÞt from the cyclosporine component.

Two open-label studies of rituximab have suggested potential beneÞt for sicca features [5, 55]. More recently a double-blind study of 30 patients showed improvement in both stimulated ßow rate

and oral dryness VAS in the active but not placebo group. This is potentially very positive support for larger studies of anti-B-cell agents in pSS.

21.9Conclusion: Clinical Trial Outcomes

The development of questionnaire tools for dryness and fatigue symptoms as well as the availability of new biological therapies has opened the possibility of conducting clinical trials of these therapies in pSS. At the present time, anti-B- cell therapies such as rituximab are the logical agent of choice and a number of studies are in progress or planned. There are, however, some remaining challenges with regard to assessment, particularly in relation to the choice of primary outcome, which is regarded as absolutely critical in an early clinical trial of a therapeutic product.

1.One question is whether to choose dryness or fatigue symptoms or a composite of both (or to include health-related quality of life and pain as well). In two expert workshops, fatigue was felt to be a particularly important outcome domain [79, 80]. We have also shown that fatigue can improve following systemic therapy [35] and there is increasing interest in its use as a secondary outcome measure in RA [14, 81]. Nevertheless, there is some reluctance to rely on it exclusively. Other approaches, therefore, are to use it as part of a composite symptomatic outcome measure [52] or to incorporate it into, or alongside, a systemic activity measure [5, 82].

2.The second issue is what constitutes meaningful clinical improvement? In rheumatoid arthritis the American College of Rheumatology response criteria require a minimum 20% improvement (ACR-20) in the number of tender and swollen joints and other parameters [83]. The ACR-50 and ACR-70 are similar but require 50% and 70% improvement in the above parameters, respectively. These criteria were developed through an analysis of the results of pre-existing trials that used different outcome measures and a

process of developing a broad consensus of experts. They have stood the test of time over the past decade and are now used in every RA trial. We now need to develop equivalent response criteria in pSS.

3.There is a relatively weak correlation between dryness symptoms and objective measures of lacrimal and salivary ßow [84]. This poses a dilemma in a clinical trial contextÑshould the primary outcome be improvement in salivary/lacrimal ßow or improvement in symptoms or both? Other uncertainties include with a placebo group response rate for improvement in symptoms of approximately 30% [35, 70] what is the minimum clinically meaningful response in the active group that should be reßected in the deÞnition of the primary outcome? Another issue to be aware of is that salivary ßow can be measured either as basal (unstimulated) ßow or as stimulated ßow (e.g., in response to a sharp stimulus such as lemon drops or a pastille). Mechanistically, reduced unstimulated basal ßow has been regarded as the main deÞcit in pSS but several successful clinical trials have used stimulated salivary

ßow in preference to this [59, 70].

Some of these issues will be addressed by a collaborative European League against Rheumatism (EULAR) sponsored project (Vitali C, Mariette X, Bowman SJ, et al.) to develop and validate consensus disease activity and patient-reported outcome measures based on our previous work [2, 5, 45, 69, 82, 85]. Part of this project will evaluate the relative importance to patients of fatigue and the common dryness symptoms as well as assessing what is minimally signiÞcant change. Information from this study as well as data from recent and current trials will inform the design of future phase II/III trials and the development of effective therapy for this debilitating condition.

Acknowledgments A variation of this article has also been published in Rheumatic Disease Clinics of North America 2008. Figures in this article have been reprinted with permission from Annals of the Rheumatic Diseases and the Journal of Rheumatology and Rheumatology

(Oxford).

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Abbreviations

R.I. Fox ( )

Rheumatology Clinic, Scripps Memorial Hospital and Research Foundation, La Jolla, CA, USA e-mail: robertfoxmd@mac.com