Outcome Measures in Sjögren’s Syndrome and Perspectives in Clinical Trial Design

1.1

Symptoms

Evaluation of the three main symptoms of primary Sjögren’s syndrome (pSS): dryness, pain, and fatigue, is pivotal, because these concerns are shared by all patients with pSS, in contrast to systemic complications, which affect approximately 30% of patients. Individual visual analog scales (VASs), ie, pain and fatigue VASs, represent the only way to assess patients’ symptoms. Early randomized clinical trials in pSS evaluating infliximab or etanercept defined the primary outcome criteria as a decrease in patients’ VAS score (pain, fatigue, and dryness). Recently, the European League Against Rheumatism (EULAR) Sjögren’s Syndrome Patient-Related Index (ESSPRI) was internationally validated. This patient-related outcome is very simple to score (it is the mean of VAS pain, fatigue, and dryness) and sensitive to change. The ESSPRI allows patients to be divided into different disease activity subsets. In addition, it has recently been shown that patients’ minimal clinically important improvement (MCII) corresponds to a decrease of at least 15% of the ESSPRI baseline value or a decrease of at least one point (on a 10-point score). Consequences of these symptoms on quality of life (QOL) can be assessed using QOL scales such as the Short Form-36 and on depression by the Health Assessment Questionnaire score. Fatigue and dryness can also be studied more in-depth by using fatigue scores such as the Functional Assessment of Chronic Illness Therapy and the Profile of Fatigue and Discomfort-Sicca Symptoms Inventory questionnaires.

1.2

Systemic Complications

Evaluation of systemic complications used to be very complicated in pSS. There was no consensus on the definition of systemic complications and there were no available scores. Patients were divided into patients with only glandular symptoms and patients with extraglandular involvement. However, the latter term was not clearly defined either. An international task force addressed this important issue and consensually defined each feature of systemic disease activity. Its objective was to set up a scale which was easy to score, sensitive to change, and capable of discriminating activity from damage. Parotid gland swelling and some biological parameters [cytopenia, elevated immunoglobulin (Ig) G, decreased complement levels, cryoglobulinemia] were also considered to mirror systemic involvement. This effort resulted in the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI), composed of 12 domains, including one biological domain. Each domain is rated according to the severity of the involvement (no involvement; low, moderate, or high disease activity). The score was developed through the evaluation of the activity of 702 clinical vignettes based on 96 real patients. These vignettes were used to analyze a large number of cases with all possible systemic complications of the disease. The weights of each domain were obtained with multiple regression models using the physician global assessment of disease activity as a gold standard. The ESSDAI is effectively easy to score and sensitive to changes of disease activity. It has already been used in clinical trials (both in open trials and retrospectively in controlled trials) and is the main outcome criteria chosen in ongoing and forthcoming randomized clinical trials. A glossary explaining the way to correctly rate the ESSDAI is now available. The ESSDAI allows patients to be divided into different disease activity subgroups. Low systemic activity is defined by an ESSDAI of less than 5, moderate activity by an ESSDAI of greater or equal to 5 and lower or equal to 13, and high activity by an ESSDAI of greater or equal to 14. In addition, it was recently shown that MCII corresponds to a decrease of at least three points of the baseline value of ESSDAI. A clinical ESSDAI, without the biological domain, was recently proposed to offer the possibility of scoring systemic disease activity immediately after clinical examination and to evaluate the clinical effect of some biological drugs independently of their effect on IgG, cryoglobulinemia, or complement.

Given the previous paragraph, the ESSDAI definitively represents a great achievement for clinical trials. It has already been adopted and used in different ongoing or forthcoming clinical trials. In these trials, an ESSDAI equal to or greater than 5 or 6 is required as inclusion criteria. The primary outcome is either a decrease of at least three points or a change in ESSDAI. Nonetheless, using the ESSDAI as a primary outcome criteria has some limitations:

• Some of its highly weighted domains refer to pulmonary or peripheral nerve involvement where discriminating activity from damage is complicated.

• Two domains (hematological and biological domains) are purely biological.

• The glandular domain requires the evaluation of the size of the parotid glands, which is complicated from a clinical point of view.

• The ESSDAI score might decrease if the activity of a domain of high weight improves while the activity of another domain of lower weight increases.

• The ESSDAI evaluation does not take into account the clinician’s global assessment.

To circumvent some of these limitations, we proposed to use a Sjögren’s Syndrome Response Index in the tocilizumab multicenter placebo controlled trial, defined in Table 17.1 .

1.3

Objective Assessment of Dryness (Tear and Saliva Secretion)