Development and Application of the Placebo Response Model in Clinical Trials for Primary Sjögren's Syndrome.

This study aimed to develop a placebo response model for pharmaceutical clinical trials of primary Sjogren's syndrome,and to quantitatively analyze the distribution and related factors influencing the placebo response to further optimize the design of clinical trials and evaluate the results of single-arm clinical trials. Public databases, including PubMed, Embase, and Cochrane Library were searched for reports on randomized placebo-controlled trials for Sjögren's syndrome which used the change from baseline in ESSDAI score as the primary outcome. The model-based meta-analysis method was used to evaluate the time course and the related influencing factors of the placebo response for ESSDAI in such clinical trials. A virtual placebo control group was constructed based on the final placebo response model to determine the treatment efficacy of belimumab and cyclosporine A for primary Sjögren's syndrome in a single-arm study. A total of 12 studies involving 450 subjects were included in the analysis. The established model described the time-course characteristics of the changes in ESSDAI score from the baseline in the 48 weeks placebo group. We found that the onset time of placebo response was approximately 12 weeks, and its efficacy plateaued at 48 weeks. The baseline ESSDAI score had a significant effect on the maximum value of the placebo response; the maximum value of the placebo response decreased by 0.552 for every 1 score rise in the baseline ESSDAI score. The efficacy of belimumab and cyclosporine A in the single-arm trial was comparable to that of the placebo response at the same baseline; no significant therapeutic advantage was observed. The placebo response model established in this study could provide a basis for designing clinical trials for primary Sjogren's syndrome in the future. It may also provide a reliable external efficacy control standard for single-arm clinical trials.

Assessment of mucin-related gene alterations following treatment with rebamipide ophthalmic suspension in Sjögren's syndrome-associated dry eyes.

Ocular surface mucins are thought to play vital roles in maintaining the homeostasis of the pre-ocular surface tear film. We performed ocular surface tests with impression cytology to assess the expression levels of mucin-related genes on the ocular surface in healthy eyes. In addition, we investigated alterations in mucin-related gene expression secondary to treatment with rebamipide ophthalmic suspension in patients with Sjögren's syndrome-associated dry eyes (SS-DE). Thirty-three healthy individuals (control group) and 13 patients from our hospital with SS-DE were enrolled. Impression cytology was performed using Schirmer's test paper for RNA sampling. The mRNA levels of SAM-pointed domain-containing ETS-like factor (SPDEF), mucin 5AC (MUC5AC), and mucin 16 (MUC16) were determined using a real-time reverse transcription-polymerase chain reaction. The ocular surface test was performed once for the control group, and at baseline as well as 2, 4, 8, and 12 weeks after treatment in the Sjögren's syndrome-associated dry eyes group. mRNA levels of SPDEF, MUC5AC, and MUC16 were not significantly different between the control and SS-DE groups before rebamipide ophthalmic suspension treatment. SPDEF mRNA levels in control subjects were significantly correlated with levels of MUC5AC. Among SS-DE patients, SPDEF mRNA levels were significantly increased at 2, 4, and 8 weeks after treatment compared with baseline levels. MUC16 mRNA levels were significantly decreased from baseline levels at 4 and 8 weeks post-treatment. Ocular surface test using impression cytology is a clinically useful tool for assessing mucous conditions on the ocular surface and can be used to determine the effects of instillation treatment with eye drops that affect mucin production at the ocular surface.

Social-economic analysis of patients with Sjogren's syndrome dry eye in East China: a cross-sectional study.

BACKGROUND: Sjogren's syndrome is the leading cause for aqueous tear-deficiency dry eye. Little is known regarding the relationship between Sjogren's syndrome dry eye (SSDE) and patients' medical expenditure, clinical severity and psychological status changes. METHODS: Thirty-four SSDE patients and thirty non-Sjogren's syndrome dry eye (non-SSDE) subjects were enrolled. They were required to complete three self-report questionnaires: Ocular Surface Disease Index, Zung Self Rating Anxiety Scales, and a questionnaire designed by the researchers to study the patients' treatment, medical expenditure and income. The correlations between expenditures and these parameters were analyzed. RESULTS: The annual total expenditure on the treatment of SSDE was Chinese Yuan 7637.2 (approximately US$1173.8) on average, and the expense paid by SSDE patients themselves was Chinese Yuan 2627.8 (approximately US$403.9), which were 5.5 and 4.5 times higher than non-SSDE patients (both P < 0.001). The annual total expense on Chinese medicine and western medicine were 35.6 times and 78.4% higher in SSDE group than in non-SSDE group (both P < 0.001). Moreover, indirect costs associated with the treatment were 70.0% higher in SSDE group. In SSDE group, the score of Zung Self Rating Anxiety Scales had significantly positive correlation with total medical expenditure and the expense on Chinese medicine (ρ = 0.399 and ρ = 0.400,both P = 0.019). Nevertheless, total medical expenditure paid by the patients in non-SSDE group positively correlated with the score of Ocular Surface Disease Index (ρ = 0.386, P = 0.035). CONCLUSIONS: Medication expenditures and associated costs is an unignorable economic burden to the patients with SSDE. The medical expense had a significantly correlation with clinical severity of SSDE and the patients' psychological status.

Randomized Controlled Trial of Rituximab and Cost-Effectiveness Analysis in Treating Fatigue and Oral Dryness in Primary Sjögren's Syndrome.

OBJECTIVE: To investigate whether rituximab, an anti-B cell therapy, improves symptoms of fatigue and oral dryness in patients with primary Sjögren's syndrome (SS). METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial that included health economic analysis. Anti-Ro-positive patients with primary SS, symptomatic fatigue, and oral dryness were recruited from 25 UK rheumatology clinics from August 2011 to January 2014. Patients were centrally randomized to receive either intravenous (IV) placebo (250 ml saline) or IV rituximab (1,000 mg in 250 ml saline) in 2 courses at weeks 0, 2, 24, and 26, with pre- and postinfusion medication including corticosteroids. The primary end point was the proportion of patients achieving a 30% reduction in either fatigue or oral dryness at 48 weeks, as measured by visual analog scale. Other outcome measures included salivary and lacrimal flow rates, quality of life, scores on the European League Against Rheumatism (EULAR) Sjögren's Syndrome Patient Reported Index and EULAR Sjögren's Syndrome Disease Activity Index, symptoms of ocular and overall dryness, pain, globally assessed disease activity, and cost-effectiveness. RESULTS: All 133 patients who were randomized to receive placebo (n = 66) or rituximab (n = 67) were included in the primary analysis. Among patients with complete data, 21 of 56 placebo-treated patients and 24 of 61 rituximab-treated patients achieved the primary end point. After multiple imputation of missing outcomes, response rates in the placebo and rituximab groups were 36.8% and 39.8%, respectively (adjusted odds ratio 1.13 [95% confidence interval 0.50, 2.55]). There were no significant improvements in any outcome measure except for unstimulated salivary flow. The mean ± SD costs per patient for rituximab and placebo were £10,752 ± 264.75 and £2,672 ± 241.71, respectively. There were slightly more adverse events (AEs) reported in total for rituximab, but there was no difference in serious AEs (10 in each group). CONCLUSION: The results of this study indicate that rituximab is neither clinically effective nor cost-effective in this patient population.

Severe Health-Related Quality of Life Impairment in Active Primary Sjögren's Syndrome and Patient-Reported Outcomes: Data From a Large Therapeutic Trial.

OBJECTIVE: To identify the principal determinants of health-related quality of life (HRQOL) impairment in patients with active primary Sjögren's syndrome (SS) participating in a large therapeutic trial, Tolerance and Efficacy of Rituximab in Primary Sjögren's Syndrome (TEARS). METHODS: At the inclusion visit for the TEARS trial, 120 patients with active primary SS completed the Short Form 36 health survey (SF-36), a validated HRQOL assessment tool. Univariate then multivariate linear regression analyses were used to assess associations linking SF-36 physical and mental components to demographic data, patient-reported outcomes (symptom intensity assessments for dryness, pain, and fatigue, including the European League Against Rheumatism [EULAR] Sjögren's Syndrome Patient Reported Index [ESSPRI]), objective measures of dryness and autoimmunity, and physician evaluation of systemic activity (using the EULAR Sjögren's Syndrome Disease Activity Index [ESSDAI]). RESULTS: SF-36 scores indicated marked HRQOL impairments in our population with active primary SS. Approximately one-third of the patients had low, moderate, and high systemic activity according to the ESSDAI. ESSPRI and ESSDAI scores were moderately but significantly correlated. The factors most strongly associated with HRQOL impairment were patient-reported symptoms, best assessed using the ESSPRI, with pain and ocular dryness intensity showing independent associations with HRQOL. Conversely, systemic activity level was not associated with HRQOL impairment in multivariate analyses, even in the patient subset with ESSDAI values indicating moderate-to-high systemic activity. CONCLUSION: The cardinal symptoms of primary SS (dryness, pain, and fatigue, best assessed using the ESSPRI) are stronger predictors of HRQOL impairment than systemic involvement (assessed by the ESSDAI) and should be used as end points in future therapeutic trials focusing on patients' well-being. New consensual and data-driven response criteria are needed for primary SS studies.

Sjögren's syndrome: managed care data from a large United States population highlight real-world health care burden and lack of treatment options.

OBJECTIVES: To better understand the real-world characteristics and costs of Sjögren's syndrome (SS). METHODS: Analysing the MarketScan Commercial Claims database from Jan. 1, 2006 to Dec. 31, 2011, we identified 10,414 patients ≥18 years old newly diagnosed with SS. Patient characteristics, drugs (commonly used for SS), resource utilisation, and medical costs were evaluated for 12 months pre- and post-diagnosis. RESULTS: Mean age was 55 years; 90% were female. At diagnosis, SS patients were most often seen by rheumatologists (39%) or internists (14.2%); the most common concurrent autoimmune conditions were rheumatoid arthritis (17.9%) and systemic lupus erythematosus (14.6%). Other common comorbidities were hypertension (37.6%), osteoarthritis (31.4%), and hyperlipidaemia/dyslipidaemia (30.3%). Post diagnosis of SS, claims for myocardial infarction and coronary artery bypass graft doubled. Medications of interest prescribed post-diagnosis were eye/mouth drugs (32.2%) and synthetic immunosuppressants (32.1%). Biologic drugs were prescribed to a minority (TNF inhibitors, ~5.0%; non-TNF inhibitors, 1%). Of note, prescriptions for all systemic immunotherapies (synthetic and biologic) were significantly lower in the subgroup without concurrent autoimmune disease, and 15.1% of the overall population had no SS-related prescriptions. Post diagnosis, total medical resource utilisation and total medical costs increased (1.2 and 1.4-fold, respectively). CONCLUSIONS: In this retrospective, real-world analysis, medical claims in the first year after SS diagnosis revealed that cardiovascular (CV) events increased and all-cause healthcare costs grew by 40%. Pharmacologic management consisted primarily of low potency immunomodulation and symptomatic treatments. Systemic disease-modifying therapies were used mostly in patients who had another concurrent autoimmune disease, suggesting a lack of treatment options for SS.

New Treatment Guidelines for Sjögren's Disease.

Sjögren's disease is associated with a high burden of illness, diminished quality of life, and increased health care costs. The Sjögren's Syndrome Foundation developed the first US clinical practice guidelines for management of the oral, ocular, and rheumatologic or systemic manifestations. Guideline recommendations were reviewed by a consensus expert panel using a modified Delphi process. This initiative should improve the quality and consistency of care for Sjögren's disease in the United States, guide insurance reimbursement, and define areas for future study. Guidelines will be periodically reviewed and revised as new information becomes available.

Brief Report: Ultrasonographic Assessment of Salivary Gland Response to Rituximab in Primary Sjögren's Syndrome.

OBJECTIVE: To evaluate changes in salivary gland echostructure and vascularization after rituximab treatment in patients with primary Sjögren's syndrome (SS). METHODS: Twenty-eight patients with primary SS included in the multicenter, randomized, double-blind, placebo-controlled Tolerance and Efficacy of Rituximab in Primary Sjögren's Syndrome (TEARS) trial underwent salivary gland ultrasonography before the first placebo or rituximab infusion and then 6 months later. Trial inclusion criteria were scores of ≥50 mm on at least 2 of 4 visual analog scales (VAS) evaluating dryness, pain, fatigue, and global disease; and recent-onset (<10 years) biologically active primary SS and/or systemic primary SS. Patients were randomly assigned (1:1) to rituximab (1 gm at weeks 0 and 2) or placebo. Ultrasonography of both parotid and submandibular glands was performed to assess echostructure (using a semiquantitative score of 0-4, with improvement defined as a ≥1-point decrease), size of each gland, and vascularization based on the resistive index of the transverse facial artery of the parotid gland before and after lemon juice stimulation. RESULTS: Of the 28 patients, 5 (18%; 3 in the placebo group and 2 in the rituximab group) had clinically detectable bilateral parotid gland enlargement at baseline. Parotid parenchyma echostructure improved in 50% of the rituximab-treated patients versus 7% of the placebo-treated patients (P = 0.03). In the submandibular glands, echostructure also improved in a larger proportion of rituximab-treated patients, although the difference was not significant (36% versus 7% of placebo-treated patients; P = 0.16). Gland sizes and resistive index remained unchanged. CONCLUSION: Ultrasonography showed improved salivary gland echostructure in patients with primary SS receiving rituximab, with no changes in salivary gland size or vascularization, 6 months after the first infusion.

Biologic agents and oral diseases -- an update on clinical applications.

Biologic agents are targeted immune modulating agents that have been widely used in the treatment of inflammatory and neoplastic conditions with favorable results. The purpose of this review is to provide an update on the biologic agents that have been used in the treatment of diseases that affect the oral mucosa. Identification of relevant data, case reports and case series was performed using the PubMed-MEDLINE database and electronic databases of accredited organizations such as the European Medical Agency, US Food and Drug Administration, and clinicaltrials.gov (USA). According to the literature, the use of biologic agents in patients with oral diseases is limited mainly to patients suffering from refractory forms of immune-mediated diseases of the oral cavity. Biologic agents were used in all cases as off-label indications. Patient's response varied, but in general biologic agents could be considered as a therapeutic option in patients with no other alternative. A point requiring extra precaution is their safety profile because severe life threatening infections are among their side effects. Another aspect that limits their broader use is their high economic cost. We aimed to provide a practical update for the clinicians who deal with oral diseases, covering as many aspects as possible of the applications of biologic agents in oral diseases reported to date.

Assessment of bromhexine as a treatment regimen in Sjögren's syndrome-like disease in the NOD (non-obese diabetic) mouse.

OBJECTIVE: Bromhexine has been reported to alleviate the xerostomia and xerophthalmia associated with secondary Sjögren's syndrome. The aim of this study was to determine if it might prove useful in the treatment of Sjögren's syndrome-like disease of the NOD mouse model for autoimmune sialoadenitis. METHODS: Groups of mice were divided into sets receiving 60 mg/kg bromhexine in drinking water and control pair-fed animals. The efficacy of drug treatment was assessed by weekly measurement of stimulated saliva volumes, protein concentration, and amylase activity. At termination (20 weeks) submandibular and lacrimal glands were removed to assess the levels of lymphocytic infiltration by histological evaluation under light microscopy. RESULTS: Control and bromhexine-treated groups of mice showed no difference in the loss or rate of reduction in stimulated saliva flow over the 12 weeks of treatment. No differences were noted in the protein concentration and amylase loss with increasing age of the animals. Similar temporal changes in total protein profiles and aberrant expression of the 20 kDa parotid secretory protein isoform were observed by SDS-polyacrylamide gel profiles and Western bolt analysis. Histological evaluation of exocrine gland sections failed to detect any reduction in focal lymphocyte infiltration. CONCLUSION: Bromhexine therapy did not alter the development or severity of Sjögren's syndrome-like disease in the NOD mouse model for autoimmune sialoadenitis.

Assessment of sulphasalazine as a treatment modality in Sjögren's disease in NZB/NZW F1 hybrid mice.

OBJECTIVE: Sulphasalazine is a recognised second-line agent in the treatment of rheumatoid arthritis. The aim of this study was to determine if it might prove useful in the treatment of Sjögren's syndrome. METHODS: The trial was performed in NZB/NZW F1 hybrid mice and efficacy was assessed on the basis of a reduction in the lymphocytic infiltration of the submandibular salivary and lacrimal glands. The animals were divided into three groups; the control group remained untreated, the second group received the drug from 14-42 weeks and the third group received sulphasalazine from 26-42 weeks. At four-weekly intervals throughout the study, five animals in each group were killed using ether and the glands assessed for lymphocytic infiltration using a modified focus scoring technique with light microscopy. RESULTS: No significant reduction in the lymphocytic infiltration occurred consistently throughout the trials with sulphasalazine. CONCLUSION: Sulphasalazine did not significantly alter the development of Sjögren's disease in NZB/NZW F1 mice.