Sjögren's syndrome (SS) is a systemic autoimmune exocrinopathy that predominantly affects women (1). SS may occur as a primary disorder or secondary to other autoimmune conditions, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or scleroderma (2). SS is characterized by lymphocytic infiltration of the lacrimal and salivary glands, which leads to loss of secretory function, and thereby, to dry eyes and dry mouth. The reported prevalence of SS varies from 0.05% to 4.8% and the physician-diagnosed incidence is approximately 4 per 100,000 patients per year (3).
The etiology of SS has not yet been elucidated. Lymphocytic infiltrates are a characteristic histopathologic finding in SS. The presence of cytokines during the formation and proliferation of these lymphocytic infiltrates has been investigated (4, 5), and evidence suggests that proinflammatory cytokines, tumor necrosis factor α (TNFα) in particular, may play an important role in the pathogenesis of the disease (6–8). Additionally, TNFα inhibition has been shown to be effective in suppressing tissue destruction in lacrimal glands (9) and in immortalized human salivary gland acinar cells in vitro (10, 11).
Currently in the US, only the secretagogues pilocarpine and cevimeline have been specifically approved for the symptomatic treatment of SS (12, 13). Pharmacologic treatment for the systemic manifestations of SS often consists of corticosteroids and other disease-modifying antirheumatic drugs (DMARDs). However, clinical trials directed at the autoimmune and inflammatory components of SS have been mostly uncontrolled and of insufficient sample size to draw any definitive conclusions regarding the efficacy of such agents (14). A small, uncontrolled, open-label trial of an anti-TNFα antibody, infliximab, given for 3 months to patients with primary SS was reported to be safe and beneficial (15). A 1-year uncontrolled followup study (16) confirmed these initial observations.
We hypothesized that soluble TNFα receptor would be effective in the treatment of inflammation of the exocrine glands in SS, ultimately leading to improved exocrine function and diminished systemic inflammation. We therefore began a 12-week randomized, double-blind, placebo-controlled, pilot clinical trial to screen for potential efficacy and to evaluate the safety and adverse effects of etanercept in SS.
PATIENTS AND METHODS
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- PATIENTS AND METHODS
This was a double-blind, randomized pilot study of etanercept versus placebo therapy in 28 patients (n = 14 per group). Patients were randomized in blocks of 4 by the Pharmaceutical Development Service at the Clinical Center Pharmacy of the National Institutes of Health. Patients were stratified according to whether they had primary or secondary SS. Medication was administered by subcutaneous injection twice each week for 12 weeks. Patients assigned to the active-treatment group received 25 mg of etanercept; those assigned to the placebo group received the identical-appearing etanercept vehicle.
Baseline evaluations included a medical history, physical examination, electrocardiogram, chest radiograph, acute care (serum electrolytes, blood glucose, blood urea nitrogen, creatinine levels), hepatic and mineral panels, complete blood cell count with differential count, Westergren erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, rheumatoid factor level, quantitative immunoglobulins, urinalysis, pregnancy test, ocular vital dye staining (lissamine green), Schirmer I test, and tuberculin skin test. Subjects were allowed to continue their other long-term medications, with the exception of tricyclic antidepressants and anticholinergics, which may affect salivary gland function. A negative pregnancy test result and the use of 2 forms of birth control throughout the trial were required of all women of childbearing potential.
Patients (males and females) with SS, as determined by the criteria of Fox et al (17), who had symptoms and complaints consistent with oral and ocular dryness and evidence of active SS, as indicated by elevated ESR or IgG levels, were included. The study patients also met the American-European Consensus Group criteria for SS (18). Patients were excluded for the following reasons: history of cancer or diabetes, positive findings on a tuberculin skin test, age ≤16 years, and use of tricyclic antidepressants or anticholinergics.
Clinical assessments of disease activity were performed at study entry and at 4, 8, and 12 weeks thereafter. To evaluate the potential efficacy of the treatment, we obtained the following data: patient's assessment of dry mouth (on a 100-mm visual analog scale [VAS]), unstimulated and stimulated parotid and submandibular salivary flow, patient's assessment of dry eyes (on a 100-mm VAS), lissamine green ocular vital dye staining (scored according to the method of van Bijsterveld ), Schirmer I test (with and without anesthetic ), serum IgG level, and ESR.
Efficacy was defined as meaningful improvement in 2 of the 3 SS disease domains: oral, ocular, and laboratory. Oral improvement was defined as ≥20% improvement in the patient's assessment of dry mouth by VAS or ≥20% improvement in total stimulated salivary flow. Ocular improvement was defined as ≥20% improvement in either the patient's assessment of dry eyes by VAS, the van Bijsterveld score, or the results of the Schirmer I test without anesthetic. Laboratory improvement was defined as ≥20% improvement in the serum IgG level or the ESR.
The protocol was approved by the Institutional Review Board of the National Institute of Dental and Craniofacial Research. Safety was monitored and patients were asked about possible side effects during interviews at each monthly visit and during weekly telephone calls (21).
The study design was derived from the oncologic screening model of Gehan (22), which was adapted by Paulus (23) for use in autoimmune rheumatic diseases, with the assumption that the placebo response rate is 20% in a single-arm study with a dichotomous response variable (24). It is expected that if there are no responders among 14 consecutive subjects, there is a 95% chance that further investigation will not reveal efficacy. However, if 1 or more individuals respond, then 16 more patients will be treated, and for 3 more responders, the treatment will be further investigated in a phase III trial. A placebo control group was included to determine whether the placebo response rate was actually 20% in the current trial. In addition, inclusion of a placebo group would allow for a sample size estimate for a definitive phase III trial, if warranted.
Differences between the etanercept and placebo groups for baseline data were determined by t-tests, and changes in outcome measures over the trial were compared by nonparametric analysis of variance. In addition, analysis of covariance was performed to adjust for differences in baseline covariates. Fisher's exact test was used to compare the proportion of responders, as determined by the primary outcome measure, in the placebo versus etanercept groups. The analyses for efficacy were based on intent-to-treat, using the last observation carried forward method.
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- PATIENTS AND METHODS
Of the 28 subjects who were enrolled, 14 were randomized to receive etanercept and 14 to receive placebo. In both treatment groups, 11 of 14 patients had primary SS and 3 had secondary SS. The 3 patients in the etanercept group with secondary SS had RA. Two of the subjects in the placebo group with secondary SS met criteria for SLE and 1 had CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia).
At baseline, age, subjective assessments of ocular and oral dryness by VAS, total unstimulated and total stimulated saliva production, results on the Schirmer I test, van Bijsterveld scores, the ESR, the IgG level, and focus scores did not differ significantly between groups (Table 1). CRP levels in the etanercept-treated patients did not differ significantly from those in the placebo-treated patients at baseline (P = 0.10). The CRP level was marginally elevated (normal range 0–0.8 mg/dl) in 1 subject in the etanercept group (0.81 mg/dl) and 1 subject in the placebo group (0.86 mg/dl) at baseline. Over the trial, the CRP levels increased in 1 etanercept-treated individual, but not beyond the normal range, and decreased in 6 patients. CRP levels increased in 4 of the placebo-treated patients. This increase was beyond the normal range in only 2 of the 4 patients (from 0 to 0.81 mg/dl in one patient and from 0.86 mg/dl to 1.38 mg/dl in the other). The mean ESR and CRP levels at baseline in the 11 patients with primary SS were 45.8 mm/hour and 0.24 mg/dl, respectively. These levels did not differ significantly from those in the placebo group (P = 0.28 for the ESR; P = 0.18 for the CRP). Mean IgA and IgM levels at baseline did not differ significantly between the two treatment groups (P = 0.63 and P = 0.32, respectively).
Table 1. Demographics and measures of disease activity at baseline, by treatment group*
| ||Etanercept (n = 14)||Placebo (n = 14)||P|
|Age, years||55.5 (46, 59)||54.5 (46, 66)||0.64|
|Sex, no. female/no. male||12/2||14/0||–|
|Focus score||11 (5, 12)||7 (4, 12)||0.53|
|SSA, no. (%) positive||12 (86)||12 (86)||–|
|SSB, no. (%) positive||7 (50)||7 (50)||–|
|Dry mouth, by 100-mm VAS†||17 (8, 25)||38 (1, 50)||0.08|
|Dry eyes, by 100-mm VAS‡||21 (17, 39)||31 (21, 64)||0.33|
|Schirmer I test, mm/5 minutes§||5 (2, 6.5)||2 (1, 5.5)||0.43|
|Van Bijsterveld score¶||5.8 (5, 8.5)||5.5 (3, 7.5)||0.24|
|Total unstimulated saliva flow, ml/minute||0 (0, 0)||0 (0, 0)||0.40|
|Total stimulated saliva flow, ml/minute||0 (−0.15, 0.02)||0 (−0.21, 0.13)||0.72|
|IgG, mg/dl||1,525 (1,410, 2,090)||1,755 (1,470, 1,970)||0.80|
|ESR, mm/hour||46 (30, 58)||29 (22, 43)||0.11|
|CRP, mg/dl||0 (0, 0.45)||0 (0, 0)||0.10|
Three patients in the etanercept treatment arm did not complete the trial. One voluntarily discontinued because of no perceived benefit from the study medication. Two patients were withdrawn from the study: one because of an atypical injection-site reaction and the other because of the development of a rapidly enlarging skin lesion. Study medication was withdrawn from 1 patient receiving placebo because of the development of a prolonged upper respiratory tract infection.
With regard to the primary outcome response criteria (20% improvement in 2 of the 3 SS disease domains: oral, ocular, and laboratory tests), 5 patients in the etanercept group and 3 in the placebo group showed improvement in the primary outcome. The difference between the groups was not significant (P = 0.2 by Fisher's exact test). When the required improvement was increased to 30%, there were 5 responders in the etanercept group and 2 in the placebo. At an improvement level of 50%, there were 2 responders in the etanercept group and 1 in the placebo group.
There were no significant differences between the treatment groups for changes in the primary out- come (Table 2), apart from the ESR, which showed a statistically significant decrease (P = 0.004) in the etanercept-treated group compared with the placebo-treated group. CRP levels were decreased in the etanercept-treated group at 12 weeks compared with baseline (P = 0.01). There were no significant differences in the change in IgA or IgM level in the etanercept group compared with the placebo group (data not shown).
Table 2. Changes in measures of disease activity at the 12-week (final) visit compared with baseline, by treatment group*
| ||Etanercept (n = 14)||Placebo (n = 14)||P|
|Dry mouth, by 100-mm VAS||−2 (−13, 2)||3 (−11, 10)||0.44|
|Dry eyes, by 100-mm VAS||1 (−6, 12)||−0.5 (−13, 5)||0.53|
|Schirmer I test, mm/5 minutes||−0.75 (−1.5, 1.00)||−0.50 (−2, 0)||0.55|
|Van Bijsterveld score||0 (−1.5, 0.5)||−0.25 (−1, 0)||0.96|
|Total stimulated saliva flow, ml/minute||−0.033 (−0.31, 0.16)||−0.22 (−0.56, 0.13)||0.63|
|IgG, mg/dl||10 (−130, −50)||−30 (−140, 10)||0.82|
|ESR, mm/hour||−5.5 (−11, −4)||1.5 (−3, 6)||0.004|
Additionally, there were no statistically significant changes in subjective levels of oral comfort, ability to swallow dry foods, levels of energy, frequency of muscle pains and aches, frequency of joint pains, or quality of sleep throughout the course of the study. These symptoms were also assessed using 100-mm VAS (data not shown).
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- PATIENTS AND METHODS
There are no previously published randomized, double-blind, placebo-controlled clinical trials investigating the efficacy and safety of etanercept in patients with SS. Although 5 subjects exhibited meaningful improvement in the primary outcome measure, there was no significant difference in the number of responders in the etanercept-treated group compared with the placebo-treated group (P = 0.2). Patients taking etanercept exhibited a decrease in the ESR compared with baseline levels.
Although there was no statistically significant difference between the study groups in the primary outcome measure, potential efficacy could not be ruled out with 95% confidence if 1 or more of the 14 consecutive patients in the etanercept group responded. However, the occurrence of responders in the placebo group violated the assumption of a ≤20% probability of response in the placebo group. Thus, the screening method for an uncontrolled active-treatment group (etanercept) could not be applied. Although the decrease in the ESR was more pronounced in the etanercept group, it did not attain the threshold of 20% improvement and therefore provided no evidence of potential efficacy. CRP levels decreased in the etanercept-treated group compared with the placebo-treated group. However, this decrease was within the normal range for this laboratory measure. This decreased CRP did not affect the exocrine component of the disease.
When a higher threshold for improvement in the primary outcome was applied (30% or 50% improvement), there were still responders in the placebo group. Furthermore, a sample size estimate indicated that a total of 288 subjects would be required for a definitive phase III trial (taking potential dropouts into account). This suggests that the effect of etanercept, if present, is not large. Given the expense and potential for adverse effects with etanercept, which include increased risk of infection, it would be unreasonable to include such a large number of subjects in a trial and expect only a 20% improvement. Therefore, other less-expensive DMARDs with acceptable safety profiles, such as methotrexate, could be considered for screening.
Results of recent open-label studies of a related biologic agent, infliximab, have shown significant improvement in measures of disease activity in SS (15, 16). The results of our trial of a TNFα blocker differ from those reported by Steinfeld et al for infliximab, a monoclonal antibody directed against this cytokine. The difference could reflect differences in the drug actions or pharmacodynamics. Another possibility is that there could have been a high placebo-response rate in the study by Steinfeld (15, 16), since that study was not placebo controlled. In a recent controlled double-blind study of infliximab, Mariette et al (25) reported no significant change in disease measures in subjects treated with infliximab compared with those treated with placebo. In an open-label trial of etanercept, Zandbelt et al (26) also found no apparent reduction in sicca symptoms and signs in patients with SS.
It is also possible that there were insufficient levels of the drug in the target tissues, either because the medication was unable to get to the target tissue or because higher doses of the drug are needed in order to demonstrate a therapeutic effect. Moreover, a longer duration of therapy may be required in order for the therapeutic effects to appear. However, the apparent lack of efficacy we observed may indicate that TNFα does not play as important a role in the pathogenesis of SS as has previously been thought and that future therapies for SS should focus on other molecular targets.
One of the patients with SS secondary to RA who was in the etanercept group showed considerable improvement in her arthritis. However, no significant changes in the exocrine measures in this patient occurred over the course of the trial. Two of the patients in the placebo arm met the American College of Rheumatology 1982 revised criteria for the classification of SLE. One of them had abnormal anti-DNA titers at baseline, and these titers had decreased at the end of the study. The second patient was negative for anti-DNA and anti-Sm at the start of the study and did not become positive for these antibodies during the course of the study.
According to a recently published review on the safety and efficacy of DMARDs (21), an adverse effect that clearly occurs with etanercept is injection-site reactions, occurring in about one-third of patients. In the current study, 2 patients experienced injection-site reactions. The reaction in 1 patient was unusual in its severity and in the progressive nature of the lesions, and the study medication was discontinued. One patient in our study had a history of multiple actinic skin lesions. She was discontinued from the study after she developed a rapidly growing lesion of the right forearm, which was considered clinically to be squamous cell carcinoma but on biopsy was found to be an actinic keratosis. The lesion was not in the region of any of the injection sites.
In conclusion, a 12-week trial of the anti-TNFα agent etanercept in patients with SS did not demonstrate any clinically meaningful improvement in the disease. The medication was well-tolerated, and there were few side effects. Since there were responders in the etanercept group, a beneficial effect from etanercept cannot be ruled out according to the study design. However, sample size estimates for a definitive trial suggest that a positive effect, if one exists, is small. The ESR showed a statistically significant decline in the etanercept group, but it was only 18.6%. The results of our study and the most recent investigations into TNF blockade in SS suggest that further pursuit of this avenue of treatment is unlikely to be fruitful and that other immunologic mechanisms should be pursued.