Pharmacotherapy of Xerostomia in Primary Sjogren's Syndrome

Geoffrey C. Wall, Pharm.D., Michelle L. Magarity, Pharm.D., Jeffrey W. Jundt, M.D.

Disclosures

Pharmacotherapy. 2002;22(5) 

In This Article

Clinical Studies of Three Main Treatment Approaches

The three main pharmacotherapeutic approaches to xerostomia in SJS are lubricating oral mucosa with saliva substitutes, attempting to stimulate salivary gland activity with muscarinic agents, and largely experimental treatment with immuno-suppressive drugs.

Given the number of functions saliva performs and its complex regulation system, it is not surprising that attempts to produce saliva artificially have been less than successful. Evaluating the literature is difficult because of variations in delivery systems and study designs. Discrepancies also are found concerning patient education and expectations in clinical settings compared with a controlled environment.[13] In general, formulations of artificial saliva were either carboxymethylcellulose or mucin based (Table 1).[14,15] Unfortunately, mucin-based products are not readily available in the United States. In controlled trials they seem to achieve higher patient satisfaction rates than carboxy-methylcellulose-based preparations.[16,17]

Three polymer-based saliva products were evaluated for patient satisfaction.[18] The authors theorized that substitutes based on polyacrylic or xanthan gum, which have rheologic and elastic properties similar to human saliva, would be more satisfying to patients with xerostomia due to SJS. In comparing different viscosities of xanthan gum substitutes, none of the saliva substitutes was superior to placebo, with no differences between high- and low-viscosity products. Thus it might be necessary for patients to try several different agents to find one that is satisfactory. Although saliva substitutes may be beneficial, their short duration of action requires frequent application, and many patients are not satisfied with the results.

Most patients with SJS have residual salivary gland function. In fact, most patients with SJS xerostomia retain about 50% of their acinar cells.[19] Thus, a rational treatment strategy could include pharmacologic agents to stimulate salivary gland function. Parasympathetic nerve stimulation activates muscarinic (M3) receptors, leading to vasodilation in the glands and increased saliva excretion.[20] Investigators have used various parasympathomimetic drugs to increase saliva production. The first to be granted Food and Drug Administration (FDA) approval for this indication is oral pilocarpine (Salagen; MGI Pharma, Minnetonka, MN), which was assessed in several clinical trials (Table 2).[21,22,23,24,25]

A randomized, placebo-controlled, multicenter trial (P92-01) investigated pilocarpine for xerostomia and dry eye symptoms in 373 patients with primary or secondary SJS.[23] Exclusion criteria were cardiac, pulmonary, kidney, or gastrointestinal disease; diabetes; multiple sclerosis; and narrow-angle glaucoma. Primary outcomes were improvement based on patient questionnaires and measurements of salivary flow. Patients were randomized to receive placebo or pilocarpine 2.5 or 5 mg orally 4 times/day, and were examined 6 and 12 weeks into the study. The higher dosage of pilocarpine was associated with significantly higher global improvement scores compared with placebo (61.3% vs 31.1%, p<0.001). In addition, it provided greater mouth comfort and decreased use of saliva substitutes. Throughout the study salivary flow rates were significantly higher in the pilocarpine group (at trial end 0.17 vs 0.37 ml/min, p<0.001). Sweating and increased urinary frequency were the most frequently reported adverse effects of active treatment. Nausea and diarrhea also occurred frequently with pilocarpine. Overall, 3% (4/127) of patients receiving pilocarpine 5 mg withdrew from the trial due to adverse effects. The authors concluded that pilocarpine tablets were effective in improving both xerostomia and dry eye symptoms of SJS, and were fairly well tolerated.

Several other trials showed similar benefit with pilocarpine; however, they also reported higher adverse effect rates and higher rates of discontinuation because of side effects. A 1-year trial (published in abstract form) explored the efficacy of pilocarpine in 212 patients with SJS.[26] Eight percent of patients receiving pilocarpine withdrew from the trial due to adverse effects, principally sweating. An additional 8% withdrew because of lack of efficacy.

Results of the P92-01 trial were combined with those of P92-02, a randomized, double-blind, multicenter trial comparing pilocarpine and placebo in patients with xerostomia and sicca symptoms (total number of patients 629).[24] Trial P92-02 used a titrated dosing schedule, starting with 5 mg 4 times/day and increasing to 7.5 mg 4 times/day after 6 weeks. Both trials were analyzed using intent-to-treat principles. The primary outcome was improvement in dryness symptoms based on a questionnaire with a visual analog scale (VAS). Specific symptoms evaluated were improvements in speaking, eating, oral comfort, and denture discomfort, and decreased used of saliva substitutes. Pilocarpine 20-30 mg/day was associated with significant improvement (defined as an increase of > 55 mm on 100-mm VAS) in global oral dryness symptoms compared with placebo (P92-02 58% vs 28%, p<0.0001). Other oral comfort variables were improved, including decreased use of saliva substitutes at the end of these 12-week trials. The frequency of sweating was high in both trials (43-64%), but only 3.1% of patients withdrew during the 12 weeks because of this side effect. Other adverse effects associated with pilocarpine were urinary frequency, flushing, and dizziness.

Pilocarpine significantly improves many symptoms of dry mouth and also seems to improve symptoms of dry eyes. Disadvantages of the drug are frequent dosing and cholinergic adverse effects, including sweating, which may make long-term therapy difficult.

Cevimeline (Evoxac; Daiichi Pharmaceuticals, Montvale, NJ) was approved by the FDA for treatment of xerostomia in patients with SJS.[27] It is a derivative of acetylcholine that, like pilocarpine, is a muscarinic agonist. The drug has an affinity for all types of muscarinic receptors but has strongest affinity for M1 and M3 receptors. Few clinical trials with cevimeline have been published, and information about the drug must be derived from abstracts and manufacturer's information.

A randomized, placebo-controlled trial assessed cevimeline in 196 patients with SJS.[28] The primary outcome measure was patients' subjective assessment of global improvement in mouth and eye dryness. Other variables examined were individual symptoms associated with xerostomia and sicca, as well as saliva and tear production. Of patients receiving cevimeline 30 mg orally 3 times/day, 66.1% had significantly improved global dry mouth scores, compared with 37.1% of those given placebo (p<0.0005). Dry eye symptoms and general dryness also were improved in the active treatment group. Adverse effects were not described in this abstract, although cevimeline was well tolerated.

The drug's product information describes four clinical trials investigating its efficacy in SJS.[27] Three of these were randomized, double-blind, placebo-controlled trials in which the primary end point was global improvement scores for dry mouth and eyes and general dryness. Active treatment was superior to placebo in relieving dryness symptoms, including xerostomia, but higher dosages of cevimeline were not more effective than lower dosages (dry mouth improvement with cevimeline 30 mg 3 times/day 76% vs placebo 34.8%, p=0.0043). Salivary flow rates increased with cevimeline at week 2 of the study and remained elevated through the final visit at 6 weeks. A phase III trial conducted over 12 weeks also showed significant improvement in dry mouth and eye symptoms with oral cevimeline 30 mg 3 times/day, but not at lower dosages compared with placebo (cevimeline 30 mg 3 times/day at 12 weeks 68.8% vs placebo 37.1%, p=0.0004).

The product literature describes a 52-week open-label safety study conducted with 434 patients with SJS. Patients previously enrolled in cevimeline phase III trials as well as new patients were included. Increased sweating was the most common adverse effect; at 60 mg 3 times/day, it occurred in 44% of patients. Nausea, rhinitis, and diarrhea also occurred, but their frequency varied with dosage. Of interest, even at higher dosages of cevimeline only 10% of patients discontinued the study because of an adverse effect. Although not a primary outcome, increased salivary flow rates remained constant throughout the 52-week trial. It appears that cevimeline significantly improves symptoms of dry mouth and increases salivary flow rates. No direct comparison of cevimeline and pilocarpine has been published.

The immunologic pathophysiology of SJS encouraged investigators to explore immuno-suppressives. These drugs usually are reserved for severe SJS that involves extraglandular manifestations or severe weakness.[17] Thus investigations looking solely into the treatment of dry mouth or eye symptoms with the agents are sparse.[29] Most published studies are unblinded and noncontrolled, making general interpretation difficult. Still, some authors attempted to expand pharmacologic options for xerostomia.

In a double-blind, placebo-controlled trial, 14 patients with primary SJS received either hydroxychloroquine 400 mg/day or placebo for 1 year, and then were crossed over to the other arm for another year.[29] Primary outcomes examined by questionnaire every 90 days determined extent of sicca symptoms or xerostomia, biochemical markers of inflammation, and serologic markers of rheumatic disease such as ANA. No significant difference was found with respect to symptom relief between groups. Laboratory and serologic markers remained unchanged for the most part, with few excep-tions. Tear and salivary gland production were not significantly increased in the treatment arm.

Twenty-five patients with primary SJS were randomized to receive azathioprine 1 mg/kg/day or placebo for 6 months.[30] Results were based on patient questionnaires concerning symptoms of SJS as well as measured unstimulated salivary flow. Seven patients had pretreatment and posttreatment lip biopsies performed. Five patients discontinued treatment before the trial was completed, mostly due to adverse effects. No significant difference was found in clinical, histologic, or serologic variables between arms. A criticism of this trial may be the low dosage of active drug. Azathioprine often is dosed in the range of 2.5 mg/kg/day for systemic inflam-matory diseases such as rheumatoid arthritis and Crohn's disease; but the investigators believed higher dosages were unjustified in non-organ-threatening SJS.

An open-label 1-year study evaluated methotrexate 0.2 mg/kg/week in 17 patients with SJS.[31] Patients were examined at 2-month intervals for objective (Schirmer I test and 5-min unstimulated whole saliva collection) and subjective changes in tear or saliva production. Serologic markers of inflammation also were recorded. The number of patients complaining of dry mouth decreased from 16/17 (94%) to 6 (44%) at 1 year (p<0.001). Dry eye symptoms, parotid gland enlargement, and dry cough rates also decreased at 1 year. Most immunologic parameters remained unchanged during the study. Elevated transaminase levels (< 3 times the upper limit of normal) required dosage reduction in 41% of patients.

Twenty patients with primary SJS received low-dosage prednisolone (range 10-30 mg) based on serum IgG levels, and tapered by 2.5 or 5 mg/day to a maintenance dosage of 5-7.5 mg in an open-label trial.[32] Patients with cataracts, obesity, hypertension, osteoporosis, or diabetes were excluded. The primary outcome was production of whole saliva as determined with chewing gauze by the Saxon method at 12 and 30 months. Various serologic parameters were measured as well. Saliva production was significantly increased at 3 months and at all data points up to 48 months (baseline saliva production 1.14 g/2 min vs 1.80 g/2 min at 48 mo, p<0.05). Adverse effects of pred-nisolone were not described, but therapy did improve immunologic markers and saliva production.

A randomized, double-blind, placebo-controlled trial investigated extemporaneously compounded interferon-a lozenges in 90 patients with primary SJS.[33] As with previous trials, main outcomes were VAS questionnaire scores completed by patients, as well as whole saliva flow rates, both examined at baseline and at 4-week intervals thereafter. Responders were defined as having improvement of at least 25 mm on a 100-mm VAS and an increase in unstimulated saliva flow of at least 0.05 g/minute. The combined end point was not significantly improved over placebo. Several secondary end points such as oral comfort and difficulty speaking showed trends toward improvement with active treatment, but none reached statistical significance. The group receiving interferon 150-IU lozenges did show an improvement in salivary flow rates over placebo (0.79 vs 0.06 g/5 min, p=0.04). No significant adverse events were reported.

Other small trials of immunosuppressive therapy in SJS were published.[13,17] In an open trial, cyclosporine improved dry mouth symptoms, but not saliva production.[34] Clinical improvement was reported in a small case series with zidovudine in primary SJS.[35] Studies such as these illustrate the uncertain role of immunosuppressives in SJS. Other modalities such as muscarinic agents and artificial saliva products seem to be first-line treatment options.

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