24.1Introduction

SjogrenÕs syndrome (SS) is an organ-speciÞc autoimmune disorder characterized by lymphocytic inÞltration and destruction of the exocrine glands such as lacrimal and salivary glands. The

K. Tsubota ( )

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan

e-mail: tsubota@z3.keio.jp

pathology is accompanied by systemic production of autoantibodies to ribonucleoprotein particles SS-A/Ro and SS-B/La [1]. The disease is not fatal, however, the dysfunctions of the exocrine glands cause hyposecretion of tears and saliva, resulting in decreased quality of life due to the dry eyes and dry mouth. These are common complaints among the elderly, and living with dry eye and/or dry mouth syndrome can be a devastating experience for the sufferer, where living with the symptoms is more severe than would non-sufferers realize.

The fundamental problem is the lack of tear, resulting in the desiccation itself. The naming of dry eye suggests that dryness itself is the major problem of sicca syndrome. In some aspects, it is right especially in the evaporative type of dry eye [2, 3]. However, the dry eye in SjogrenÕs syndrome is often severer than the evaporative dry eye or simple tear-deÞcient dry eye [4]. We have previously hypothesized that the severity of dry eye in SjogrenÕs syndrome is due to the lack of the tear component supply to the ocular surface, because SjogrenÕs syndrome-type dry eye do not only have basic tearing but also reßex tearing, resulting in the deÞciency of the tear components [4]. Thus the treatment options include not only the prevention of desiccation but also the supply of essential tear components.

fully elucidated, and future study is expected to be ongoing.

The third option, the use of autologous serum eye drops, has been gaining in popularity by Japanese dry eye specialists. The Þrst several cases using autologous serum were originally described by Fox et al. [7]. The theory and further development have been mainly followed by our dry eye team and now is a widely accepted therapy [8Ð10]. The Dry Eye Society of Japan compiles a list of ophthalmologists who are preparing and administering autologous serum for the treatment of severe dry eye (http://www. dryeye.ne.jp/). Patients looking for relief are able to Þnd ophthalmologists who can provide such treatment. In this review, I would like to focus on the treatment for SjogrenÕs syndrome with autologous serum eye drops.

24.2How to Provide the Essential Tear Components to the Ocular Surface

Available artiÞcial tears are known to improve symptoms of dry eye such as irritation, they do not include the essential tear components, thus we have had to seek an alternative way. There are several options for this purpose.

(1)Punctal plug

(2)Secretagogues

(3)Autologous serum eye drops

Punctal plug is often used for the treatment of severe dry eye [5]. The occlusion of the punctum increases the volume of tears on the ocular surface, providing the tear components to the ocular surface, because SS patients still have minimal lacrimal secretion even in the late stage. This treatment is popular in the United States, estimating that 400,000 plugs are used every year. The second option is the use of secretagogues such as cevimeline or pilocarpine to stimulate muscarinic receptors. Those drugs are effective for the salivation, but the efÞcacy to the recovery of lacrimal function is somehow limited [6] and not widely used by ophthalmologists. I believe there are patients with certain types of dry eye who respond well to these secretagogues but the efÞcacy and dosage of these drugs have not been

24.3Use of Autologous Serum Eye Drops for the Treatment of Dry Eye

SjogrenÕs syndrome patients exhibit more severe ocular surface changes than those seen in nonSjogren dry eye patients due to insufÞcient basic and reßex tearing. This is caused by inÞltrating lymphocytes that destroy the lacrimal gland [11Ð13]. Basal tears and serum share many similar components (Table 24.1) such as epidermal growth factor (EGF) and vitamin A and are important for maintaining the health of the ocular surface epithelium [14Ð17]. In addition, transforming growth factor (TGF)-β concentration in human serum, which is Þve times higher than in tear, is believed to control epithelial proliferation and maintain cells in an undifferentiated state such as the induction of basic keratins in epidermal cells [18]. Fibronectin, insulin-like growth factors, and substance P, all present in serum, have been reported to be essential for wound healing, especially for patients with dry eye [19Ð 21]. Since artiÞcial tears do not contain these components, it became important to Þnd a tear substitute, and the use of autologous serum is appealing for this reason [22].

Table 24.1 Comparison of tears and autologous serum

24.4Ongoing Research with Autologous Serum Eye Drops

Our study of SjogrenÕs syndrome patients showed the advantage of using autologous serum eye drops for the treatment of dry eye by measuring EGF, vitamin A, and TGF-β concentrations in serum and tears. We demonstrated that autologous serum application provided these components to the ocular surface [23]. Autologous serum is preservative-free so patients were instructed to diligently take precautions to avoid contamination. The concentration of essential serum components remained stable after 1 month of refrigeration and 3 months of being frozen. Serum contains proteins such as albumin or globulin, which can protect the deterioration of key cytokines. Clinical application of autologous serum is possible through the extended preservation offered by these components. Ohashi et al. reported that the concentration of EGF was 0.7Ð 8.1 ng/mL in reßex tears and 1.9Ð9.7 ng/mL

in non-reßex tears [15], which is higher than EGF found in serum, which is approximately 0.5 ng/mL [23]. In contrast, the amount of retinol in human tear ßuid was reported by Speek et al. to be 0.4Ð10.6 ng/mL [24]. Retinol in serum is 55 ng/mL, which contains over 1000 times the amount in tears. Squamous metaplasia tends to occur when the epithelium lacks enough vitamin A [23Ð25]. The application of autologous serum may provide appropriate levels of retinol for ocular health.

TGF-β in serum is Þve times higher than in tears so in high concentrations it remains controversial due to its anti-proliferative effects and possible suppression of wound healing of the ocular surface epithelium [23]. In order to maintain TGF-β levels similar to tears, the serum was diluted, which also enabled the preparation of serum eye drops from a small blood sample.

24.5Preparation of Autologous Serum Eye Drops

First, informed consent should be obtained after explanation to the patient of the autologous serum preparation and use, including effects of the treatment. The patient should test negative for HIV and hepatitis B and C infections. Next, 40 mL of venous blood is obtained and centrifuged (Fig. 24.1). This provides 20 mL of serum, which is then diluted with saline in a sterile manner to 20%. The 40-mL sample provides 100 mL of serum and is adequate for a 3-month supply. Figure 24.2 shows the graphic preparation of autologous serum eye drops.

One 100-mL supply yields about 2,000 eye drops of 5 μL each. SjogrenÕs syndrome dry eye patients use a maximum of 20 drops a day (up to 10 drops per eye), thus 2,000 drops are enough for more than 100 days. The autologous serum eye drops are divided into 20 5-mL bottles, and patients are advised to store bottles in the freezer until use [23]. The patients are encouraged to keep the bottle currently being used in the refrigerator.

24.6Autologous Serum Eye Drops for Sjogren’s and Non-Sjogren’s Syndrome

Studies have shown the beneÞcial effects of autologous serum eye drops for both SjogrenÕs syndrome and non-SjogrenÕs syndrome dry eye patients, with striking improvements seen in Rose Bengal (Fig. 24.3a, b) and ßuorescein staining scores, which may be multifactorial. Additionally, increased mucin (MUC)-1 expression of the cultured conjunctival epithelium suggested a direct effect of the serum on the ocular surface epithelium [23].

The study by Nobel et al. evaluated the efÞcacy of autologous serum for the treatment of severe ocular surface disorders, including SjogrenÕs syndrome patients in a prospective randomized controlled crossover study comparing 50% autologous serum eye drops and conventional treatment. When the treatment was reversed to conventional therapy from autologous serum eye drops, the cytological improvements and ocular surface vital staining scores were reversed [26].

We performed a randomized prospective controlled clinical trial by evaluating the solitary effects of autologous treatment by assigning patients into two groups using only autologous

serum eye drops or artiÞcial tear drops after a washout period of 2 weeks. After 2 weeks of treatment, tear stability, ocular surface vital staining scores, and pain symptom scores in patients treated with autologous serum eye drops showed signiÞcant improvement compared to those assigned to preservative-free artiÞcial tears (Fig. 24.4) [9].

are also present in serum. The primary disadvantage of autologous serum treatment is the necessity of obtaining blood from the patients and contraindication in cases with HIV or hepatitis B or C infection. Cultured conjunctival cells by autologous serum increased MUC-1 expression, which suggests a direct effect of the serum on the ocular surface epithelia, but it remains unknown if serum upregulates other ocular surface mucins. Hyaluronate eye drops are popular

Serum Treatment

Future studies may shed light on the exact mechanism of the use of serum on the ocular surface epithelium, which still remains unexplained. However, several studies have shown the positive beneÞts of serum as a likely tear substitute for the maintenance of ocular surface health since many of the essential components in tears

in combination with serum would prove interesting, especially in consideration of the longer exposure hyaluronate would provide the essential components of serum to the ocular surface. Additionally, combining other conventional treatments with serum would also be highly valuable. ReÞnement of an artiÞcial tear substitute containing all essential tear components would be ideal. Long-term studies showing the efÞcacy and