Ocular surface disorders do not have to be treated routinely by systemic immunosuppression, as various local treatment options are available and sufficiently effective in many patients. These are: (1) lid closure, enable or improve it surgically; (2) local corticosteroids, they suppress local inflammation, but may deteriorate dry eye symptoms and increase risk of local infections; (3) topical cyclosporin A (CsA) acts as an anti inflammatory with rare side effects; (4) local lubricants, apply them frequently, but be aware of local toxicity resulting in intolerance to components of these drops (mostly preservatives); (5) vitamin A containing substances, they improve superficial epithelial cell layers; (6) autologous serum, it contains various cytokines and growth factors as useful adjunct for healing of epithelial defects; (7) therapeutic contact lens, apply it for superficial epithelial defects, but take care of infectious complications; (8) punctum plugs, insert them or obliterate nasolacrimal duct, and (9) amniotic membrane transplantation for reconstruction of superficial layers of the cornea and conjunctiva.

The use of the various local treatment options were recently recommended by an international expert panel. There is increasing evidence that dry eye problems beside other pathophysiological disturbances also show increased inflammatory cells and proinflammatory cytokines in the conjunctiva, lacrimal glands and tear fluid. Topical anti inflammatory substances are therefore a logical therapeutical adjunct. Glucocorticosteroids should be applied only for short time period as they are effective within several days, but severe side effects are probable in long term use.

Topical CsA is an anti inflammatory substance with a slowly acting effect increasing within weeks to 6 months; this substance can be applied topically for a long time, as side effects are very rare.

However, there are some systemic disorders with involvement of the ocular surface and adnexa, where the above-mentioned local treatment options are not sufficiently working. Among these systemic inflammatory disorders are atopic disorders, bullous mucocutaneous disorders with ocular involvement or inflammatory disorders due to collagenous or vasculitic systemic diseases. These systemic disorders may show heavy inflammatory involvement of the ocular surfaces and adnexa, therefore systemic anti inflammatory treatment regimens are reasonable.

The main indications for any systemic immunosuppression are (1) to prevent eyes from becoming blind by inflammation, (2) to maintain the integrity of the eye, and (3) to reduce mortality caused by systemic inflammation. A prerequisite for any immunosuppression is to rule out infection as the possible cause of inflammation. Immunosuppressive treatment regimens are sometimes shown to be effective in randomized controlled studies, but quite often only uncontrolled case series are available to justify the treatment.

In addition, the relative efficacy of different treatment regimens is not determined and interindividual variations of the effectiveness for the same substance is well known for various drugs. Therefore, at present each patient will be best treated with an individualized treatment regimen. In general, the use of alkylating substances often results in long term drug free remissions, but treatment with other substances needs to be continued long term or even indefinitely. A guideline gives advice how to manage this topic.

First line anti inflammatory treatment consists of corticosteroids, which can be applied topically, periocularly or systemically. Their anti inflammatory capacity becomes evident within a few days. However, side effects, possible complications, or sometimes ineffectivity limit their application. Usually, in patients with liver insufficiency about lmg/kg/day prednisolone is applied, and in severe inflammation pulses of 1 g/day for 3-5 days are possible.

The dose should be reduced stepwise (lOmg every 1-2 weeks, at the level of 40mg/day reduce in 5-mg steps, at 20mg/day in 2.5-mg steps, at lOmg in 1-mg steps), reduction intervals can be prolonged from 1 to 4 weeks depending on the clinical course. During glucocorticosteroid treatment, monitoring of hypertension, body weight, blood glucose (every 3 months), serum lipids, density of bones (once a year) should be performed. Important and frequent side effects are (a) increased risk of infection, (b) fluid retention, (c) diabetes mellitus, (d) hyperlipidemia, (e) osteoporosis, (f) atherosclerosis, (g) glaucoma, (h) cataract, (i) anxiety, (j) sleepiness, (k) mood changes, (1) easy bruising, and (m) poor wound healing. As supplements to steroids, calcium l,500mg/day, vitamin D 800IU/day, estrogens, if decreased or postmenopausal, and antiabsorbants should be added.

Adverse effects of glucocorticosteroids are cushingoid changes (weight gain, moon facies, fat redistribution, acne) for doses >5-10mg/day prednisone, suppression of adrenal glands, and delay of pubertal growth in children. Sometimes severe side effects such as pancreatitis, aseptic bone necrosis, IDDM, myopathy, or psychosis require immediate reduction of corticosteroids. In cases of concomitant use of NSAID, the risk of gastric ulceration increases. Long term corticosteroid therapy is associated with an increase in mortality. If corticosteroids fail to induce improvement of the inflammation within 2-4 weeks or if a continuous dose of > 10 mg/day is needed, then additional systemic immunosuppression with alternative drugs should be performed. The immunosuppressive substances frequently applied in such human disorders are outlined in table.

Cyclophosphamide (Cyc) is a cytotoxic alkylating drug. It effects resting and dividing lymphocytes and results in a broad T and B cell impairment. The drug is well absorbed and metabolized in the liver. It is eliminated via the kidneys and therefore some metabolites can cause bladder toxicity. The main indications for Cyc are as antineoplastic drug in oncology, in autoimmune disorders especially SLE and Wegener's granulomatosis, uveitis and ocular cicatricial pemphigoid. Usually a dose of Cyc of 1-3 mg/kg/day is given. Pulse treatment every 3-6 weeks of about 600-1,500mg is a possible alternative. The main side effects are bone marrow depression, rarely myelodysplasia, hemorrhagic cystitis, teratogenicity, ovarian suppression, testicular atrophy, azospermia, alopecia, nausea, vomiting, and opportunistic infections due to lymphopenia. Routine monitoring of blood cell count, platelets, urinalysis, every week initially and later every month is recommended.

Chlorambucil is a cytotoxic alkylating drug inducing crosslinking of DNA to proteins. It is metabolized in the liver to phenylacetic acid mustard. Inactive compounds will be eliminated in the urine. Indications are as antineoplastic drugs in oncology, Behcet's disease, uveitis especially due to Behcet's syndrome and sympathetic ophthalmia. The dosage should be 0.1-0.2 mg/kg/day for about 1 year. Alternatively a short-term (3-6 months) treatment is possible with initiation of 2 mg/day and an increase every week by 2 mg until complete suppression of inflammation or white blood cells are <2,400/|xl or platelets <100,000/|xl are reached. The side effects are bone marrow suppression, mostly reversible, but often prolonged, opportunistic infections (e.g., herpes zoster, Pneumocystis carinií), permanent sterility in men and amenorrhea in women, teratogenicity, increased risk of malignancy in the long term. Monitoring of blood cell counts every week initially, later monthly, in cases of short-term regimen every week is advised. Azathioprine (Aza) interferes with adenine and guanine ribonucleotides resulting in reduced numbers of lymphocytes, mixed lymphocytes reactivity, IL-2 synthesis and IgM production. The substance is orally well absorbed; metabolism of Aza needs activity of xanthine oxidase, which can be inhibited by allopurinol. The main general indications are rheumatoid arthritis, organ transplantation, psoriasis, Reiter's syndrome, or systemic lupus erythematosus; in ophthalmology, chronic uveitis, uveitis in Behcet's syndrome and intermediate uveitis are frequent indications. The dosage ranges between 1 and 3 mg/kg/day, reduction is recommended when allopurinol is applied. The main side effects are reversible bone marrow suppression, increased risk of non-Hodgkin's lym-phoma, hepatotoxicity 2%, and gastrointestinal intolerance 25%. Monitoring of blood cell counts and platelets at 4- to 6-week intervals and liver enzymes every 12 weeks is recommended. The dosage should be reduced if liver enzymes increase > 1.5-fold, stop Aza application if the rise is >5 times of normal.

Mycophenolate mofetil (MMF) selectively inhibits inosine monophosphate dehydrogenase, it reduces lymphocyte proliferation, suppresses antibody synthesis, reduces cellular adhesion to vascular endothelium, and inflammatory cell recruitment. MMF shows renal elimination and has a high oral bioavailabihty. The main indications are transplantation of solid organs, uveitis, and scleritis. However, no controlled studies are available. In most cases, MMF reduces ocular inflammation if applied with other immunomodulating substances. The recommended dosage is 2 X 1 g/day. The main side effects are gastrointestinal pain, nausea, vomiting, and diarrhea in up to one third, rarely infections, and neoplas-tic disorders. One should monitor blood cell counts every week for the first month, later at 2-month intervals, and liver enzymes at 3-month intervals.

Methotrexate (Mtx) is a folie acid agonist inhibiting dihydrofolate reduc-tase. It inhibits rapidly dividing cells. Oral absorption is reduced by metaboliza-tion of the drug by intestinal flora in up to one third, parenteral application is therefore much safer. Addition of lmg/day folate reduces nausea. Patients should abstain from alcohol consumption during treatment. The substance is eliminated by the kidneys. The main indications for Mtx are rheumatoid arthritis, juvenile chronic arthritis, psoriasis arthritis, systemic lupus erythematosus, several neoplastic disorders, uveitis, scleritis, orbital pseudotumor. Major side effects are cytopenia, hepatotoxicitiy, interstitial pneumonia, stomatitis, and nausea. Mtx is contraindicated during pregnancy. During treatment one should monitor blood cell counts and liver enzymes at 1- to 2-month intervals.

CsA inhibits preferentially immunocompetent T lymphocytes. CsA is metabolized in the liver and excreted in the bile. Bioavailabihty of CsA shows a broad range. The main indications are solid-organ transplantation, treatment-resistant rheumatoid arthritis, severe plaque psoriasis, uveitis, and Behcet's syndrome. The currently recommended dosage is 2-5 mg/kg/day. Serious side effects include nephrotoxicity, hypertension, less common hepatotoxicity, gingival hyperplasia, myalgia, tremor, paresthesiae, hypomagnesemia, and hir-sutism. It is recommended to monitor blood pressure often, at least every month, serum creatinine every 2 weeks for 2 months, then monthly. Detection of CsA blood levels is not necessary.

Tacrolimus (FK-506) inhibits activation of T lymphocytes. The absorption of the drug from gastrointestinum varies. Tacrolimus is metabolized by the cytochrome P450 system and shows mainly fecal elimination. Indications for FK-506 are solid-organ transplantations, and uveitis, although only small numbers of patients have been reported. The dosage is usually 0.1-0.15 mg/kg/day for transplantation and 0.05 mg/kg/day for uveitis, respectively. During treatment, monitor drug blood concentration weekly for about 2 months, then monthly; test liver enzymes, bilirubin, blood urea nitrogen, creatinine, electrolytes including calcium, magnesium, phosphate; cholesterol, triglycerides, glucose, blood cell count; blood pressure. The main known side effects are nephrotoxicity, neurologic symptoms, gastrointestinal symptoms, hyperglycemia, hypomagne-semia, tremor, and hypertension.

Immunosuppressive drugs as outlined above have a broad range of effects; they interact with pathologic immune reactions and should block them effectively. However, a lack of specificity or evolving severe side effects sometimes prevents a therapeutic success. In these situations combination therapy with multiple immunosuppressive drugs is sometimes useful. But with regard to a more specific immune regulatory effect, a lot of monoclonal antibodies or sometimes fusion proteins have been developed which specifically block a receptor. This blockade can downregulate an immune reaction if the blocked molecule has a key function in the pathological immune process. An overview of the substances currently used in patients with autoimmune disorders or in studies is given in table.

Biological substances with specificity for TNF-a receptors are frequently used in chronic polyarthritis. It has been noted that TNF-a is one key molecule responsible for destruction of cartilage of joints and blocking of this cytokine receptor will stop inflammation and structural tissue disorganization highly effectively. But aside from joint inflammation, the blockade of TNF-a receptors is also effective in psoriasis, Bechterew's arthritis and inflammatory bowel diseases. Some authors also report beneficial effects of blocking TNF-a receptors in various inflammatory eye disorders.

TNF-a is a cytokine produced by various cells (i.e. monocytes, macro-phages, neutrophils, activated lymphocytes, endothelial cells, fibroblasts, and other cells). The main function of this proinflammatory cytokine is to induce cachexia and fever. In addition, inflammatory cells will immigrate locally. An increase in synovia cell apoptosis and expression of adhesion molecules takes place. There are two known receptors of TNF-a, one is p55 and the second p75. They are located in the cell membrane and can be cleaved by matrix metalloproteinases. With regard to the eye, we know that TNF-a is expressed in the cornea, especially during inflammation. TNF-a may induce corneal angiogenesis in vivo. There is an interaction between TNF-a and sVCAM-1. TNF-a may increase NOS2, fibroblast apoptosis, and various MMPs - 1, 3, 10, 11, 13. TNF-a is elevated in psoriatic skin lesions.

Infliximab is a chimeric monoclonal antibody specific for TNF-a with a humanized Fc part and Fab fragment from mouse. In man the usual dosage is 3-5mg/kg b.w intravenously. The interval of treatment should be 0, 2 and 6 weeks and then every 8 weeks afterwards. Etanercept is a fusion protein specific for the p75 receptor of TNF-a. The usual dosage is 25 mg subcutaneously applied twice a week. Adalimumab is another monoclonal antibody fully humanized and specific for TNF-a. The usual application dosage is 40mg given subcutaneously every 2 weeks. These inhibitors of TNF-a show a very rapid anti-inflammatory response and rare side effects. The clinical efficacy of infliximab is superior to adalimumab and etanercept (personal experience). One has to look for possible infections which may cause lethal complications, especially in cases of tuberculosis. Active tuberculosis has to be ruled out before application of these drugs. Skin reactions may sometimes develop in the area of local application. Possibly myocardial insufficiency may become worse, induction of functional autoanti-bodies and autoimmunity is very rare. The long-term side effects are unclear at present, but an increase in neoplastic disorders is suspected.

Inhibition of the cell surface molecule CD20 is frequently performed in treatment of lymphomas and leukemias. As B cells with CD20 molecules on their cell surface are also involved in a variety of autoimmune disorders, the effect of the monoclonal antibody rituximab, which is able to block the CD20 cell surface antigen, is currently being investigated. At present, favorable clinical results have been reported in the treatment of rheumatoid arthritis or treatment-resistant scleritis due to primary Sjógren's syndrome. However, another study showed no promising effects in Wegener's granulo-matosis with complicated longstanding orbital granulomas. At present it is not clear what medical indication is best for rituximab application.

Severe forms of ocular cicatricial pemphigoid are best treated by systemic Cyc. Local treatment with corticosteroids and CsA is not sufficient, data for a possible effect of subconjunctivally injected mitomycin have not been reported yet, but the risks of that treatment are known, i.e. reduction of limbal stem cells, necrosis of the sclera and ciliary body. Early cases of ocular pemphigoid with moderate activity can be successfully managed with dapsone or related sul-fapyridine substances. But new treatment options have the potential to reduce side effects and seem to be as effective as Cyc. Promising results show daclizumab (antibody against CD25), intravenous immunoglobulins and methotrexate. In addition, surgical treatment may include keratolim-bal allografts and amniotic membrane transplantation in combination with penetrating keratoplasty in cases with sufficient immunosuppression.

Presumably, similar drugs will be developed for other disorders in the near future. Although we have a few guidelines and recommendations for the use of immunosuppressive substances in general, a lack of controlled studies complicates recommendations, for example for the application of immunosuppressive substances in Sjógren's syndrome. Therefore, it is still a big challenge which substance or combinations should be applied at what dosages and for how long in an individual patient. This matter is still a difficult task for every physician, even for those experienced in that field. Therefore, further work is still needed on evaluation of objective data for optimal adjustment of treatment. Possibly new options will be available in the future, hopefully with a more specific interaction to correct specifically the immunopathology without changing the physiologic conditions elsewhere in the body.