Anti-Inflammatory and Immunosuppressive Concepts
Ocular surface disorders do not have to be treated routinely by systemic immunosuppression, as various local treatment options are available and suffi-ciently 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 intol-erance to components of these drops (mostly preservatives); (5) vitamin-A-con- taining 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.
Details of the above-mentioned local treatment options are outlined in chapters 4-9. The use of the various local treatment options were recently rec¬ommended 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 conjunc¬tiva, lacrimal glands and tear fluid . Topical anti-inflammatory substances are therefore a logical therapeutical adjunct. Glucocorticosteroids should be applied only for short time period (2-4 weeks) as they are effective within sev¬eral 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 inflamma-tory 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 inflamma¬tion. 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 indef¬initely. 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 capac¬ity becomes evident within a few days. However, side effects, possible complica¬tions, or sometimes ineffectivity limit their application. Usually, in patients with liver insufficiency about 1mg/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 (10 mg every 1-2 weeks, at the level of 40mg/day reduce in 5-mg steps, at 20mg/day in 2.5-mg steps, at 10 mg 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) osteo¬porosis, (f) atherosclerosis, (g) glaucoma, (h) cataract, (i) anxiety, (j) sleepiness, (k) mood changes, (l) easy bruising, and (m) poor wound healing. As supple¬ments to steroids, calcium 1,500 mg/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 >5-10 mg/day prednisone, uppression 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 alter¬native drugs should be performed . The immunosuppressive substances fre¬quently applied in such human disorders are outlined.
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 kid¬neys and therefore some metabolites can cause bladder toxicity. The main indi¬cations 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 600-1,500 mg is a possible alternative. The main side effects are bone marrow depression, rarely myelodysplasia, hemorrhagic cysti¬tis, 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/^1 or platelets < 100,000/^l are reached. The side effects are bone marrow suppression, mostly reversible, but often prolonged, opportunistic infections (e.g., herpes zoster, Pneumocystis carinii), 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; metabo¬lism of Aza needs activity of xanthine oxidase, which can be inhibited by allopurinol. The main general indications are rheumatoid arthritis, organ trans¬plantation, 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 synthe¬sis, reduces cellular adhesion to vascular endothelium, and inflammatory cell recruitment. MMF shows renal elimination and has a high oral bioavailability. The main indications are transplantation of solid organs, uveitis, and scleritis. However, no controlled studies are available. In most cases, MMF reduces ocu¬lar inflammation if applied with other immunomodulating substances. The rec-ommended 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 folic 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 1 mg/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 arthri¬tis, 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. Bioavailability of CsA shows a broad range. The main indications are solid-organ transplantation, treatment- resistant rheumatoid arthritis, severe plaque psoriasis, uveitis, and Behcet's syn-drome. The currently recommended dosage is 2-5 mg/kg/day. Serious side effects include nephrotoxicity, hypertension, less common hepatotoxicity, gin- gival 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 num¬bers 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 treat¬ment, 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
Ocular surface disorders do not have to be treated routinely by systemic immunosuppression, as various local treatment options are available and suffi-ciently 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 intol-erance to components of these drops (mostly preservatives); (5) vitamin-A-con- taining 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.
Details of the above-mentioned local treatment options are outlined in chapters 4-9. The use of the various local treatment options were recently rec¬ommended 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 conjunc¬tiva, lacrimal glands and tear fluid . Topical anti-inflammatory substances are therefore a logical therapeutical adjunct. Glucocorticosteroids should be applied only for short time period (2-4 weeks) as they are effective within sev¬eral 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 inflamma-tory 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 inflamma¬tion. 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 indef¬initely. 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 capac¬ity becomes evident within a few days. However, side effects, possible complica¬tions, or sometimes ineffectivity limit their application. Usually, in patients with liver insufficiency about 1mg/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 (10 mg every 1-2 weeks, at the level of 40mg/day reduce in 5-mg steps, at 20mg/day in 2.5-mg steps, at 10 mg 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) osteo¬porosis, (f) atherosclerosis, (g) glaucoma, (h) cataract, (i) anxiety, (j) sleepiness, (k) mood changes, (l) easy bruising, and (m) poor wound healing. As supple¬ments to steroids, calcium 1,500 mg/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 >5-10 mg/day prednisone, uppression 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 alter¬native drugs should be performed . The immunosuppressive substances fre¬quently applied in such human disorders are outlined.
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 kid¬neys and therefore some metabolites can cause bladder toxicity. The main indi¬cations 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 600-1,500 mg is a possible alternative. The main side effects are bone marrow depression, rarely myelodysplasia, hemorrhagic cysti¬tis, 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/^1 or platelets < 100,000/^l are reached. The side effects are bone marrow suppression, mostly reversible, but often prolonged, opportunistic infections (e.g., herpes zoster, Pneumocystis carinii), 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; metabo¬lism of Aza needs activity of xanthine oxidase, which can be inhibited by allopurinol. The main general indications are rheumatoid arthritis, organ trans¬plantation, 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 synthe¬sis, reduces cellular adhesion to vascular endothelium, and inflammatory cell recruitment. MMF shows renal elimination and has a high oral bioavailability. The main indications are transplantation of solid organs, uveitis, and scleritis. However, no controlled studies are available. In most cases, MMF reduces ocu¬lar inflammation if applied with other immunomodulating substances. The rec-ommended 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 folic 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 1 mg/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 arthri¬tis, 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. Bioavailability of CsA shows a broad range. The main indications are solid-organ transplantation, treatment- resistant rheumatoid arthritis, severe plaque psoriasis, uveitis, and Behcet's syn-drome. The currently recommended dosage is 2-5 mg/kg/day. Serious side effects include nephrotoxicity, hypertension, less common hepatotoxicity, gin- gival 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 num¬bers 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 treat¬ment, 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
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