Ординатура / Офтальмология / Английские материалы / Retinal Vascular Disease_Joussen, Gardner, Kirchhof_2007

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c

Fig. 25.6.3. c Fundus photo, left eye, 3 years after vein occlusion, at the time of presentation with visual symptoms in the right eye. Panretinal photocoagulation was applied because of neovascularization of the optic nerve head and macular edema. Multiple sclerotic vessels are visible. Vision is stable at 20/20

25.6.3.2 Histopathology

Granulomatous inflammation forms first, often with a typical palisade of histiocytes, followed by a necrotizing vasculitis involving small arteries, veins, and capillaries. The necrosis is basophilic, and collagenolytic, so-called “blue granuloma” [28]. Microabscesses and isolated multinucleated giant cells are also present [41]. The frequent association with antineutrophil cytoplasmic antibody (anti-serine pro- teinase-3) and the correlation of c-ANCA levels with disease activity indicate that these antibodies play a pathogenetic role. Passive transfer of ANCA antibodies can induce disease [8]. Neutrophils may be the principal effector of tissue damage, after being attracted to the site by endothelial bound c-ANCA. The pauci-immune glomerulonephritis of Wegener is characterized by focal necrosis and not by deposition of immunoglobulins or complement activation. In the lungs, necrotizing granulomatous inflammation is present in the lung fields and capillaritis in the alveoli.

25.6.3.3 Systemic Course of Disease

Organ involvement typically involves the “aerorespiratory” tract: upper airways and lungs. Sinusitis, nasal obstruction, subglottic stenosis occur. Hemoptysis, cough, dyspnea, or respiratory failure may occur or patients may be asymptomatic. On chest X- ray involvement may manifest as nodules, infiltrates, or cavities. Renal involvement is usually asymptomatic but can be detected on laboratory evaluation. Arthralgia, mononeuritis multiplex, purpuric rash also occur.

Diagnostic evaluation is directed toward the usual sites of disease and specific diagnostic criteria have been defined by the American College of Rheumatology (ACR). Anti-neutrophil cytoplasmic antibodies, especially c-ANCA (anti-serine proteinase 3), are highly useful; specificity increases in classic disease and may be accepted as proof of disease without biopsy with a compatible clinical presentation. C- ANCA may be negative and occasionally patients negative for c-ANCA are instead positive for p- ANCA, anti-myeloperoxidase.

25.6.3.3.1 Diagnosis

ACR Criteria [20]

Two of Four

–Inflammation in the nose or mouth

–Abnormal urinary sediment

–Abnormal chest X-ray

–Granulomatous inflammation of artery on biopsy

25.6.3.4 Ocular Manifestations [5]

Orbit (13 %)

Eyelid or nasolacrimal duct (13 %) Episcleritis or scleritis (11 %) Keratitis (8 %)

Optic neuropathy or compression (6 %) Conjunctivitis (4 %)

Retinal vasculopathy (5 %) Uveitis (3 %)

Orbital and external ocular involvement far exceeded intraocular involvement in a series of 140 biopsyproven patients reported in 1983, as shown above. Forty patients had at least one ocular manifestation (29 %). In the 1983 series, among the 7 patients considered to have retinal disease, 4 had findings consistent with vasculitis with retinal hemorrhages and cotton-wool spots; choroidal thickening resolved with retinal pigment epithelial changes after treatment. One patient had occlusion of a small branch retinal vein.

An earlier series reported ocular involvement in 47 % of 29 patients with Wegener disease, one of whom had bilateral retinal artery occlusion and recovered vision in one eye after corticosteroid treatment [17]. A 2005 case report of bilateral central retinal artery occlusion cites 16 prior cases of central retinal artery occlusion (CRAO) in Wegener granulomatosis and 6 bilateral cases [7]. There is a case report of a hemiretinal vein occlusion in Wegener granulomatosis in 2003 [39].

25.6.4 Differential Diagnosis

Conclusions of a consensus congress on the nomenclature of systemic vasculitides are helpful in distinguishing these similar diseases from one another [22].

For Wegener granulomatosis, differential diagnosis includes Goodpasture syndrome, which has renal disease with immune complex deposition as well as pulmonary manifestations, and lethal midline granuloma, which occurs without renal disease.

Sarcoidosis produces granulomas, but is a T-cell- mediated disease of less severity than Wegener granulomatosis [11]. Giant cell arteritis is not associated with anti-neutrophil antibodies [3].

25.6.5 Treatment

Severe disease in all three systemic ANCA-associated necrotizing vasculitides is similar usually initiated with high-dose prednisone and cyclophosphamide [25]. Pulse cyclophosphamide may be inferior to oral cyclophosphamide, especially for preventing relapse [10]. Transition from cyclophosphamide to methotrexate or azathioprine after 3 – 6 months is usually successful and reduces the potential for toxicity [13]. Relapse with cessation of therapy may be reduced by maintenance therapy of at least 1 year after quiescence. Supportive therapy for end-organ damage is often needed and the involvement of multiple medical specialists, including ophthalmologists, is common.

Treatment of ocular manifestations in limited Wegener granulomatosis mimics that for systemic disease; limited disease is more likely to be treated initially with the alternative agents methotrexate or azathioprine. There is increasing interest in the use of tumor-necrosis alpha inhibitors for treatment of Wegener granulomatosis; a randomized controlled trial of etanercept showed no benefit [38]. Concomitant use of trimethoprim-sulfamethoxazole in Wegener granulomatosis may reduce relapse by an unknown mechanism [36]. Because of the mechanical effect of granulomatous masses in Wegener granulomatosis, surgical therapy can be required, for example, orbital decompression (which may spread disease into the sinuses), or tracheostomy for subglottic stenosis.

25.6.6 Prognosis

Systemic prognostic factors were assessed in PAN and CSS [15]. Risk of mortality increased with proteinuria, elevated serum creatinine, or GI tract involvement. Presence of more than three factors from a list of five (proteinuria, creatinemia, cardio-

myopathy, GI tract involvement, and CNS signs) was associated with a statistically significant increase in mortality.

Death can ensue directly from complications of Wegener granulomatosis or its treatment, with infection being the leading cause of death; less than 80 % survivorship at 6 years has been reported [30].

Churg-Strauss syndrome has a better prognosis than III 25 Wegener granulomatosis or PAN/MPA with mortali-

ty no greater than the general population in one study of 91 patients [23].

In a large prospective trial of etanercept in Wegener disease in which 5.2 % of 180 patients had ocular involvement, visual impairment or diplopia was noted in 3.9 % of patients either due to vasculitis or to the treatment of the disease and the same percentage were blind in one eye [34]. In Churg-Strauss syndrome, some vision loss can be reversible with treatment [37].

References

1.Acheson JF, Cockerell OC, Bentley CR, Sanders MD (1993) Churg-Strauss vasculitis presenting with severe visual loss due to bilateral sequential optic neuropathy. Br J Ophthalmol 77:118 – 119

2.Alberts AR, Lasonde R, Ackerman KR, Chartash EK, Susin M, Furie RA (1994) Reversible monocular blindness complicating Churg-Strauss syndrome. J Rheumatol 21:363 – 365

3.Baranger TA, Audrain MA, Castagne A, Barrier JH, Esnault VL (1994) Absence of antineutrophil cytoplasmic antibodies in giant cell arteritis. J Rheumatol 21:871 – 873

4.Bosch-Gil JA, Falga-Tirado C, Simeon-Aznar CP, OrriolsMartinez R (1995) Churg-Strauss syndrome with inflammatory orbital pseudotumour. Br J Rheumatol 34:485 – 486

5.Bullen CL, Liesegang TJ, McDonald TJ, DeRemee RA (1983) Ocular complications of Wegener’s granulomatosis. Ophthalmology 90:279 – 290

6.Chang TS et al (1995) Idiopathic retinal vasculitis, aneurysms, and neuro-retinitis. Retinal Vasculitis Study. Ophthalmology 102:1089 – 1097

7.Costello F, Gilberg S, Karsh J, Burns B, Leonard B (2005) Bilateral simultaneous central retinal artery occlusions in Wegener granulomatosis. J Neuroophthalmol 25:29 – 32

8.Csernok E (2003) Anti-neutrophil cytoplasmic antibodies and pathogenesis of small vessel vasculitides. Autoimmun Rev 2:158 – 164

9.Dagi LR, Currie J (1985) Branch retinal artery occlusion in the Churg-Strauss syndrome. J Clin Neuroophthalmol 5:229 – 237

10.De Groot K, Adu D, Savage CO (2001) The value of pulse cyclophosphamide in ANCA-associated vasculitis: metaanalysis and critical review. Nephrol Dial Transplant 16: 2018 – 2027

11.DeRemee RA (1994) Sarcoidosis and Wegener’s granulomatosis: a comparative analysis. Sarcoidosis 11:7 – 18

12.Font RL, Mehta RS, Streusand SB, O’Boyle TE, Kretzer FL (1983) Bilateral retinal ischemia in Kawasaki disease. Postmortem findings and electron microscopic observations. Ophthalmology 90:569 – 577

29.Masi AT et al (1990) The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 33:1094 – 1100

30.Matteson EL, Gold KN, Bloch DA, Hunder GG (1996) Longterm survival of patients with Wegener’s granulomatosis from the American College of Rheumatology Wegener’s Granulomatosis Classification Criteria Cohort. Am J Med 101:129 – 134

31.Newman NM, Hoyt WF, Spencer WH (1974) Macula-spar- ing monocular blackouts. Clinical and pathologic investigations of intermittent choroidal vascular insufficiency in a case of periarteritis nodosa. Arch Ophthalmol 91:367 – 370

32.Rosen ES (1968) The retinopathy in polyarteritis nodosa. Br J Ophthalmol 52:903 – 906

33.Schmidt D, Lagreze W, Vaith P (2001) Ophthalmoscopic findings in 3 patients with panarteritis nodosa and review of the literature. Klin Monatsbl Augenheilkd 218:44 – 50

34.Seo P et al (2005) Damage caused by Wegener’s granulomatosis and its treatment: prospective data from the Wegener’s Granulomatosis Etanercept Trial (WGET). Arthritis Rheum 52:2168 – 2178

35.Stefani FH, Brandt F, Pielsticker K (1978) Periarteritis nodosa and thrombotic thrombocytopenic purpura with serous retinal detachment in siblings. Br J Ophthalmol 62:402 – 407

36.Stegeman CA, Tervaert JW, de Jong PE, Kallenberg CG (1996) Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener’s granulomatosis. Dutch Co-Trimoxazole Wegener Study Group. N Engl J Med 335:16 – 20

37.Takanashi T, Uchida S, Arita M, Okada M, Kashii S (2001) Orbital inflammatory pseudotumor and ischemic vasculitis in Churg-Strauss syndrome: report of two cases and review of the literature. Ophthalmology 108:1129 – 1133

38.The Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group (2005) Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med 352:351 – 361

39.Venkatesh P, Chawla R, Tewari HK (2003) Hemiretinal vein occlusion in Wegener’s granulomatosis. Eur J Ophthalmol 13:722 – 725

40.Vitali C, Genovesi-Ebert F, Romani A, Jeracitano G, Nardi M (1996) Ophthalmological and neuro-ophthalmological involvement in Churg-Strauss syndrome: a case report. Graefes Arch Clin Exp Ophthalmol 234:404 – 408

41.Yi ES, Colby TV (2001) Wegener’s granulomatosis. Semin Diagn Pathol 18:34 – 46

Core Messages

Retinal vasculitis is often associated with underlying systemic diseases

The diagnosis and the treatment of the underlying systemic diseases dictate the immunosuppressive regimen used for therapy

Corticosteroids are often the first line therapy, offering rapid and effective control of most retinal and systemic vasculitis

For patients with a chronic condition requiring long-term therapy or who are intolerant of corticosteroids therapy, steroid-sparing immunosuppressive agents are used, with the tapering of the corticosteroids

Immunosuppressive treatments often require cooperation between the patient, the ophthalmologist, and the internist or rheumatologist

A stepladder approach is used for the escalating vigor of treatment required for the severity of the disease process. Combination therapies are often required for additive and synergistic effects of each medication. At the lower dose of these medications, there is an associated reduction of toxicity and side effects of each immunosuppressive medication

A new class of biologic drugs that inhibit the specific inflammatory mediators in the inflammatory cascade may offer high efficacy with reduced systemic toxicity compared to traditional immunosuppressive agents

25.7.1 Introduction

Retinal vasculitis represents a group of disorders with retinal vascular inflammation and associated ocular inflammation. Many of the patients with retinal vasculitis have been previously diagnosed with an associated systemic disease, but some may develop retinal vasculitis as the initial manifestation of an underlying systemic disorder. The critical aspect for the ophthalmologist’s diagnosis of retinal vasculitis is the implication of possible associated systemic and central nervous system inflammation. The underlying etiology for the various causes of retinal vasculitis will ultimately determine the therapy for the inflammation.

Common clinical manifestations of retinal vasculitis include vascular sheathing, vitritis, intraretinal hemorrhage, macular edema, and vascular leakage. The retinal vascular changes are often demonstrated more prominently by fluorescein angiography. Untreated, retinal vasculitis may eventuate to severe ocular complications such as cystoid macular edema, macular ischemia, peripheral vascular occlusion, retinal neovascularization, optic nerve atrophy, and retinal detachment.

Table 25.7.1. Indications for immunosuppressive chemotherapy

Absolute

1.Adamantiades-Beh¸cet disease with retinal involvement

2.Sympathetic ophthalmia

3.Vogt-Koyanagi-Harada syndrome

4.Rheumatoid arthritis with necrotizing scleritis/peripheral ulcerative keratitis

5.Wegener’s granulomatosis

6.Polyarteritis nodosa

7.Relapsing polychondritis with scleritis

8.Juvenile idiopathic arthritis associated iridocyclitis

9.Ocular cicatricial pemphigoid

10.Bilateral Mooren’s ulcer

Relative

1.Intermediate uveitis

2.Retinal vasculitis with vascular leakage

3.Severe chronic iridocyclitis

4.Sarcoid-associated uveitis

The goal of treatment for patients with retinal vasculitis is the suppression of intraocular inflammation, the prevention of visual loss and its long-term ocular complications. While therapy may not be required for some patients with mild disease with a good visu-

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loss after control of the inflammation. For patients on systemic treatment for retinal vasculitis, significant improvement can be evident on clinical examination with subtle residual inflammation evident only on fluorescein angiography. Patients with retinal vasculitis on immunosuppressive therapy typically require two or more angiograms each year to determine the efficacy of the treatment and the persistence of mild active disease.

An additional angiography technique employed commonly for diagnosing and monitoring active inflammation is indocyanine green (ICG), a high molecular weight dye commonly used as an adjunct to fluorescein angiography. The protein bound ICG molecules remain intravascular; unlike fluorescein, ICG is used to study choroidal vasculature. Two common patterns of ICG findings can be seen: inflammation of the choriocapillaris or of the large choroidal stromal vessels. The white-dot uveitis syndromes commonly involve the choriocapillaris, while uveitides such as sarcoidosis, sympathetic ophthalmia, Vogt-Koyanagi-Harada disease, toxoplasmosis, and Admantiades-Beh¸cet’s disease commonly show deeper stromal vascular involvement.

Two additional useful tests for the evaluation of patients with ocular inflammatory diseases include optical coherence tomography (OCT) and electroretinogram (ERG) testing. Optical coherence tomography uses the difference in optical reflectivity of the various retinal layers to obtain detailed cross-sec- tional images of the macula and optic nerve with a

spatial resolution of 10 μm. This resolution far exceeds ultrasound and scanning laser ophthalmoscope images. OCT has the same limitations as the other diagnostic instruments using the optical systems, difficulty obtaining images through media opacities such as dense cataract and vitreous hemorrhage. The OCT image provides a detailed anatomical

structure of the vitreoretinal interface and foveal III 25 architecture with great correlation to the histologic

section of the macula. The ability of OCT to detect subtle macular edema with associated intraretinal fluid is extraordinary, far more sensitive than the most expert contact lens examination of the retina. OCT has become the gold standard for diagnosing and evaluating the treatment of patients with macular edema and vitreoretinal pathology of any etiology. Electroretinograms (ERG) have been used for the study of various retinal degenerations and dystrophies. In certain uveitides such as birdshot retinochoroidopathy (BSRC), ERG changes are noted before clinical evidence of decreased vision, increased vitreous cells and macular edema. With early initiation of therapy for BSRC, the abnormal ERG findings normalize with the control of inflammation.

25.7.2.1 Laboratory Tests

In patients with noninfectious systemic diseases, evaluation for underlying collagen vascular diseases and systemic vasculitis syndromes is critical. Appropriate tests include erythrocyte sedimentation rate

(ESR), C-reactive protein level (CRP), rheumatoid factor (RF), antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), anti-DNA, antiSmith, anti-cardiolipin, anti-phospholipids, serum electrophoresis, serum cryoglobulins, complement levels and anti-hepatitis B antibodies.

25 III 25.7.3 Treatment

25.7.3.1 Corticosteroids

Corticosteroids, since their initial discovery in 1935 by Edward C. Kendall and their first clinical use in 1949 by Hench for the treatment of rheumatoid arthritis, have been the mainstay of therapy for patients with noninfectious inflammatory diseases. The drug is fast-acting, highly effective and generally well tolerated briefly, with limited short-term side effects. In an attempt to limit side effects, increase absorption, and efficacy, various corticosteroid preparations have been formulated for the treatment of ocular and systemic inflammation. All formulations of corticosteroids comprise 21 carbon molecules consisting of a cyclopentoperhydrophenathrene nucleus. The mechanism of action for corticosteroids is at the molecular level inside the cell nucleus. The steroid molecule, after entry into the cell, binds to the cytoplasmic steroid-receptor protein. The ste- roid-receptor protein complex then crosses the nuclear membrane and binds to sites known as glucocorticocoid response elements (GREs). The GREs directly control the transcription of various mRNAs and the translation of the protein end products. Anti-inflammatory and immunosuppressive effects of corticosteroids include lymphopenia, reduction of eosinophils and monocytes, inhibition of macrophage recruitment and migration, attenuation of bactericidal activity of macrophages, inhibition of prostaglandin synthesis and reduction of capillary permeability.

Orally administered corticosteroids are absorbed in the jejunum with a bioavailability of 90 %. The most commonly employed form of the oral corticosteroid preparations is prednisone, which is typically initiated at a dose of 1 mg/kg/day. The regimen is tapered over a span of weeks to months. In patients with severe vision and life-threatening inflammation, intravenous methylprednisolone may be used at a dose of 250 mg/day to 1,000 mg/day for 3 days before the initiation of oral prednisone. In patients with monocular disease who are intolerant of oral prednisone, several regional applications of corticosteroid can be used as treatment option. These options include transeptal, subtenons, and intravitreal triamcinolone acetonide steroid injections. For patients who may require long-term regional steroid

delivery, a slow release steroid implant may be a reasonable alternative. All these regional steroid delivery techniques are associated with risk of increased intraocular pressure and the development of cataract. While most steroid-related glaucoma can be controlled with topical ocular hypotensive medications, a small percentage of patients will require glaucoma surgery (trabeculectomy or a glaucoma drainage valve).

The side effects of systemic corticosteroid therapy are numerous. Chronic corticosteroid use is associated with adrenal suppression through its effect on the hypothalamic-pituitary-adrenal axis. Altered moods ranging from euphoria to depression are well known complications of steroid use. Mineralocorticoid activities of corticosteroids significantly alter the patient’s intravascular fluid status, with sodium retention and concomitant potassium wasting. With the retention of sodium comes the risk of associated systemic hypertension. The alteration of protein synthesis and gluconeogenesis in the liver result in hyperglycemia, hyperlipidemia, and ketosis. Longterm use of corticosteroids should be avoided in all patients due to the guaranteed side effects of the chronic therapy. In children, growth retardation can occur rapidly. In patients where inflammation is steroid dependent and low dose steroid therapy is required long-term, all necessary steps should be taken to avoid bone loss through calcium and vitamin D supplementation. In other patients, bisphosphonate or calcitonin therapy may be indicated.

25.7.3.2Nonsteroidal Anti-inflammatory Drugs

In the past 2 decades, many nonsteroidal antiinflammatory medications have been developed for the treatment of pain and inflammation. Their application in ophthalmology has been extended to topical use for patients with postsurgical cystoid macular edema, prevention of intraoperative miosis, and of steroid-responsive postoperative inflammation. In patients with mild episodic uveitis, topical and systemic NSAID are routinely used in conjunction with other medications for the prevention of relapse and associated macular edema. Since the demonstration of the inhibition of prostaglandin production by aspirin and other NSAID in the 1970s, this class of medication has been one of the most prescribed for the treatment of inflammation and pain. Several different classes of NSAID currently exist.

The mechanism of action for all NSAID involves the inhibition of the cyclooxygenase conversion of arachidonic acid to endoperoxidase, the precursors of prostaglandin. All NSAID are readily absorbed in the gastrointestinal system and reach peak serum

concentrations in 0.5 – 5 h. Over 90 % of all NSAID in the serum are protein bound. The liver is the major site of NSAID metabolism.

NSAID therapy in patients with uveitis and retinal vasculitis is an important adjunct to other therapeutic approaches. Systemic use of oral NSAID may reduce the dose of systemic prednisone needed to control inflammation. In patients with acute anterior uveitis, chronic NSAID therapy can reduce the number of flare ups and the amount of topical steroids required for the control of inflammation. In patients with posterior uveitis and retinal vasculitis, the use of oral NSAID with transseptal steroid (triamcinolone acetonide 40 mg) is effective in eliminating cystoid macular edema (CME) and can prevent CME recurrence. While primary retinal vasculitis is not amenable to treatment with NSAID, NSAID are a key component of the multiple drug regimen including corticosteroids and steroid-sparing immunosuppressive agents.

The most common potential side effect of NSAID therapy is gastrointestinal irritation ranging from symptoms of nausea, vomiting, mucosal ulcers and frank bleeding. Other significant potential side effects can involve the central nervous system, hematologic, hepatic, dermatologic and cardiovascular systems. Recent clinical studies in high-risk cardiovascular patients postmyocardial infarction indicated a significantly increased risk of cardiovascular related death for all classes of NSAID therapy. The increased mortality in patients with postmyocardial infarction has raised significant concerns for all patients and prescribing physicians. The increased risk of cardiovascular disease may be related to renal and metabolic changes from NSAID therapy, including salt and fluid retention, edema, and associated systemic hypertension. The risks and benefits of chronic NSAID therapy for the treatment of uveitis and retinal vasculitis should be considered for all patients in a manner similar to all immunosuppressive steroid-sparing agents, and especially in elderly patients with cardiovascular disease or a family history of myocardial infarction.

25.7.3.3 Immunosuppressive Agents

As our knowledge of the cells and molecules involved in the inflammatory cascade have broadened in the past 2 decades, the number of medications used for immunosuppression have exponentially increased. The majority of the current immunosuppressive medications work through the inhibition of DNA and RNA synthesis, and protein translation. Lymphoid proliferative cells, due to their high mitotic activity, are extremely sensitive to this group of medications. A new class of medications, called “biolog-

ic,” target the various cytokines of the inflammatory cascade for the suppression of inflammation.

Patients who are candidates for immunosuppressive therapy include patients intolerant or unresponsive to corticosteroids, and patients with chronic disease requiring prednisone doses greater than 6 mg/ day. The selection of the proper immunosuppressive

regimen is a contract between the treating physician III 25 and the patient. An understanding of the disease

process along with the risks and benefits of various treatment options is critical. Mild to moderate chronic uveitis may be treated by monotherapy of a single immunosuppressive agent and the successive taper of the corticosteroids. In severe uveitis with a vision threatening disorder, combination therapy using agents with synergistic or additive effects is employed.

25.7.3.3.1 Transcription Factor Inhibitors

Cyclosporine A (Neoral, Sandimmune)

Cyclosporine A (CSA) is an 11 amino acid peptide formed by the fungus Beauvaria nivea. The drug exerts its effect on lymphocyte proliferation by blocking the T-cell receptor to genes that encode for multiple lymphokines and enzymes for the activation of resting T cells. CSA also inhibits the calcium dependent intracellular transcriptional signaling of the nuclear factor of activated T cells (NF-AT) for the production of interleukin-2 (IL-2), a potent T-cell mitogen. CSA binds to cyclophilin, a 17-kDa protein in the family of immunophilins. In short, CSA halts the progression of T-cell activation early in the cells cycle, significantly decreasing antibody production and decreasing cytotoxic T-cell activities. Its first application as an immunosuppressive agent in uveitis was reported by Nussenblatt, and CSA was subsequently used in various rheumatic diseases [26].

CSA is often administered as a single or combination agent for moderate to severe uveitis at a dose of 2 – 5 mg/kg/day. At higher levels, the drug is associated with unacceptable degrees of nephrotoxicity. CSA is formulated in 25 mg and 100 mg tablets. Absorption of CSA in the gastrointestinal tract is usually slow and poor, with bioavailability in the range of 20 – 50 %. Peak serum levels are reached 3 – 4 h after ingestion. Over 90 % of the drug is protein bound. Ocular penetration of the drug is normally poor, but in inflamed eyes, the concentration may reach up to 40 % of serum levels. The majority of the drug is processed in the hepatic system through the cytochrome P-450 system. Most clinicians believe that CSA is most effective when used along with low dose prednisone. Side effects of CSA include nephrotoxicity and systemic hypertension, especially at doses above

5 mg/kg/day, such as those used for organ transplant patients. Nephrotoxicity is detected by increased serum creatinine with a disproportionate increase in BUN. Early reduction of CSA dose will reverse CSA induced nephrotoxicity. However, at chronic toxic levels, irreversible interstitial fibrosis of the renal tubules occurs. Hypertension is typically observed

25 III in a dose dependent fashion and is reversible in 15 – 25 % of patients during the first weeks of CSA therapy. It is more commonly observed in patients on concomitant therapy with oral steroids and in patients with renal disease. Other common adverse reactions include paresthesia, temperature hypersensitivity, nausea, vomiting, hirsutism, gingival hyperplasia, neurotoxicity and increased risk of infections. Routine monitoring of blood pressure and serum creatinine levels are mandatory. If no clinical response is observed after 3 months of maximum therapy, the medication should be discontinued for an alternative immunosuppressive agent. In patients where a favorable response is observed, the drug is maintained for at least 2 years with subsequent slow gradual taper. In ours and other clinicians’ experience, the reduction of CSA is associated with recurrent inflammation, at times necessitating the addition of a second steroid-sparing agent such as mycophenolate mofetil.

CSA have been widely used for therapy in a variety of ocular inflammatory diseases, including Adaman- tiades-Beh¸cet disease, birdshot retinochoroidopathy, sarcoidosis, par planitis, Vogt-Koyangagi-Harada disease, multiple sclerosis associated uveitis, sympathetic ophthalmia and idiopathic vitritis. Ozdal in a large series of patients with Admantiades-Beh¸cet’s Disease demonstrated improvement in visual acuity in one-third of the patients, one-third with stable or decreased vision. Half of the patients did not have a flare up of uveitis during CSA treatment. Relapse after the discontinuation of CSA therapy was typical for patients in the study [28]. The use of CSA for the treatment of uveitis and retinal vasculitis is considered off-label.

Tacrolimus (FK-506, Prograf)

Tacrolimus is a macrolide antibiotic. A chemical product of the fungus Streptomyces tsukubaensis, first discovered in 1984, tacrolimus has a similar spectrum of immunosuppressive activity as CSA, inhibiting NF-AT signaling. It has been approved by the United States Food and Drug Administration for the prophylaxis of organ rejection in patients with liver transplant. Early transplant studies demonstrated that tacrolimus, while similar in action to CSA, allowed for a faster taper of steroid in transplant patients. Tacrolimus, like CSA, blocks the acti-

vation of lymphocytes through the suppression of lymphokines and the expression of IL-2 receptor on activated T cells. However, tacrolimus is at least 10 times more potent both in vivo and in vitro. Tacrolimus has a side effect profile similar to that of CSA, with significant effect on renal function and blood pressure. Common side effects include headache, dizziness, nausea, and electrolyte imbalance. The drug is given orally at 0.15 – 0.3 mg/kg/day. Tacrolimus is available in 1 mg or 5 mg anhydrous oral preparation or for intravenous injections. The drug is poorly absorbed from the GI tract after oral ingestion. Bioavailability ranges from 5 % to 67 % in studied transplant patients. The presence of food may decrease absorption of the tacrolimus. The drug is highly lipophilic and is strongly bound to the erythrocytes and plasma proteins, mainly albumin. Tacrolimus is metabolized in the liver, with two of the nine metabolites demonstrating persistent immunosuppressive activity. The half-life of the medication is highly variable, ranging from 3.5 to 40.5 h, and is further extended in patients with liver disease. Close monitoring of blood pressure and renal function is critical for patients on tacrolimus.

Mochizuki was the first to demonstrate the efficacy of tacrolimus in uveitis patients and as a monotherapy for patients with Admantiades-Beh¸cet’s disease. The majority of the treated patients had a reduction of inflammation as well as a decrease in the number and degree of flare ups during treatment. In patients refractory to CSA and prednisone therapy, a switch to tacrolimus therapy brought the inflammation under control [22].

Tacrolimus and CSA share similar side effect profiles, including nephrotoxicity, hypertension, neurotoxicity and hyperglycemia. However, hirsutism and gingival hyperplasia have not been reported in patients treated with tacrolimus. Neurotoxic symptoms include headache, paresthesia, tremors, aphasia, seizures, encephalopathy and coma. Systemic hypertension associated with tacrolimus in general occurs less frequently and requires less antihypertensive therapy than that occurring with CSA therapy. Opportunistic bacterial, viral and fungal infections are a potential risk with the use of the medication. Close monitoring of liver, renal function and blood pressure is essential for patients receiving tacrolimus. The use of tacrolimus for the treatment of uveitis and retinal vasculitis is considered off-label.

Sirolimus (Rapamycin)

Sirolimus macrolide isolated from the actinomycete

Streptomyces hygroscopicus is commonly used for the prophylaxis of organ rejection. Although chemically similar in structure to tacrolimus and functionally

similar to both CSA and tacrolimus in immunosuppression, rapamycin exerts its action through a separate mechanism. In contrast to CSA and tacrolimus, rapamycin does not act through a calcium dependent pathway. Its mechanism of action involves the binding of FK-binding proteins which target TORs (targets of rapamycin) or FRAPs (FK-rapamycin associated proteins). The drug blocks the signaling transduction of various proinflammatory cytokines, including IL-2 and IL-4. In short, rapamycin blunts the response of B cells and T cells to specific interleukins rather than inhibit their production. Both CSA and tacrolimus exert their effect on resting lymphocytes with no activity against activated lymphocytes, while the effects of rapamycin are independent of lymphocyte state.

Rapamycin is given orally with a loading dose of 6 mg, followed by a maintenance dose of 2 mg/day. Currently, rapamycin is available in 1 mg tablets with variable bioavailability. The pharmacokinetics of rapamycin is relatively unknown. The drug is commonly well tolerated. Common side effects of the drug include hyperlipidemia, thrombocytopenia, and leukopenia. All these side effects are reversible with the cessation of the drug. Routine laboratory monitoring of lipid profile and complete blood count (CBC) is required. Currently, rapamycin is FDA approved for kidney and liver transplant rejection prevention.

Due to the novel mechanism of action, rapamycin may be a good new alternative single agent or may be used in combination with other immunosuppressive agents for patients with moderate to severe ocular inflammation. The use of rapamycin for the treatment of uveitis and retinal vasculitis is considered off-label.

25.7.3.3.2 Antimetabolites

Methotrexate (Rheumatrex)

Methotrexate (MTX) was initially used for the treatment of leukemia in children. Today, MTX is widely used to treat acute lymphoblastic leukemia (ALL), central nervous system lymphoma, and a variety of inflammatory conditions including psoriasis, rheumatoid arthritis, juvenile idiopathic arthritis, Reiter’s syndrome, and sarcoidosis. Due to its long track record of safety and efficacy, it has become the first line agent for various pediatric and adult inflammatory diseases.

MTX is a folic acid antagonist that inhibits DNA synthesis and repair, RNA transcription through the prevention of dihydrofolate to tetrahydrofolate conversion by competitively and irreversibly binding the enzyme dihydrofolate reductase (DHFR). Tetrahy-