Ординатура / Офтальмология / Английские материалы / New Treatments in Noninfectious Uveitis_Miserocchi, Modorati, Foster_2012

Miserocchi E, Modorati G, Foster CS (eds): New Treatments in Noninfectious Uveitis.

Dev Ophthalmol. Basel, Karger, 2012, vol 51, pp 29–46

Corticosteroid-Sparing Agents: Conventional

Systemic Immunosuppressants

Jonathan Kruh C. Stephen Foster

Massachusetts Eye Research and Surgery Institution, Ocular Immunology and Uveitis Foundation, Cambridge, Mass., USA

Abstract

The introduction of corticosteroids in the mid-20th century to control inflammatory eye disease revolutionized treatment practices. As long-term use of corticosteroids became the backbone of immunosuppressive therapy, it soon became evident that it was associated with significant morbidity to the patient. For this reason, other immunosuppressant agents were sought. Thereafter, the first generation of immunosuppressive agents were born. The main action of all such agents involves the inhibition of lymphoid proliferation. The agents can be further subdivided into the following categories based on their specific mechanism of action: alkylating (cyclophosphamide and chlorambucil), antimetabolite (methotrexate, mycophenolate mofetil and azathioprine), and antibiotic/calcineurin inhibitor (cyclosporine, tacrolimus and sirolimus). These immunomodulating agents serve as the foundation to modern corticosteroid-sparing immunosuppressive therapy. Many times, these agents are now even indicated as first-line therapy for the treatment of systemic inflammatory diseases with destructive ocular sequela, e.g. Behçet’s disease and granulomatosis with polyangiitis (Wegener’s). Choosing the most appropriate immunomodulatory agent to initiate therapy can often be difficult; a multifactorial approach in the decision-making process is essential. Special attention must be given to the patient’s medical history, type and severity of inflammatory disease, social history, compliance, age, and sex. Oftentimes, it takes a joint effort between the ophthalmologist and multiple sub-specialists (rheumatology, oncology, and hematology) to administer and monitor these therapies. Even though each of these systemic immunosuppressive agents has its own array of potential side effects, with careful monitoring and titration of dosages, such potential side effects can be minimized or avoided altogether. Ultimately, these patients are afforded a much more favorable longterm outcome, free of the devastating effects of chronic corticosteroid use.

Copyright © 2012 S. Karger AG, Basel

Indications & Dosage

For an overview of the drugs to be discussed in this chapter, see Tables 1 and 2.

Table 1. Major indications for the use of conventional immunosuppressive drugs

Table 2. Suggested dosing for medications

Alkylating Agents

Alkylating agents are so named because of their ability to form covalent bonds (alkylation) with neutrophilic substances. Specifically, they function by attaching an alkyl group onto 7-nitrogen guanine [1].

Cyclophosphamide (Cytoxan®, Neosar®)

History and Source

Cyclophosphamide is a member of the nitrogen mustard family of alkylating agents. The first use of nitrogen mustard predates its medicinal applications. This agent was first used for chemical warfare during World War I. At the time, it was found that exposure to nitrogen mustard had profound effects on the bone marrow, causing leukopenia and aplasia of lymphoid tissue [2]. Although, it was not until the 1950s

when its application for the treatment of uveitis was first reported by Roda-Perez [3–5].

Pharmacology

Cyclophosphamide is a prodrug converted by the hepatic microsomal cytochrome P-450 mixed function oxidase system into its active metabolites phosphoramide mustard and 4-hydroxycyclophosphamide [6]. Through nucleophillic substitution reactions, these metabolites form covalent cross-linkages with DNA. It is through alkylation with DNA that this agent has its immunosuppressive function. The active form of cyclophosphamide targets the 7-nitrogen atom of guanine, which promotes guanine-thymidine linkages. Ultimately, this leads to miscoding, breaks in singlestranded DNA, and the formation of phosphodiester bonds after repair of those breaks, with subsequent defective cell function [7]. These interactions occur between both DNA and RNA, and are cell-cycle nonspecific [8].

Clinical Pharmacology

In its clinical application, cyclophosphamide has been found to have depressive actions on both B and T cell populations. With acute administration of high doses, B cells are more specifically targeted [9]. However, when treated at lower doses, and more chronically, both B and T cells are equally affected [10, 11]. The effects on the humoral arm of the immune system result in suppression of both primary and secondary antibody responses [9, 12, 13]. Additionally, it is effective in inhibiting cell-mediated immunity [8]. Finally, it aids in the inhibition of monocyte precursors.

Therapeutic Value

Even though there can be the potential for significant toxicity from cyclophosphamide therapy, it still maintains an important role in the treatment of many inflammatory diseases, especially when recalcitrant to other therapies. In particular, cyclophosphamide is the treatment of choice for patients with ocular disease from granulomatosis with polyangiitis (Wegener’s) and polyarteritis nodosa. When used as either monotherapy or as adjuvant treatment with corticosteroids, it can be invaluable in improving both patient survival as well as maintaining ocular integrity [14–17]. Bilateral Mooren’s ulcer, often nonresponsive to more conventional treatments may have good response to cyclophosphamide therapy. Significant recovery rates and improved outcomes in patients with aggressive bilateral Mooren’s ulcer have been reported by Foster, Brown and Mondino [18, 19]. In patients with active ocular cicatricial pemphigoid, cyclophosphamide may also be considered a first-line agent [20]. The evidence for this was supported by Foster in a randomized, double-masked, clinical trial proving the superiority of combination treatment with cyclophosphamide and prednisone versus prednisone alone [20]. The efficacy of cyclophosphamide over corticosteroid monotherapy for the treatment of ocular

manifestations of Adamantiades-Behçet’s Disease (ABD) has also been reported in the literature [21]. Both cyclophosphamide and chlorambucil were also shown to be superior to cyclosporine in the treatment of ABD [22]. Other ocular inflammatory disorders that are often refractory to treatment with prednisone and other immunosuppressive agents, but successfully treated with cyclophosphamide, include pars planitis and sympathetic ophthalmia [23, 24].

Dosage and Side Effects

Cyclophosphamide may be given orally, intramuscularly, intravenously, intrapleurally, or intraperitoneally. Orally, ~75% is absorbed in the gastrointestinal tract. It reaches peak plasma levels within 1 h of ingestion and can be found distributed throughout the body, including the brain [25]. Cyclophosphamide undergoes conversion to its cytotoxic metabolites in the liver. These active metabolites are 50% bound to plasma albumin. The plasma half-life of cyclophosphamide is 4–6 h. Ultimately, ~10–20% of the native drug is excreted in the urine unchanged [26].

There are numerous side effects that patients may encounter when being treated with cyclophosphamide. The array and severity of side effects that one might experience is usually dose related. The most frequent complaint from patients is gastrointestinal upset. This may manifest as anorexia, nausea, vomiting, or stomatitis [26]. Oftentimes, when this medication is given intravenously, this side effect can be decreased by giving prophylactic ondansetron.

The most common dose-limiting effect from cyclophosphamide is bone marrow depression. Leukocytes are significantly affected, more commonly than platelets. Leukopenia and/or thrombocytopenia has a peak incidence 1–2 weeks after i.v. therapy, and usually resolves within 10 days after the last received dose [1]. Often trimethoprim-sulfamethoxazole is given prophylactically to prevent pneumocystis pneumonia, a complication found in immunosuppressed individuals.

Another serious potential side effect is gonadal dysfunction. Azoospermia and amenorrhea can be found in 60% of individuals after 6 months of treatment [27]. Since this is often irreversible, sperm or ovum banking is suggested for those who wish to have children.

If one is on oral cyclophosphamide therapy, we suggest that it be taken in the morning, and that the patient consume 3–4 l of fluids throughout the day, in order to promote frequent voiding. Active metabolites (acrolein) in the bladder cause irritation of the mucosa which may lead to hemorrhagic cystitis and to malignant transformation of bladder epithelium, leading to bladder cancer. This may occur as early as 24 h after initiation and as late as several weeks after suspension of therapy [1]. Most often, this complication resolves with discontinuation of the drug, high fluid intake, and bed rest. In rare but severe cases, supravesical urinary diversion may be required [28]. On the other hand, i.v. therapy is often the preferred method of administration because it allows for rapid induction, decreased rates of hemorrhagic cystitis, and transient neutropenia, making infections less frequent.

Table 3. Special considerations for cyclophosphamide

Contraindications to treatment

•Patients receiving other concurrent immunosuppressive therapy for an independent reason; e.g. previous radiation therapy, tumor cell infiltration of the bone marrow, or previous cytotoxic therapy

•Patients with focal chorioretinitis, herpes simplex, herpes zoster, CMV, AIDS retinopathy, toxoplasmosis, tuberculosis, and fungal infections

•Those with a severely depressed bone marrow function

•Hypersensitivity to the drug

•Pregnancy class D

•Excreted in breast milk

Drug interactions

•The metabolism of cyclophosphamide is affected by drugs that interact with the P-450 mixed-function oxidase system

Other possible side effects range from alopecia, dry eye, increased intraocular pressure, cardiac myopathy, hepatic dysfunction, irreversible pulmonary fibrosis, impaired renal clearance of water with resultant hyponatremia, and anaphylaxis [25, 26, 29] (see table 3).

Systemic Immunosuppressive Therapy for Eye Disease Study

Cyclophosphamide was not found to be significantly associated with an increase in the incidence of mortality (fully adjusted hazard ratio 1.14, 95% CI 0.81–1.60), but was found to be non-significantly associated with an increase in cancer-related mortality (fully adjusted hazard ratio 1.61, 95% CI 0.81–3.22) [see 50, 51]. These results corroborate evidence from other studies which support that there is an association with the development of secondary malignancies, specifically acute myelocytic leukemia, bladder cancer and skin cancer [30–33].

Chlorambucil

History and Source

Chlorambucil was first created in the 1950s, and was primarily used for the treatment of malignant lymphoma [3]. Its role in the ophthalmic world came about in 1970 when Mamo and Azzam [34] first reported its use and efficacy for the treatment of ABD.

Pharmacology

Chlorambucil is a nitrogen mustard derivative. Likewise, its affect as an alkylating agent is similar to that of cyclophosphamide. Its functions are cell-cycle nonspecific,

Table 4. Special considerations for chlorambucil

Contraindications to treatment

•No known drug-to-drug interactions

•Hypersensitivity to drug

•Pregnancy class D

•Unknown excretion into breast milk

as it impedes both DNA replication and RNA transcription [7, 8]. As an unmetabolized prodrug, chlorambucil is both plasma and tissue bound. Like cyclophosphamide, this prodrug is metabolized into its active form in the liver. There, it is converted to its active metabolite, phenylacetic acid. The major route of excretion is through the kidney [26].

Clinical Pharmacology

The immunosuppressive effect of chlorambucil is manifested through B cell suppression. Of the nitrogen mustard-based agents, it is the slowest acting, taking up to 2 weeks to have an effect [35].

Therapeutic Value

Since its first use for ABD by Mamo and Azzam, chlorambucil has shown great efficacy in the treatment of active ABD by many other investigators [34, 36–40]. It also has been shown to allow for long-term remission of this disease [41, 42]. This agent may also have a significant role in the treatment of juvenile idiopathic arthritis (JIA)- associated iridocyclitis, and sympathetic ophthalmia [24, 43–46].

Dosage and Side Effects

Expectedly, chlorambucil has a similar side effect profile to cyclophosphamide. The most prominent of these is bone marrow suppression. Under normal circumstances, myelosuppression is moderate, gradual, and reversible. However, persistent leukopenia, requiring many months for resolution following discontinuation of the drug, has also been reported. This is most notable in patients who had been receiving high doses of this drug [47].

Other notable side effects include gonadal dysfunction, gastrointestinal upset, cystitis, pulmonary fibrosis, hepatitis, rash, and CNS stimulation (i.e. seizures) [1, 48, 49] (see table 4).

Systemic Immunosuppressive Therapy for Eye Disease Study

Chlorambucil was not found to be associated with an increased incidence of mortality (fully adjusted hazard ratio: 1.43, 95% CI 0.72–2.85), but was found to be significantly associated with an increase in cancer-related mortality (fully adjusted hazard

ratio: 2.29, 95% CI 0.53–9.83) [50, 51]. These results appear to be in line with other reports, which suggest a correlation between chlorambucil and the incidence of acute myelogenous leukemia [33, 52, 53].

Antimetabolites

Antimetabolites are chemicals that act to inhibit the functionality of a metabolite. Disabling a metabolite prevents the completion of a pathway in an enzymatic/metabolic reaction [54].

Methotrexate

History and Source

Methotrexate made its debut in 1948, first reported for the treatment of acute leukemia in children [55]. Today, in addition to acute lymphocytic leukemia, it is utilized to treat a variety of systemic inflammatory diseases. These include psoriasis, rheumatoid arthritis, JIA, reactive arthritis, polymyositis, and sarcoidosis [8, 56, 57]. The efficacy of methotrexate for the treatment of ocular inflammatory disease was first reported by Wong and Hersh in 1965 [58]. Since that time, it is often regarded as the first line agent when starting a patient with uveitis on immunosuppressive therapy.

Pharmacology

Methotrexate is analogous in structure to folic acid, excluding two areas; the amino group in the 4-carbon position is substituted for a hydroxyl group, and a methyl group is substituted for a hydrogen atom at the n-1 position [8, 59]. It acts as an irreversible, competitive inhibitor of the enzyme dihydrofolate reductase. The disruption of this enzymatic pathway prevents the conversion of dihydrofolate to tetrahydrofolate, an essential cofactor in the synthesis of the purine nucleotides and thymidylate [7]. Additionally, methotrexate offers partial, reversible, competitive inhibition of thymidylate synthetase. Ultimately, DNA synthesis, repair, RNA synthesis, and cell division (S-phase cell cycle specific) are inhibited.

Clinical Pharmacology

Methotrexate targets cells that are actively dividing. Thus, rapidly dividing cell populations are most dramatically affected, e.g. malignant cells, fetal cells, cells of the gastrointestinal tract, urinary bladder, buccal mucosa, and bone marrow.

Methotrexate suppresses both B and T cells. At low doses, it has little effect on cell-mediated immunity, but has been shown to depress acute-phase reactants [60,

61]. Therefore, it is suspected that the action of methotrexate is more likely antiinflammatory than immunosuppressive [62].

Therapeutic Value

In the early years following the advent of methotrexate use, it was sparsely used in fear of its adverse side effects. Initial case studies by Wong proved it efficacious in treating steroid-resistant uveitis and sympathetic ophthalmia [58, 63, 64]. But it was the fields of rheumatology and dermatology that paved the way for widespread acceptability of this medication. At lower doses and decreased frequencies, it was found that there could be significant benefits to patients with inflammatory disorders with fewer of the serious side effects [65]. Methotrexate is now used to control scleritis associated with collagen vascular diseases, such as reactive arthritis and rheumatoid arthritis, but not disease complicated by relapsing polyangiitis [66]. In particular, it has been found that weekly dosing either orally or intramuscularly may be effective for the treatment of reactive arthritis, ankylosing spondylitis, psoriatic arthritis, and JIA [8, 45]. Although not as effective as monotherapy for retinal vasculitides, it does play a role in its treatment and has been met with success in specific case studies [62, 67].

Dosage and Side Effects

Once methotrexate is absorbed, it undergoes a triphasic reduction. The first phase occurs within 75 min of ingestion and relates to systemic distribution throughout the body. The second phase lasting 2–4 h represents renal excretion. Lastly, the third phase can last between 10 and 27 h, being especially long because it corresponds with the slow release of methotrexate from DHFR in tissues [68]. While ~50% of methotrexate is plasma bound, its toxicity lies in the remaining amount that is found unbound [8]. Factors that may influence its toxicity may be prolonged drug clearance (renal insufficiency) time, as well as displacement from plasma proteins by other drugs (increasing plasma methotrexate concentrations). Methotrexate is minimally metabolized throughout the body; 50–90% is excreted unchanged in the urine [7]. Drug accumulation in the liver and kidney can occur at high doses and over prolonged periods of therapy. Ultimately, this may play an important role in toxicity [59].

Bone marrow suppression is the major dose-limiting factor when administering methotrexate therapy [69]. Methotrexate-induced hepatotoxcity may also occur during shortor long-term use. Chronically, this may lead to hepatic fibrosis and, rarely, cirrhosis [59]. Pulmonary toxicity manifested as acute pneumonitis or pulmonary fibrosis may also occur in this patient population. Resolution usually occurs after discontinuation of therapy. The cause of pneumonitis is thought to be an idiosyncratic reaction or a hypersensitivity reaction [70].

Gastrointestinal toxicity commonly occurs and is dose dependent. This may manifest as nausea, ulcerative mucositis, and diarrhea [71]. Other side effects include renal failure, alopecia, dermatitis, photophobia, increased ocular discomfort and epiphora [29, 59] (see table 5).

Table 5. Special considerations for methotrexate

Contraindications to treatment

•Decreased renal and liver function, especially in the elderly

•Alcoholics, alcoholic liver disease, or known active hepatic disease

•Hypersensitivity to drug

•Pregnancy class X

•Excreted in breast milk

Drug interactions

•Drugs that displace methotrexate from plasma proteins may increase systemic concentrations (e.g. consumption of salicylates, sulfonamides, chloramphenicol, tetracycline)

•Drugs that decrease renal blood flow or tubular secretion may increase systemic concentrations (e.g. NSAIDs or probenecid)

Systemic Immunosuppressive Therapy for Eye Disease Study

Methotrexate was not found to be associated significantly with an increase in the incidence of mortality (fully adjusted hazard ratio: 1.02, 95% CI 0.78–1.34) or cancerrelated mortality (fully adjusted hazard ratio: 0.89, 95% CI 0.48–1.63) [50, 51]. These findings are well supported in the literature by multiple studies in patients who have received chronic treatment with methotrexate for psoriasis and rheumatoid arthritis [72–76].

Azathioprine

History and Source

Azathioprine was first developed in the 1960s for the use of immunosuppression in transplant patients, and in the treatment of autoimmune diseases [25]. By 1966, Newell began using it to treat ocular immune-mediated disorders [77, 78].

Pharmacology

This prodrug is metabolized in the liver to its active metabolite 6-mercatopurine. As 6-mercaptopurine is converted to thionosine-5-phosphate (a purine analog), it is able to act as false precursor to the formation of purine nucleotides, thus, inhibiting the formation of adenine and guanine. This results in impaired DNA synthesis, RNA synthesis, and protein synthesis [7].

Clinical Pharmacology

At the normally prescribed dose, 2–3 mg/kg, azathioprine strongly suppresses T cells, but weakly suppresses B cells [79]. In addition, it depresses the formation of monocyte precursors [8]. At larger doses, alteration in antibody response may be elicited [79].

Therapeutic Effects

Azathioprine has been shown to be effective in the treatment of various corticosteroidresistant ocular inflammatory diseases. In particular, the literature notes its efficacy for the treatment of scleritis associated with polychondritis, ocular cicatricial pemphigoid, pars planitis, and JIA-associated iridocyclitis [20, 66, 78, 80]. In a 2-year doublemasked, randomized, controlled study, it was demonstrated that azathioprine (2.5 mg/ kg/day) was able to prevent the formation of new eye lesions and reduce the frequency and intensity of inflammation in patients with ABD [81]. However, Foster found more equivocal efficacy in a series of 8 patients treated similarly [82]. There has also been varying results for its use in the treatment of sympathetic ophthalmia [24, 78].

Dosage and Side Effects

Once ingested orally, within 2 h 50% is absorbed [25]. From there, it is metabolized in erythrocytes and in the liver to its active form, 6-MP. Approximately 30% of 6-MP is maintained bound by plasma proteins. Renal clearance accounts for only 2% of drug excretion; however, there is increased cytotoxicity in patients with renal insufficiency [25].

Myelosuppression is a common side effect of azathioprine often occurring as a delayed response to treatment, following 1–2 weeks after beginning therapy [1]. The most common side effects experienced by patients on this therapy are gastrointestinal upset, nausea, vomiting, and diarrhea. Often, these symptoms become the reason for discontinuation of this drug [81]. Other known side effects, albeit less common, include interstitial pneumonitis, hepatocellular necrosis, pancreatitis, stomatitis, alopecia, and (rarely) secondary infections [83, 84] (see table 6).

Systemic Immunosuppressive Therapy for Eye Disease Study

Azathioprine was not found to be significantly associated with an increase in the incidence of mortality (fully adjusted hazard ratio: 0.99, 95% CI 0.72–1.38) or cancerrelated mortality (fully adjusted hazard ratio: 1.13, 95% CI 0.60–2.14) [50, 51]. Multiple previous studies support these findings in patients who have been treated with azathioprine chronically for rheumatoid arthritis and inflammatory bowel disease [85–89].

Antibiotics

Cyclosporine

History and Source

In the early 1970s, cyclosporin A (CSA) was discovered by the researchers at Sandoz laboratories [90, 91]. It was derived from cultures of the fungi Tolypocladium inflatum. The effectiveness of CSA for the treatment of autoimmune uveitis was first reported by Nussenblatt et al. [92, 93] in 1983.