Ординатура / Офтальмология / Английские материалы / Dry Eye and Ocular Surface Disorders_Pflugfelder, Beuerman, Elliot Stern_2004

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to act, whereas systemic steroids act immediately and are undoubtedly the most effective option [25]. Intravenous methylprednisolone pulse therapy is unnecessary, even for acute inflammatory exacerbations. Prednisone is the most widely used oral steroid, at an initial daily dosage of 1 mg/kg. The dose is then tapered, either to withdrawal or to a daily long-term maintenance dose which should not exceed 10 mg. Indeed, severe complications can occur even with this low dose of prednisone, especially in elderly patients [26]. Ocular inflammation often relapses during steroid tapering [27], and steroid-sparing strategies are therefore useful. At all events, high-dose oral corticosteroids should not be used for more than 1 month, because of their potentially severe adverse effects. Ophthalmologists are sometimes faced with new patients who are already on chronic moderateto highdose oral prednisone. In such cases the steroid dose should be tapered over a period of weeks to months, depending on the therapeutic response and the duration of hypothalamic–pituitary–adrenal axis steroid-induced impairment [28].

The list of steroid-related adverse effects is impressive, including cushingoid facial changes, weight gain, elevated blood pressure, fluid retention, diabetes mellitus (sometimes insulin-dependent), hyperlipidemia, atherosclerosis, osteoporosis, aseptic necrosis of the femoral head, myopathy, infections pancreatitis, mood changes, psychosis, easy bruising, impaired wound healing, cataract, glaucoma, and delayed pubertal growth. Monitoring should include blood pressure and blood glucose measurements every 3 months, and blood lipid assay and bone mineral density measurement annually. Daily intake of 1500 mg of calcium and 800 IU of vitamin D are recommended for patients on chronic oral

Figure 3 Example of a scoring system for fibrosis [13]. Stage IIC-IIIB2 (right eye) = lower fornix foreshortening (50–75%) associated with two symblephara occupying 25–50% of the length of the lower lid. The redness score is 2 in the temporal and lower quadrants. (Reprinted with permission from Hoang-Xuan T: Inflammatory Diseases of the Conjunctiva. New York: Thieme, 2001, p. 75.)

corticosteroid therapy who have osteoporosis, possibly combined with sexhormone replacement therapy, weight-bearing exercises, and antiresorptive agents [29,30]. The risk of gastrointestinal ulceration is increased when oral nonsteroidal anti-inflammatory agents are prescribed concomitantly with oral steroids. Unfortunately, despite the use of diverse combinations of steroid-spar- ing agents in order to increase therapeutic effectiveness and limit the side effects of each individual drug, oral steroids sometimes cannot be stopped, and yet the disease still progresses [11].

VI. ALTERNATIVES TO STEROIDS AND STEROID-SPARING AGENTS

The adverse effects of long-term systemic steroids are especially troublesome in OCP, as most patients are elderly. Steroid-sparing immunosuppressive agents induce more readily preventable and reversible complications than systemic corticosteroids if they are properly prescribed and monitored [31]. However,

immunosuppressive therapy requires the ophthalmologist to collaborate closely with an internist, oncologist, or experienced general practitioner. Many antiinflammatory drugs have been used, alone or in combination, for the treatment of OCP. A panel of experts recently reviewed the peer-reviewed literature on immunosuppressive therapy for ocular inflammatory diseases [28]. Only one well-designed randomized, double-blind, controlled study was retained, leading the experts to recommend the use of the cyclophophamide prednisone combination rather than prednisone alone for the treatment of severe OCP [3]. This paucity of data means that treatment of OCP will essentially be based on personal experience, nonrandomized and uncontrolled clinical trials, cohort-controlled analytic reports, and case reports.

VII. SYSTEMIC DRUGS FOR TREATMENT OF OCP

Available systemic drugs for the treatment of OCP include, in addition to steroids, cytotoxic immunosuppressants and other agents with anti-inflammatory activity. A list of available drugs, their doses, and their monitoring is given in Table 3.

A.Dapsone

Dapsone (diaminodiphenylsulfone) is the most widely used oral medication for OCP which does not belong to the cytotoxic immunosuppressant drug category. The anti-inflammatory effects of this sulfone derivative, which is used primarily to treat leprosy, were first demonstrated in bullous pemphigoid, dermatitis herpetiformis, and relapsing polychondritis. Its mechanism of action seems to involve inhibition of polymorphonuclear cell lysosomal activity [32,33].

Although dapsone is a first-choice therapy for nonsevere OCP and for OCP in old and fragile patients [34], it is in no way risk-free. Its long-term use almost always induces dose-dependent hemolytic anemia associated with methemoglobinemia, even in glucose-6-phosphate dehydrogenase-nondeficient patients [3,35–37]. Dapsone-induced neutropenia with bone marrow suppression has been reported in two patients with ocular cicatricial pemphigoid [38]. Gastrointestinal disorders were noted in 12% of patients in one study [34]. Neurological, allergic, renal, and hepatic complications are rare. In a retrospective analysis of 51 OCP patients who received dapsone, 43 (84%) experienced adverse effects; this was the highest complication rate associated with the different drugs used in this study [11].

B.Sulfasalazine

Sulfasalazine, an oral precursor of sulfapyridine, is used mainly to treat rheumatoid arthritis and ulcerative colitis, but also can control the inflammation in OCP [39,40]. Its mechanism of action is not clear, but may involve inhibition of lymphocyte functions and the peroxidase system [41,42].

The main adverse effects of sulfasalazine are gastrointestinal disorders, headache, and dizziness [40]. Hematological disorders including hemolytic anemia, agranulocytosis, neutropenia, leucopenia, pancytopenia, and thrombocytopenia are rare. Like other sulfonamides, sulfasalazine should be avoided in case of previous allergy to this drug class or to salicylates.

C.Methotrexate

Methotrexate, a folic acid analog and dihydrofolate reductase inhibitor, is an antimetabolite which produces its anti-inflammatory effects by inhibiting leukocyte functions [43]. Folate (1 mg/day) must be prescribed concomitantly to prevent nausea. Methotrexate has low toxicity, but carries a risk of hepatotoxicity, cytopenia, and interstitial pneumonia. The most frequent adverse effects are gastrointestinal disturbances, nausea, appetite loss, and stomatitis. Methotrexate is contraindicated during pregnancy because of its teratogenecity.

D.Azathioprine

Azathioprine is an antimetabolite which interferes with DNA replication and RNA transcription. It decreases the activity of both T and B lymphocytes [44]. Reversible bone marrow suppression is the most serious side effect of azathioprine. The serum level of thiopurine methyltransferase activity is a good predictor of myelotoxicity [45]. The most common adverse effects are gastrointestinal disturbances such as nausea and vomiting, which may lead to drug discontinuation. Rare cases of hepatotoxicity have been reported. Induction of non-Hodgkin lymphoma also has been reported in renal transplant patients.

E.Cyclophosphamide

Cyclophosphamide is a nitrogen-mustard alkylating agent that alters DNA and RNA [46], and induces lymphotoxicity [47].

The most common adverse effect induced by cyclophosphamide is dosedependent reversible bone marrow suppression, which is more frequent in older patients. Some investigators advocate oral cyclophosphamide dosage adjustment until the white blood cell count is lowered to 3000–4000 leukocytes and 2500 neutrophils per microliter to obtain adequate immunosuppression [3]. However,

close blood cell count monitoring is mandatory because the risk of infections increases if the neutrophil count falls below 1000/ L.

Hemorrhagic cystitis is the second most serious complication. It is induced mainly by the metabolite acrolein [48]. It usually provokes microscopic hematuria, and it is preventable if patients take their tablets in the morning and drink at least 2 L of fluids daily. Onset of bladder toxicity requires cyclophosphamide discontinuation. Once this toxicity has resolved, the oral tablets can be replaced by intravenous cyclophosphamide pulses, possibly combined with 2-mercaptoethane sulfonate [49].

Other unwanted effects of cyclophosphamide are reversible hair loss, nausea, vomiting, teratogenicity, and sterility.

F.Intravenous Immunoglobulin Therapy

Intravenous immunoglobulin therapy recently proved effective on refractory OCP [22]. The rationale was the low toxicity and efficacy of intravenous immunoglobulin therapy seen in patients with other autoimmune diseases such as idiopathic thrombocytopenic purpura, systemic lupus erythematosus, and rheumatoid arthritis. The mechanisms of action are poorly understood, but include complex immunomodulatory effects on T- and B-cell functions, such as autoantibody neutralization [50].

G.Other Immunosuppressants

Cyclosporine and tacrolimus, which selectively target T cells, were disappointing in uncontrolled case series [3,11,22]. Subcutaneous cytosine arbinoside (ara-C) (0.3 mg/kg/day) has been used as an alternative in severe forms, although it is highly toxic for bone marrow [11,22]. Mycophenolate mofetil (1–3 g/day), a relatively new immunosuppressive antimetobolite that acts on both T and B lymphocytes and has been used successfully to prevent kidney allograft rejection, showed some efficacy in bullous pemphigoid, pemphigus vulgaris, and OCP [51].

H.Adjuvant Therapy

Symptomatic therapy of dry eye syndrome includes frequent instillation of various preservative-free lubricants of different viscosities, and possibly autologous serum [52], punctal plugs, and oral tetracycline or derivatives, plus lid hygiene in patients with meibomitis.

I.New Pharmaceutical Approaches

As our understanding of the immune mechanisms underlying OCP improves, new pharmaceutical approaches should emerge. Some molecules currently being tested in other inflammatory ocular diseases may also be good candidates for the

treatment of OCP. They include daclizumab (Zenapax®), a monoclonal antibody directed against the interleukin-2 receptor [53], infliximab (Remicade®) and etanercept (Enbrel®), two anti-TNF-α agents [54], and leflunomide (Arava®), a novel immunomodulatory drug, the primary action of which is inhibition of de-novo pyrimidine synthesis [55].

VIII. INDICATIONS FOR OCP

Because OCP is a rare disease with many clinical variants, there have been very few clinical trials involving large series of patients [3,11,12] on which therapeutic recommendations can be based [5,28,34]. These strategies depend on various factors, including disease stage and progression, overall health status and other patient characteristics, and practitioners’ personal experience (Table 4). The final treatment goal is disease control, i.e., complete resolution of inflammation and halting the conjunctival fibrotic process, without inducing deleterious side effects. As previously mentioned, because OCP is a chronic disease often requiring chronic systemic anti-inflammatory therapy, long-term systemic corticosteroid therapy should be avoided whenever possible; if this cannot be done, the lowest possible maintenance dose should be used. Ophthalmologists have benefited greatly from advances made by dermatologists who treat autoimmune blistering diseases such as pemphigus vulgaris [24,56] and bullous pemphigoid [35]. However, drugs effective in these conditions are not always as effective in OCP.

The optimal duration of immunosuppressive therapy is not clearly defined. It is usually recommended to stop this treatment when OCP has been fully controlled for 1 year [27]. In a series of 104 consecutive patients by Neumann et al., one-third of patients were able to remain free of therapy, but 22% experienced a generally insidious inflammatory reactivation after treatment withdrawal. Fortunately, the relapses responded well to the same treatment given at a lower dose. The same group reported that an additional one-third of patients needed chronic therapy to remain free of inflammation or recurrent relapses, while the last third had either partial or absent responses [27]. In our unpublished series of 63 OCP patients, we found that 13 (20%) patients were off systemic treatment after more than 1 year.

IX. TREATMENT OF MILD TO MODERATE OCP

Dapsone is a first-line therapy for mild to moderate OCP, provided that the patient is not glucose-6-phosphate dehydrogenase-deficient. Despite the high risk of hemolysis, dapsone is also a drug of choice for elderly and/or fragile patients with active disease in whom cytotoxic immunosuppressants are contraindicated.

In 1982, Rogers et al. were the first to use dapsone successfully in patients with OCP [37]. However, dapsone as monotherapy is less effective than cyclophosphamide in progressive forms of OCP associated with symblepharon formation [3]. If hemolytic anemia and methemoglobinemia occur, simple dapsone dose tapering and possible combination with another anti-inflammatory drug may be sufficient, as both complications are dose-dependent.

Sulfasalazine is another nonimmunosuppressive drug that can be prescribed as initial therapy for moderate or less severe forms of OCP. We have shown that it can replace dapsone in patients who are intolerant of or unresponsive to this drug [40].

In patients whose disease is not highly active or who cannot sustain aggressive therapy, second-line drugs include the cytotoxic agents methotrexate and azathioprine. Systemic methotrexate was administered successfully to selective patients who were intolerant of dapsone or cyclophosphomide, or who did not respond to dapsone. Methotrexate has the advantage of low toxicity [3,11]. Methotrexate monotherapy was used by dermatologists to treat bullous pemphigoid, but its efficacy in OCP remains to be demonstrated, and use of this drug is not very widespread.

More data on azathioprine in OCP have been available since 1974, when Dave and Vickers first reported its efficacy in patients with cicatricial pemphigoid who were steroid-dependent and/or had steroid-induced side effects [57]. According to an expert consensus, azathioprine is a good treatment for mild to moderate OCP [5]. Although it has been used successfully to replace cyclophosphamide in OCP [12,34], azathioprine monotherapy is less effective than cyclophosphamide monotherapy in severe OCP [3,5,28]. Hence, azathioprine often needs to be combined with other drugs, particularly dapsone. The combined drugs act as mutual sparing agents [3]. Preliminary results also indicate that mycophenolate mofetil is an effective steroid-sparing agent, but there are too few data on its use as monotherapy [51].

X.TREATMENT OF SEVERE OCP

Cyclophosphamide has become the immunosuppressive drug of choice to treat severe OCP, since the pioneering work of Brody and Pirozzi [58], who successfully treated a patient with severe steroid and azathioprine-resistant cicatricial pemphigoid involving both eyes, the mouth, and the esophagus. Subsequent uncontrolled case series confirmed the beneficial impact of cyclophosphamide in severe OCP [1,12]. In 1986, in the only well-designed, randomized, double-masked clinical study in OCP, Foster demonstrated the superiority of cyclophosphamide combined with prednisone over prednisone alone [3,28]. In another randomized double-masked comparative study,