EyeNet Magazine


 
Tame Inflammation: 10 Immunosuppressive Drugs to Consider
By Richard Trubo
 
 

Ocular inflammation typically has been treated with corticosteroids. But more clinicians are now turning to steroid-sparing immunosuppressive agents— sooner, more frequently, and sometimes in combination with steroid treatment.

Corticosteroids are the most common drugs to which ophthalmologists turn in treating patients with serious ocular inflammatory disease. But increasingly these agents have been joined by immunosuppressive medications, which are now important weapons in the treatment arsenal.

“There definitely is a trend to use immunosuppressive drugs more often and more aggressively, not only in severe disease, but even in some patients with moderate disease,” said Howard H. Tessler, MD.

Many uveitis specialists say that as ophthalmologists become familiar with systemic immunosuppressives, they’re feeling more comfortable than even a decade ago in using steroid-sparing agents, or balancing their use with corticosteroids.

“I don’t think any of us are putting our patients on long-term high-dose oral prednisone anymore, which used to be our only therapy,” said Debra A. Goldstein, MD. “Today, with many immunosuppressive agents to choose from, our treatment armamentarium is much larger than it used to be.”

Yet many ophthalmologists are still navigating the learning curve in the optimal use of these agents. “In traditional ophthalmology training, we aren’t trained to use these immunosuppressive medications, and many clinicians don’t have experience with them,” said Edward J. Holland, MD. “But when used in the proper fashion, they certainly are a great adjunct to the management of anterior segment as well as posterior segment inflammatory disease.”

The Current Role of Steroids

When topical and periocular steroids fail or are considered an inappropriate choice in the treatment of ocular inflammation, most clinicians turn to oral corticosteroids. Typically, the initial daily dose is 60 to 80 milligrams. But the goal is to taper the drug to a very low dose over a three to 12-month period, or withdraw the patient completely. Most ophthalmologists concur that long-term moderate- and high-dose prednisone is inadvisable, since systemic corticosteroids are associated with serious side effects, such as cataracts, glaucoma, myalgias, weight gain, hypertension, hypercholesterolemia, atherosclerosis, osteoporosis and bone fractures, among others. “Side effects like high blood pressure and elevated blood sugar make corticosteroids a complicated medication to manage,” said Dr. Holland. “So we’d prefer to taper the oral steroids when we can.”

Useful to a point. Long-term oral corticosteroid monotherapy is becoming less common, no matter what the specific ocular inflammatory disorder. “Corticosteroid therapy that lasts more than three months—at a dose above 10 mg a day—is generally discouraged,” said Robert B. Nussenblatt, MD. “So we are much more inclined to introduce a second agent—specifically, a steroid-sparing agent—much earlier in the course of a patient’s disease than we might have done a number of years ago.”

This recommendation falls into line with the most recent expert panel guidelines for the use of immunosuppressive agents in ocular inflammatory disorders, which concluded that “patients who require chronic oral corticosteroid therapy, especially at doses greater than 10 mg per day, may require immunosuppressive drug therapy.”¹

The Immunosuppressives

The need for immunosuppressive drugs depends on the cause of the inflammation. Only 15 percent of patients with intermediate uveitis need immunosuppressive agents, said Douglas A. Jabs, MD, MBA. For patients with scleritis, about one-third will respond to oral corticosteroid drugs, and one-fourth will need other immunosuppressive drug treatment. Nearly all patients with Behçet’s disease and about two-thirds of those with sympathetic ophthalmia require immunosuppressive drugs.

The most commonly used steroid-sparing immunosuppressives include antimetabolites, T-cell inhibitors and alkylating agents. But there is ongoing research into newer agents called biologics, which are monoclonal antibodies being investigated for the treatment of uveitis.

Antimetabolites. Methotrexate and azathioprine are the antimetabolites with the longest track record for the management of chronic ocular inflammatory disease. Methotrexate, for example, remains a common choice for treating conditions ranging from chronic iridocyclitis to idiopathic panuveitis to scleritis. Azathioprine is often chosen first for Behçet’s disease and multifocal choroiditis, among other disorders.

“I use methotrexate a lot,” said Dr. Goldstein. “It’s easy to take, and patients like it because it’s administered orally once a week, as opposed to azathioprine’s once-a-day regimen.”

When treating mild to moderate scleritis, Dr. Holland typically relies on methotrexate as a first-line drug, in conjunction with corticosteroids. “I initiate both at the same time because methotrexate will take several weeks to produce an effective anti-inflammatory response,” he said. “If the patient presents with severe acute inflammation, I’ll manage it short-term with corticosteroids, and long-term with methotrexate.”

The newest antimetabolite, mycophenolate mofetil, is more widely prescribed to prevent solid organ transplant rejection. It tends to have lower toxicity than the other drugs in this class, but is much more expensive than methotrexate or azathioprine.

T-cell inhibitors. Cyclosporine, the first highly successful T-cell inhibitor, is like mycophenolate in that it is also used to prevent rejection in organ transplantation. In inflammatory eye disorders, cyclosporine is typically prescribed in starting doses of 5 milligrams/kilogram/day, and may be chosen as a primary therapy for a number of uveitis conditions, or as an alternative immunosuppressive when antimetabolites have failed. For example, it is often prescribed to manage the ocular inflammation of active Behçet’s disease and severe sympathetic ophthalmia. Adverse effects associated with cyclosporine, however, are potentially serious and include hypertension, and renal and hepatic toxicity.

Tacrolimus, another T-cell inhibitor, has been studied for years as a research agent called FK-506; it is now marketed as Prograf. At this time, it is not used widely in managing ocular disorders. “The limited data so far suggest that the toxicity rates of tacrolimus at the doses tried are too high to warrant its widespread use in treating uveitis,” said Dr. Jabs. “However, with further experience at lower doses, tacrolimus may yet prove to be useful.”

Alkylating agents. Although the alkylating agents—cyclophosphamide and chlorambucil—are available in the ophthalmologist’s black bag for treating ocular inflammatory disorders, there are certain caveats surrounding their use. Of all the systemic immunosuppressive agents, these alkylating drugs have the greatest potential for serious side effects, and thus should be reserved for sight-threatening or life-threatening disease. “Clinical experience indicates that the alkylating agents are the most potent but potentially the most toxic immunosuppressive drugs,” said Dr. Jabs.

These medications are sometimes selected to manage severe cases of uveitis, including Behçet’s disease, serpiginous choroiditis and sympathetic ophthalmia. Although chlorambucil has its proponents, many uveitis specialists believe that cyclophosphamide is a safer and easier drug to use. While chlorambucil may take three to four weeks before its effects are seen, cyclophosphamide works more quickly. Chlorambucil is used rarely, due in part to a theoretical risk of late cancer, particularly leukemia or lymphoma. The alkylating agents can also induce sterility, and thus may be inappropriate for patients of childbearing age.

A study published in Ophthalmology discussed 53 patients with severe sight-threatening uveitis who were treated with a specialized regimen of short-term, high-dose chlorambucil for an average of 16 weeks. After an average follow-up of four years, 77 percent of treated patients were in remission.²

“The risk of cancer can’t be ignored,” said Dr. Goldstein, lead author of the study. “We haven’t found any cases of cancer in our patients, but that’s not to say that they won’t develop cancer in 25 years. It is probable that the short-term aspect of the regimen reduces the malignancy risk. With the advent of newer agents like the biologic therapies, the need for alkylat-ing agents has declined.”

The New Biologics

In the world of immunosuppressives, biologic agents are the new kids on the block. A number of these targeted drugs are in development or are already on the market, and are capable of selectively blocking interleukin-2 (IL-2) or tumor necrosis factor (TNF).

“These biologic agents are extremely promising,” said Dr. Nussenblatt. “Not everything new, of course, is necessarily better, but these biologic agents have shown great specificity in their response.”

Front-runners. The most widely studied biologics are infliximab (Remicade) and daclizumab (Zenapax), although there have been no large randomized trials assessing any of the biologics in eye diseases. Even so, fairly small case series have suggested their efficacy in shutting down the inflammatory response in patients with severe or intermediate ocular inflammatory disorders. “We’ve had a few cases of patients with very recalcitrant scleritis, and treatment with TNF inhibitors appears to work in these individuals,” Dr. Nussenblatt said.

Infliximab, which is a chimeric human-murine antibody to TNF, has been FDA-approved since 1998 for the management of Crohn’s disease. A recently published study by researchers at the Rotterdam Eye Hospital evaluated 13 patients with serious sight-threatening uveitis who were treated with a 200 mg infliximab infusion; the treatment was repeated based on clinical response. The use of infliximab effectively suppressed ocular inflammation in all patients, and improved or stabilized visual acuity in most patients.³

Encouraging results have also emerged from studies of daclizumab, which is a humanized monoclonal antibody to the IL-2 receptor. At the Massachusetts Eye and Ear Infirmary, 14 patients with ophthalmologic inflammatory disorders were treated with daclizumab, improving visual acuity in 44 percent of treated eyes, and inflammation status in 59 percent. 4

Some inconvenience. Despite their promise, the biologic therapies like infliximab and daclizumab are more difficult to use than oral agents, requiring intravenous administration, typically every four to six weeks. In the future, other routes of administration may be available for the biologic therapies. In a multicenter study involving researchers at NEI, the University of Southern California and the Massachusetts Eye and Ear Infirmary, patients were given subcutaneous injections of daclizumab, with positive outcomes. “Patients could potentially give these injections to themselves at home,” said Dr. Nussenblatt. “That would be a great advantage.”

Any risks? In the early development of the biologics, some investigators felt that they would essentially have no side effects. But that hasn’t proven true with infliximab. “There’s the risk of developing a lupus-like syndrome with some of the TNF inhibitors,” said Dr. Goldstein. There is also the risk of exacerbating multiple sclerosis or tuberculosis infection.

Nevertheless, daclizumab appears to be safe, although the drug has only been used in a limited number of patients. “We have not seen side effects that can definitively be assigned to daclizumab itself, although relatively few patients have been treated thus far,” said Dr. Nussenblatt.

What Factors to Consider

So how should ophthalmologists decide which systemic immunosuppressive agent to prescribe? There are limited data indicating when one immunosuppressive medication should be selected over another. Most experts advise that each patient be evaluated individually in order to choose the best therapy for him or her. Factors such as patient history, disease severity and the location of the inflammation are considered.

Drug selection. Patients are different from each other, Dr. Nussenblatt emphasized, which means that side effects associated with a particular drug can vary from one person to another. “Some uveitis patients will take cyclosporine or mycophenolate with absolutely no problems at all, and others will have constant gastrointestinal symptoms,” he said. “So there’s some art to this, and you need to titrate dosage based on what the patient is telling you.”

Some ophthalmologists will start patients on an antimetabolite no matter what the specific inflammatory ocular disease is, because of the longer track record of drugs like methotrexate, as well as the ease of administration and the relatively low cost. According to Dr. Nussenblatt, younger patients may be candidates for the T-cell inhibitor cyclosporine and the antimetabolite mycophenolate. Other clinicians use mycophenolate in other age groups as well. Dr. Nussenblatt might prescribe methotrexate in patients who have retinal vasculature problems.

“I don’t like to use cyclosporine in older patients because the risk of hypertension associated with this drug can be very high,” said Dr. Goldstein. “In children, I’ll almost always use methotrexate first; there are plenty of data from the rheumatologic literature showing the safety of methotrexate in children.”

Concurrent pathology. An underlying disease can play a role in immunosuppressive drug selection. In a patient with liver failure, for example, many clinicians stay away from methotrexate and azathioprine. When kidney disease is present, cyclosporine may be avoided.

“There are some ocular diseases, such as Behçet’s disease, that have a high incidence of blindness,” said Dr. Goldstein. “While I wouldn’t go to a biologic first, I’d put it quite high on the list, and switch to a biologic very quickly.”

Cost. Economic factors may also be part of the decision-making process. Even though no systemic therapy is FDA-approved for uveitis, insurance companies are typically willing to provide reimbursement for relatively inexpensive drugs like methotrexate, whereas reimbursement for the expensive biologics in treating uveitis is rare.

Combination therapy? In patients with ocular inflammatory disorders, multiple systemic drug therapy is increasingly common, starting with a corticosteroid and then adding two immunosuppressive agents to the mix—perhaps cyclosporine plus azathioprine, methotrexate or mycophenolate.

“Patients with Behçet’s disease or ocular mucous membrane pemphigoid, for example, don’t do very well on prednisone alone,” said Dr. Jabs. “So they should be treated with immunosuppressive drugs from the outset. The same with scleritis associated with vasculitis. There are also emerging data suggesting that patients with birdshot retinochoroid- opathy may do better with immunosuppressive drugs from the outset.”

Nevertheless, some patients may be poor candidates for immunosuppressive agents. Since these drugs require blood tests to monitor toxicity, they should be prescribed for patients who are reliable enough to come in for testing, from every week to every few months, depending on the drug, according to Dr. Tessler.

The long term. Just as the goal is to taper and eventually withdraw patients from systemic corticosteroids, the same is true with the immunosuppressive agents, although this may be difficult in the real world. More realistically, the drug regimen should be fine-tuned to minimize the risk of toxicity. “That’s why the biologics may make such a big difference,” said Dr. Nussenblatt. “Patients may be able to take them for extended periods of time—over five years, in our experience with daclizumab. Even so, the best dose for any of these medications is none.”

______________________________
1 Am J Ophthalmol 2000;130(4):492–513.
2 Ophthalmology 2002;109:370–377.
3 Br J Ophthalmol 2005;38(5):533–536.
4 Ophthalmology 2003;110(4):786–789.

An Answer to Graft Rejection?
Although limbal stem cell transplantation is used to treat ocular surface disorders, it has remained a challenge. The leading reason for failure is graft rejection, prompting investigators to use systemic corticosteroids and immunosuppressive agents.

“In the early 1990s, we weren’t as aggressive with immunosuppression with these patients, and our success rates weren’t very good,” said Dr. Holland. “We didn’t begin seeing excellent success rates until we started to put patients on organ transplant immunosuppression protocols, which we’ve done now for the last 10 years.”

Dr. Holland’s own experience shows that about 75 percent of these patients have successful outcomes; in those without immunosuppression, the success rate has been less than 20 percent. “The field of ocular surface transplantation really wouldn’t be anywhere without systemic immunosuppression,” he said

Instead of using a very high dose of one medication, Dr. Holland has found that moderate doses of a triple-drug regimen are preferable, such as the common three-agent protocol of prednisone, mycophenolate and tacrolimus. “By using multiple medications, you can lower the dose of each and thus reduce the risk of side effects,” he said. “And in selecting a T-cell inhibitor, we’ve found that tacrolimus is better tolerated and a little more efficacious than cyclosporine.” Although some published case series indicate that only short-term use of these immunosuppressive drugs is needed, “in our experience, it’s a minimum of two to three years,” explained Dr. Holland. “The duration depends on the patient. Those with ocular cicatricial pemphigoid or Stevens-Johnson syndrome tend to be particularly challenging, with conjunctival inflammation that can persist. They require long-term—and in some cases, lifetime—immunosuppression.”


Managing Inflammation

The choice of drug or drug combination for ocular inflammation will vary with diagnosis. Most of the agents below can be given orally, but infliximab and daclizumab are intravenous formulations. (A recent study of daclizumab demonstrated efficacy with subcutaneous administration.1)

Corticosteroids
Prednisone
Prednisolone
Methylprednisolone

Antimetabolites
Azathioprine (Imuran)
Leflunomide (Arava)
Methotrexate (Rheumatrex)
Mycophenolate mofetil
(CellCept)
T-cell Inhibitors
Cyclosporine (Sandimmune, Neoral)
Tacrolimus (Prograf)

Alkylating Agents
Cyclophosphamide (Cytoxan)
Chlorambucil (Leukeran)



Biologics
(Inhibitors of Interleukin-2 or Tumor Necrosis Factor)
Infliximab (Remicade) Daclizumab (Zenapax)








1 Ophthalmology 2005;112(5):764–770.


MEET THE EXPERTS
Debra A. Goldstein, MD, associate professor of ophthalmology and director of the uveitis service at University of Illinois at Chicago. Financial interests: None.

Edward J. Holland, MD, professor of ophthalmology at the University of Cincinnati and director of cornea at the Cincinnati Eye Institute. Financial interests: None.

Douglas A. Jabs, MD, MBA, professor of ophthalmology and medicine at the Johns Hopkins University. Financial interests: None.

Robert B. Nussenblatt, MD, chief of the laboratory of immunology at the National Eye Institute. Financial interests: None.

Howard H. Tessler, MD, professor of ophthalmology at the University of Illinois at Chicago. Financial interests: None.

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