Combination Immunosuppressive Therapies: Title and subTitle BreakThe Promise and the Peril

In recent years, enormous progress has been made in our understanding of the immune system's role in the pathogenesis of immunologically mediated disorders, including psoriasis and psoriatic arthritis, rheumatoid arthritis (RA), multiple sclerosis, Crohn's disease, and ankylosing spondylitis. Many broad-based, nonspecific immunosuppressive agents such as glucocorticoids, methotrexate, mycophenolate mofetil, 6-mercaptopurine, azathioprine, cyclosporine, and cyclophosphamide have been used to treat these disorders, but their use may be limited by toxic effects.

As more has been learned about molecular pathways that regulate the development of immunologically mediated diseases, targeted immunotherapeutic agents (TIs), also known as biological agents, have been developed that are directed against specific elements of those pathways, allowing us more effectively to treat these diseases. By targeting specific elements of the immune system, TIs may prove to be more effective and less toxic therapeutic options than the nonspecific immunosuppressive agents. In the present review, we focus our attention on TIs being used in combination with other TIs or nonspecific immunosuppressive agents and discuss the promise and the peril of combination therapy.

Targeted immunotherapeutic agents have been used successfully as combination therapy to treat several diseases. For the treatment of RA, the combination of tumor necrosis factor (TNF) inhibitors (etanercept, infliximab, and adalimumab) with nonspecific immunosuppressive agents, including methotrexate and other disease-modifying antirheumatic drugs (DMARDs), is superior to monotherapy with nonspecific immunosuppressive agents.^{1 - 3} Patients with RA have been treated with infliximab in combination with cyclosporine in a small trial (n = 18)⁴ and in combination with azathioprine or leflunomide in a retrospective analysis (n = 225)⁵ with good efficacy and minimal toxic effects. The addition of azathioprine or 6-mercaptopurine to the infliximab regimen is more effective than azathioprine or 6-mercaptopurine alone for the treatment of corticosteroid-dependent Crohn's disease.⁶ Furthermore, when infliximab was used to treat Crohn's disease, the addition of the immunosuppressive agent methotrexate, azathioprine, or 6-mercaptopurine reduced the formation of infliximab antibodies, which play an etiologic role in infliximab infusion reactions.⁷

Much of the data from the rheumatology and gastroenterology literature suggest that TIs can often be used safely and effectively in combination therapy. In fact, the US Food and Drug Administration has approved infliximab and etanercept in combination with methotrexate for the treatment of RA. The excellent clinical results that have been obtained using TIs have led many physicians to use them as the first-line approach in many patients, and for patients with the most severe disease, the combination of TIs with nonspecific immunosuppressive agents is becoming more common.

The success of TIs as monotherapy and combined with nonspecific immunosuppressive agents has prompted further exploration of synergistic efficacy when TIs are used in combination. A great deal of excitement has been generated by the success of combination therapy and the hope it may hold for major disease control or perhaps even a cure. However, certain TIs used in combination with each other or with certain nonspecific immunosuppressive agents cause serious adverse effects, including severe infections and malignancies. Herein, we examine several examples that illustrate the potential perils of using TIs in combination therapy (Table 1).

The first example of combination therapy leading to increased infections occurred when etanercept and anakinra, an interleukin 1 receptor antagonist, were evaluated for potential synergistic efficacy in patients with RA.⁸ In this study, the quality of evidence was high (I) (Table 2). A total of 244 patients with RA were randomly assigned to 1 of 3 treatment groups: (1) 25 mg of etanercept twice weekly (full dose) plus placebo; (2) 25 mg of etanercept once weekly (half dose) plus 100 mg of anakinra daily; or (3) 25 mg of etanercept twice weekly (full dose) plus 100 mg of anakinra daily. Patients continued taking stable doses of methotrexate and corticosteroids. While no patients in the etanercept-only group developed serious infections, those who received combination etanercept and anakinra had a marked increase in serious infections: 3.7% of the patients in the combination group with half-dose etanercept and 7.4% in the combination group with full-dose etanercept developed serious infections. These serious infections included pneumonia and cellulitis (3 patients each), herpes zoster (1 patient), pneumonitis (1 patient), and pyelonephritis (1 patient).⁸

Abatacept, a fusion protein that binds to the CD80 and CD86 ligands present on antigen-presenting cells, was recently studied in combination with other therapies for the treatment of RA (quality of evidence, I).⁹ In a randomized controlled trial of 1441 participants, patients were randomized to 4 treatment groups: (1) abatacept (10 mg/kg) and DMARDs; (2) abatacept (10 mg/kg) and TIs; (3) placebo and DMARDs; and (4) placebo and TIs. The TIs included etanercept, infliximab, adalimumab, or anakinra. Some patients were treated with concurrent DMARDs, including methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, gold, and azathioprine. Overall, the abatacept and placebo groups had similar incidences of adverse events, but patients receiving abatacept in combination with other TIs had more than twice the rate of serious infections (defined as fatal or life-threatening, resulting in hospitalization or persistent or significant disability or incapacity, or deemed a significant medical event by the investigator) when compared with other treatment groups. Another trial evaluated the safety and efficacy of low-dose abatacept (2 mg/kg) given in combination with 25 mg of etanercept twice weekly (quality of evidence, I).¹⁰ In the 121 patients enrolled in this study, there were increased rates of serious infections in the patients who received low-dose abatacept in combination with etanercept when compared with placebo.

Another example of combination therapy leading to increased infection occurred when natalizumab, a humanized monoclonal antibody directed against the α₄ integrin, was added to interferon β for the treatment of multiple sclerosis. Two patients^{11 - 12} in this clinical trial developed (and 1 ultimately died from) confirmed progressive multifocal leukoencephalopathy (PML), a rare, often fatal, demyelinating disease usually found in immunocompromised patients and caused by the JC virus (quality of evidence, IV).^{11 - 12} No cases of PML have been reported in patients receiving interferon β monotherapy, but PML has been reported in a patient receiving natalizumab monotherapy for Crohn's disease.¹⁶

Combination therapy with TIs has also been associated with the development of malignancies. The Wegener's Granulomatosis Etanercept Trial Research Group¹³ evaluated twice-weekly 25-mg etanercept doses vs placebo when added to standard therapy for Wegener’s granulomatosis, which included cyclophosphamide and glucocorticoids for patients with severe disease or methotrexate and glucocorticoids for patients with limited disease (quality of evidence, I). The rate of sustained remissions and the total number of adverse events were not significantly different between the placebo and etanercept groups. However, 6 solid cancers (2 cases of mucinous adenocarcinoma of the colon, 1 cholangiocarcinoma, 1 renal cell carcinoma, 1 breast carcinoma, and 1 liposarcoma) developed in the combination etanercept and cyclophosphamide group compared with none in the control groups. These findings demonstrate a 3-fold increase in relative risk for malignancy in the group who received combination etanercept and cyclophosphamide compared with the control group who received placebo and cyclophosphamide.

Two different malignancies were recently associated with combination therapy when infliximab was added to either azathioprine or 6-mercaptopurine to treat Crohn's disease. Azathioprine is converted to 6-mercaptopurine after oral ingestion, and the active metabolite works by blocking lymphocyte proliferation. In the first report, Chen et al¹⁴ reported the development of hepatocellular carcinoma occurring in a patient treated with combination infliximab and azathioprine who had no identifiable risk factors for liver disease (quality of evidence, IV).¹⁴ Hepatocellular carcinoma has been reported in patients with Crohn's disease treated with either azathioprine alone or in combination with corticosteroids. In a second report, Thayu et al¹⁵ described a patient with Crohn's disease treated with 6-mercaptopurine who had infliximab added to her therapeutic regimen owing to continued disease progression. After 27 months on combination 6-mercaptopurine and infliximab, the patient was diagnosed as having and subsequently died from hepatosplenic T-cell lymphoma, a rare, aggressive peripheral T-cell lymphoma (quality of evidence, IV). Previous cases of hepatosplenic T-cell lymphoma have also occurred in immunocompromised patients after organ transplantation and in a patient with Crohn's disease treated with azathioprine and corticosteroids.^{17 - 18} According to the manufacturer of infliximab (Centocor, Horsham, Pennsylvania; written communcation, May 2006), there have been 10 other cases of hepatosplenic T-cell lymphoma occurring in adolescents and young adults with Crohn's disease or indeterminate colitis who were treated with combination infliximab and azathioprine or 6-mercaptopurine.

Dermatologists care for many patients who require treatment with immunosuppressive agents. To date, the TIs have been studied most extensively in the treatment of psoriasis, but dermatologists have begun to use these agents to treat patients with other skin diseases, including alopecia areata, atopic dermatitis, hidradenitis suppurativa, and lichen planus, among others.^{19 - 22}

Even before the advent of TIs, combination therapy was a treatment strategy frequently used by dermatologists because of its potential to increase efficacy while limiting toxic effects. Topical therapies are often combined with UV light and systemic therapies, including TIs, with the goal of optimizing efficacy without adding significant toxic effects.²³ Methotrexate and cyclosporine are each effective as monotherapy for psoriasis, but their use may be limited by toxic effects. One series of patients with psoriasis (n = 19) demonstrated that combination therapy with methotrexate and cyclosporine was efficacious using lower doses of both agents than might have been used in monotherapy (mean ± SD doses, methotrexate 13.9 ± 4.4 mg/wk; cyclosporine, 2.6 ± 0.9 mg/d).²⁴ Six patients undergoing long-term therapy (mean duration, 193 weeks) developed mild renal impairment, which improved with the reduction in cyclosporine dose. The combination of UV light with methotrexate has also been shown to be efficacious and well tolerated.²⁵

Until now, to our knowledge, clinical trials evaluating TIs as psoriasis treatment have excluded the use of concurrent therapies, including immunosuppressive agents. However, dermatologists have started to use combination regimens that include TIs, and several case reports have suggested that these combinations are safe and effective for the treatment of psoriasis. It is important to note, however, that these reports all involve a small number of patients and do not provide conclusive evidence.

Since acitretin alters cell differentiation without any immunosuppressive effects, it is presumably the safest agent to combine with TIs. Conley et al²⁶ evaluated the combination of acitretin with TIs in the treatment of 8 patients with psoriasis. All patients (6 treated with etanercept, 1 with adalimumab, and 1 with alefacept, each in combination with acitretin) had significant improvement in their psoriasis, and the combination therapy was well tolerated. Another series of 6 patients evaluated etanercept in combination with either methotrexate, cyclosporine, calcipotriene cream and ointment, acitretin and hydroxyurea (another nonspecific immunosuppressive agent), or weekly UV-B and every-other-day acitretin. All 6 patients showed significant improvement without any toxic effects.²⁷ The combination treatments of UV light with alefacept (n = 60)²⁸ or etanercept (n = 86) (data not shown) have both been shown to be effective and without any added toxic effects.

Combination alefacept and methotrexate (n = 185) was somewhat beneficial for the treatment of psoriatic arthritis and was without any added toxic effects,²⁹ while efalizumab when added to methotrexate (n = 107) revealed no added benefit for the treatment of psoriatic arthritis, and combination therapy revealed no added toxic effects.³⁰ Nonspecific immunosuppressants have also been used in combination with TIs as transitional agents. This approach was used in 8 patients with severe psoriasis undergoing cyclosporine treatment for an average of 8 weeks followed by the addition of etanercept with subsequent tapering of cyclosporine over a 4- to 6-month period.³¹ The combination of etanercept and cyclosporine was well tolerated without any added toxic effects. Additionally, methotrexate and cyclosporine may be added to efalizumab therapy as short-term transitional agents in the treatment of efalizumab-associated flares.³²

In the first reported case series to our knowledge of combination therapy with 2 different TIs for psoriasis and psoriatic arthritis, Krell³³ described 3 patients who were treated with combined etanercept and alefacept. In all 3 patients, etanercept therapy improved the psoriatic arthritis but did not adequately improve the psoriasis. A 12-week course of alefacept was then added to the etanercept, which significantly improved the psoriasis in all 3 patients. No adverse events were observed in any of the patients.

While previous studies have suggested that some TIs can be safely used in combination with certain nonspecific immunosuppressive agents, the 6 examples we have discussed demonstrate a possible increased risk with certain combination therapies (Table 1). In evaluating these data and applying the findings to the management of dermatologic disorders, several points must be considered.

While 3 of the 6 examples derive from randomized, placebo-controlled trials that yield the most convincing levels of evidence, the other 3 derive from case reports that provide the least convincing level of evidence. Three examples describe combinations of TIs with cyclophosphamide, 6-mercaptopurine, or azathioprine. These 3 are the most potent of the nonspecific immunosuppressive agents, and therefore, combining any of these agents with a TI may pose a higher risk of toxic effects. In addition, the observations that both low-dose abatacept combined with etanercept and half-dose etanercept combined with anakinra led to an increased risk of serious infections do not support the concept that combining TIs at lowered dosages will mitigate toxic effects.^{8 ,10}

Five of the 6 examples of toxic effects associated with combination therapy occurred in patients taking TNF antagonists. This observation may be secondary to an overall higher usage of TNF inhibitors. Another potential explanation for this observation may be that TNF inhibitors are more potent immunosuppressive agents than T-cell blocking agents, although controlled studies verifying this suggestion are lacking.

Short-term data suggest that the combination of methotrexate, and to a lesser extent cyclosporine, with TIs appears to be safe and efficacious in the treatment of psoriasis. Indeed, when transitioning patients with psoriasis from these therapies to a TI, a period of overlap may be used so that the methotrexate or cyclosporine is tapered and then discontinued while the TI is being initiated.³⁴

Dermatologists have begun to use TIs in novel combinations. However, the rare and dangerous infections and malignancies encountered in several other diseases are worrisome and should raise concern regarding the use of combination therapy in the treatment of patients with psoriasis. Targeting individual components of the immune system to redirect critical pathways has proven to be an elegant therapeutic approach that is usually, but not always,³⁵ safe and effective. Owing to the complexities of the immune system, it can be very difficult to predict outcomes when combining more than one TI. Combination therapies that include TIs given along with other TIs or with nonspecific immunosuppressive agents for dermatologic diseases may eventually be supported by the results of controlled clinical trials. However, the details by which TIs can be used safely in combination will not be known until such trials are complete. Therefore, dermatologists should exercise caution when treating patients with TI combination therapy.

Correspondence: Neil J. Korman, MD, PhD, University Hospitals Case Medical Center, Murdough Family Center for Psoriasis, 11100 Euclid Ave, Cleveland, OH 44106 (njk2@po.cwru.edu).

Financial Disclosure: Drs Korman and Robinson have worked as investigators for clinical trials sponsored by Abbott, Amgen, Biogen Idec, Centocor, and Genentech. Dr Korman is also a member of the speakers bureau for Amgen, Abbott, and Genentech and is also an advisory board member for Genentech.

Accepted for Publication: February 3, 2007.

Author Contributions:Study concept and design: Robinson, B. Korman, and N. Korman. Acquisition of data: B. Korman and N. Korman. Analysis and interpretation of data: Robinson, B. Korman, and N. Korman. Drafting of the manuscript: Robinson. Critical revision of the manuscript for important intellectual content: B. Korman and N. Korman. Study supervision: N. Korman.