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Infliximab is currently being studied in several diseases. Clinical trials have returned positive results using infliximab in rheumatic disorders such as ankylosing spondylitis and adult Still disease. TNF-α blockade is being studied in uveitis, myelodysplastic syndromes, and graft-versus-host disease. There is some research looking at sepsis and septic shock, though with more limited success.

In the first study reported in this Journal Club, infliximab plus methotrexate proved valuable in treating the signs and symptoms of rheumatoid arthritis (RA), as well as halting the progression of joint damage that occurs as this disease progresses. The ATTRACT trial (Anti-TNF-α Trial in Rheumatoid Arthritis with Concomitant Therapy¹) showed significant improvement of the participants with RA that received infliximab plus methotrexate as opposed to methotrexate alone.

To recap this study, 428 participants who had previously failed to control their RA despite treatment with methotrexate therapy were enrolled to receive one of two doses of infliximab plus methotrexate at one of two different intervals (every four weeks or every eight weeks) for a total of 102 weeks (54 week trial with follow-up through week 102). This study evaluated three main outcomes. First, participants were able to control symptoms of their RA with this therapy. Second, joint damage was halted when using this therapy. Third, physical functionality improved as measured quantitatively and as perceived by the participants. Differences between the infliximab plus methotrexate groups and the methotrexate-alone group in these three key areas were significant, and side-effects were about the same. Reimold summarized by noting that this large and long study showed the effectiveness of infliximab on reducing the signs and symptoms of RA, as well as providing new information on the ability to halt and possibly reverse the progression of joint damage that results.

The efficacy of infliximab in Crohn’s disease is well-documented. Crohn’s disease is an inflammatory bowel disease with cell damage caused by cytokines such as TNF-α. The initial stimulus for this immune response is unknown, but infliximab is known to reduce the intestinal TNF-α as well as reset the cytokine balance. Two randomized, multicenter, double-blinded, placebo-controlled trials demonstrated the efficacy of infliximab in Crohn’s disease.

The first study involved 108 participants with moderate to severe Crohn’s disease. Participants were given either infliximab in varying doses, or placebo. Disease status was measured using the Crohn’s Disease Activity Index (CDAI) taken at four weeks of therapy. For this trial a response to therapy was defined as an improvement of at least 70 points. In the infliximab groups 65% of participants achieved a response, while only 17% of the placebo group did so. Remission of their disease (defined as a CDAI score of <150) was achieved by a third of the infliximab groups versus 4% of the placebo group. During subsequent weeks the participants who continued to get infliximab showed a maintenance effect (62%) versus the placebo group which showed a gradual loss of response (37%). At eight weeks after the last infusion, 52.9% of the infliximab groups were still in remission compared to only 20.0 % of the placebo group.

A different study addressed the treatment of fistulas in Crohn’s disease. This randomized, double-blinded, placebo-controlled, multicenter trial involved 94 participants receiving either infliximab or placebo. After 18 weeks of follow-up, complete closure of their fistulas was achieved by 46% of the infliximab group versus 13% of the placebo group.

In a larger randomized, placebo-controlled trial, participants with Crohn’s disease were assessed as to whether repeated dosing of infliximab was of benefit. In this trial, participants who had responded to an initial dose of infliximab were given follow-up doses of either infliximab or placebo at two, six, and then every eight weeks. The infliximab groups more frequently remained in remission (and were able to discontinue steroids) while the placebo group did not, as measured at weeks 30 and 54.

Adult Still disease, a systemic form of chronic arthritis that occurs in adults, is typically treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. Infliximab has been used in two small studies with some success suggesting that further investigation is warranted. The first results were of two cases of patients with refractory Still disease. Infliximab was given initially, then at two and six weeks, then every eight weeks thereafter. Patients improved with the first infusion with respect to rash, fever, articular manifestations, and laboratory measurements. The second report discussed the treatment of six patients with severe Still disease. Patients were given 3-5 mg/kg of infliximab and noted improvements in fever and rash, joint damage progression, myalgias, splenomegaly, and serologic abnormalities. Reimold concluded by noting that these limited, small studies may indicate that TNF-α should be more fully investigated as a therapy in adult Still’s disease where initial NSAID therapy has failed.

Ankylosing spondylitis (AS) is a form of spinal arthritis that affects young people between the ages of 17 and 35. The cause is unknown, and the results of the disease can be severe with other areas affected, such as hip and shoulder joints, eyes, heart, and lungs. In some severe cases the spine can fuse permanently so that the afflicted person has a forward-stooped posture. Infliximab has been studied in AS with good results. The rationale behind this off label use in this spondylarthropathy is based on the assumption that TNF-α plays a major inflammatory role in the affected synovium and skin lesions of patients with AS. It is also known that spondylarthropathies are associated with chronic inflammatory bowel disease. Because the gut is responsible for strongly expressing TNF-α in this disease, infliximab, acting as an anti-TNF-α agent may be of benefit—similar to the benefit in the treatment of Crohn’s disease.

Two studies have been conducted with positive results. The first involved enrolling 70 participants with AS pain that caused functional limitations. In this double-blinded, placebo-controlled, multicenter trial infliximab at 5mg/kg or placebo was given at baseline, then again at week two and six. All participants had active disease, had only received prior NSAID therapy, and were observed for 12 weeks from baseline. Infliximab performed well in this population. More than half of the infliximab group achieved a 50 % improvement in the Bath AS disease activity index, which measures the severity of fatigue, spinal pain, joint pain and swelling, tenderness, morning stiffness and its duration. Other tests were used to identify specific quality of life issues. Only 9% of the placebo group achieved some improvement.

In another study, 40 participants with various spondylarthropathies were enrolled in a randomized, placebo-controlled study lasting 12 weeks. Infliximab or placebo was given at baseline, then again at weeks two and six. Infliximab was judged significantly superior to placebo as measured by participant and physician global assessment surveys, laboratory values, and spinal and peripheral arthritis.

These trials demonstrate that there is a benefit to infliximab in spondylarthropathies that should be explored in longer-term trials. Infliximab produced a rapid, significant and sustained effect in this population. Long-term outcomes as well as precise dosing and interval guidelines are not yet available.

In patients with elevated TNF-α levels, infliximab has been shown to be an effective mediator of inflammatory process and damage. Patients with psoriasis have elevated levels of TNF-α in their synovial fluid and tissues and in psoriatic skin lesions. While rheumatoid arthritis is distinguishable from psoriatic arthritis when looking back at the patient’s history of skin disease and the presence of joint involvement, similarities exist in the small joints, the inflammation and joint destruction of the arthritis, and the presence of TNF-α.

Concentrating on psoriasis, trials have been undertaken to determine the effectiveness of infliximab in psoriatic skin disease. One trial involved using two doses of infliximab in two groups of patients (n=33) with plaque-type psoriasis in a double-blinded, randomized design. Participants were infused at baseline, week two and again at week six, with an analysis of the participant performed at week ten. This final assessment included a global assessment by the physician, measurements taken according to the National Psoriasis Foundation psoriasis score (NPF-PS), the Psoriasis Area and Severity Index (PASI), as well as biopsies of normal and affected skin. Infliximab at the lower dose (5mg/kg) yielded response in 9 of 11, while the higher dose (10mg/kg) resulted in response in 10 of 11. The placebo group responded in only 2 of the 11 participants. PASI scores were improved by at least 75% in 9 participants in the first group, 8 participants in the second group, and 2 of the placebo group. The infliximab groups were the only ones to show improvement in the biopsies. CD3+ cells were significantly decreased and overall skin thickness was reduced in the infliximab groups. This study demonstrated that infliximab can reduce skin lesions in patients with plaque-type psoriasis.

Uveitis is characterized by an inflammation of the inner eye tissue that can lead to irritation, pain, and loss of vision. Uveitis is usually associated with systemic inflammatory diseases due to the nature of the inflammation. Diseases such as Behcet syndrome, juvenile chronic arthritis, sardcoidosis, and spondylarthropathy have all been linked to uveitis. Infliximab’s properties as an anti-inflammatory agent can have an impact on uveitis and the associated systemic disease due to its TNF-α-blocking characteristics.

Infliximab has been studied in uveitis with the underlying systemic disorder juvenile idiopathic arthritis. In one case series study eight children with uveitis and juvenile idiopathic arthritis were treated with infliximab every four to six weeks for six months. The previous treatments included at least topical steroids and methotrexate. Six of the children had also been treated with oral steroids and cyclosporin. Differences were seen according to frequency of treatment with the six children treated monthly experiencing reduced eye cellularity. The two children who were treated every six weeks did not experience the same benefits. The researchers concluded that monthly dosing provided better response in these children.

An open label trial of infliximab monotherapy resulted in complete resolution of uveitis in six of seven patients enrolled. After one year a follow up noted that there were relapses in three of the seven patients. Further infliximab therapy was not explored for these three patients.

Infliximab has been explored in several small open and uncontrolled trials with some promise of benefit. Inflammation responded to infliximab therapy within 24 hours with complete remission within seven days in five patients receiving a single dose at the onset of panuveitis. Improvement in vitreous haze was seen in seven patients at month four after receiving three treatments of infliximab (baseline, week two, and week six).

Reimold notes that infliximab is a beneficial therapy in the treatment of uveitis associated with rheumatic and other inflammatory diseases. However, all studies to date have been small, uncontrolled trials or case reports. Larger, controlled studies are needed to validate these findings. There is a larger, controlled study underway being conducted by the National Institutes of Health studying anti-TNF-α therapy in uveitis.

Graft-versus-host-disease (GVHD) is a chronic complication of hematopoietic stem cell transplantation that occurs in nearly 50% of patients that receive an allogeneic graft. GVHD in bone marrow transplant occurs when bone marrow from the donor is injected into the recipient and the donor’s T-cells recognize the recipient’s body as being foreign. Two forms of GVHD exist: early and late/chronic. Early GVHD, as the name suggests, occurs immediately after the transplant when white cell levels rise. Late or chronic GVHD occurs two to three months post transplant and is characterized by skin and mouth problems.

It has been thought that TNF-α has detrimental effects in all three phases of GVHD. Phase I is the conditioning regimen where the body receives cyclophosphamide or whole body radiation, damaging the intestinal mucosa and the liver. This causes a typical host response of inflammatory cytokines and TNF-α and IL-1, leading to increased T-cell reactivity. The second phase is cytokine-activated antigen presenting cells that interact with T-cells. The result is a proliferation of lymphocytes. The third phase is characterized by lymphocytes and monocytes facilitating cytotoxic T-cell lysis that generates more IL-1 and TNF-α, leading to more tissue damage.

Standard treatments for GVHD include high-doses of corticosteroids; steroid-resistant disease has a poor prognosis. Recent studies have shown benefit to the use of infliximab in GVHD, including patients with previous steroid resistance. In one recent study of patients in phase three, 32 participants with acute GVHD were given 10mg/kg infliximab. Nineteen participants were complete responders and 5 were partial responders. 19 of these partially or fully responding participants had been steroid-resistant. In another trial, 13 patients with gastrointestinal involvement and diarrhea showed complete response and resolution of diarrhea with infliximab. Based on these promising findings, a multicenter, randomized trial is currently underway.

Current literature describes TNF-α blockers as a salvage procedure, infliximab’s usefulness may be seen in earlier phases of GVHD if response can be demonstrated in phases one and two. This approach awaits further trials.

Sepsis elicits an immune response characterized by systemic inflammation and coagulation. Sepsis can manifest itself in several ways, from a systemic inflammatory response or organ dysfunction, to multiple organ failure. In this review, Reimold found that current literature did not demonstrate a significant reduction in mortality with the use of TNF-α blockers. In one group, a non-significant advantage was seen in the first three days of therapy using a murine mAb to recombinant human TNF-α, but when evaluated at 28 days, no significant difference was seen from the placebo group. Other trials were conducted with similar survival results. Reimold concluded that anti-TNF-α therapy had not had a significant impact on survival in septic patients. While improvements have been documented in certain subgroups such as patients with very high levels of IL-6 and those with early septic shock, more study is necessary to validate these findings.

Infliximab’s anti-inflammatory capabilities have been demonstrated to have promising benefits in treating inflammatory diseases such as RA and Crohn’s disease (even in refractory disease). Though infliximab is an FDA-approved therapy for these diseases, patients with other diseases may benefit as well. Reimold examined literature from several other diseases that showed a benefit to this drug’s use: adult Still's disease, ankylosing spondylitis, psoriasis, and uveitis. In general, benefits from infliximab therapy were demonstrated with minimal side effects. The adverse effects profile was more acceptable than with other therapies such as corticosteroids. In Reimold’s discussion of potential side-effects of infliximab therapy he points out that more trials are necessary to find the mechanism of action in several disease states to help explain why certain side-effects occur. Continued work to find new and optimal ways to use infliximab in inflammatory disease should prove valuable to patients with a variety of inflammatory conditions.