Other Immunosuppressant Drugs
Mycophenolate mofetil (CellCept)
acts by inhibiting a de novo pathway of purine synthesis in lymphocytes, leading to intracellular depletion of guanosine monophosphate. This results in the suppression of cytotoxic T cells and the formation of antibodies by activated B cells. A dose of 500 mg twice a day in 2 divided doses is well tolerated by patients and can be used to reduce the steroid dose (Panes J et al, 2007Panes J, Gomollon F, et al. Crohn's disease: a review of current treatment with a focus on biologics. Drugs. 2007;67(17):2511-37; Robinson M, 1997Robinson M. Optimizing therapy for inflammatory bowel disease. Am J Gastroenterol. Dec 1997;92(12 suppl):12S-17S).
The use of IL-10 ilodecakin resulted in a trend toward clinical improvement but not remission in chronic active Crohn disease, and IL-11 oprelvekin was found to be effective in inducing remission in a preliminary study in patients with mild to moderate Crohn disease (Panes J et al, 2007)Panes J, Gomollon F, et al. Crohn's disease: a review of current treatment with a focus on biologics. Drugs. 2007;67(17):2511-37.
The principal adverse reactions associated with the administration of Mycophenolate mofetil (CellCept) include diarrhea, leukopenia (- loss of white blood cells that can be fatal), sepsis (i.e. general bacterial infection involving the whole body which can also be fatal), vomiting, and there is evidence of a higher frequency of certain types of opportunistic infections. Other possible side effects include gastrointestinal bleeding, disorders of the nervous system, fetal harm in pregnant women. Lymphoproliferative disease or lymphoma (blood cancer) were developed in 0.4% to 1% of patients receiving CellCept (2 g or 3 g) with other immunosuppressive agents.
Tocilizumab (Actemra)
is a monoclonal antibody to the IL-6. The drug has been approved in 2010 by the FDA for the treatment of rheumatoid arthritis and had been approved before in Japan and Europe.
Tocilizumab has been approved for use in adults with moderate to severely active rheumatoid athritis who have not responded to one or more anti alpha TNF therapies.
It has been suggested to have a beneficial clinical effect in Crohn disease (Matsuyama M et al, 2007)Matsuyama M, Suzuki, et al. Anti-interleukin-6 receptor antibody (tocilizumab) treatment of multicentric Castleman's disease. Intern Med. 2007;46(11):771-4. as well as antibody to IL-12, which has been found to decrease the T helper-1 mediated inflammatory cytokines at the site of disease (Panes J et al, 2007Panes J, Gomollon F, et al. Crohn's disease: a review of current treatment with a focus on biologics. Drugs. 2007;67(17):2511-37; Mannon et al, 2004Mannon P. GAIN for loss: adalimumab for infliximab-refractory Crohn disease. Ann Intern Med. 2007 Jun 19;146(12):888-90).
It may be used as monotherapy or concomitantly with methotrexate or other DMARDs. It has not been studied, and should not be used, in combination with other biologic DMARDs because of the possibility of increased toxicity.
Natalizumab (Tysabri)
is a monotherapy for Crohn's disease and
should not be used concurrent with other immunosuppressants or TNF-alpha inhibitors. Due to its severe side effects,
prescribers must be registered in a particular program. For the same reason, it should only be used in moderate to severe cases of the disease and when other treatments were ineffective or could not be tolerated.
Natalizumab is a humanized monoclonal antibody against the cellular adhesion molecule alpha4-integrin. It reduces the ability of inflammatory immune cells to attach to and pass through the intestinal epithelial cells. In 2008, the FDA approved natalizumab for treatment of moderate-to-severe Crohns disease in patients with evidence of inflammation that have not responded well to, or are unable to tolerate, conventional Crohn's disease drug therapies. The ENACT-1 study has shown an increase in rates of remission and prevention of relapse in patients treated with natalizumab (Sandborn W et al, 2005)Sandborn W et al. Certolizumab pegol (CIMZIATM), a humanized anti-TNF PEGylated Fab' fragment, is safe and effective in the maintenance of response and remission following induction in active Crohn's disease: a Phase III study (PRECiSE). In the ENCORE trial natalizumab induced response and remission at week 8 that was sustained through week 12, demonstrating the early and sustained efficacy of natalizumab as induction therapy in patients with elevated C-reactive protein and active Crohn's disease (Targan SR et al, 2007)Targan SR, Feagan BG, et al. International Efficacy of Natalizumab in Crohn's Disease Response and Remission (ENCORE) Trial Group. Natalizumab for the treatment of active Crohn's disease: results of the ENCORE Trial. Gastroenterology. 2007 May;132(5):1672-83. Natalizumab is given by infusion. Because natalizumab carries some serious potential risks, patients who take this medication must enroll in a special program, called Crohn's Disease-Tysabri Outreach Unified Commitment to Health (CD-TOUCH) Prescribing Program that helps the FDA monitor side effects of the drug.
Natalizumab is indicated for inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn's disease with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF-α. TYSABRI should not be used in combination with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or inhibitors of TNF-α
Side effectsThe most serious side effect of Natalizumab or Tysabri® is increased risk for a rare neurological condition called progressive multifocal leukoencephalopathy (PML), which can lead to death or severe disability. Other serious side effects of natalizumab include allergic reactions, and increased susceptibility to infections including serious herpes infections. Natalizumab should not generally be used in patients who are currently taking immunosuppressant drugs. Natalizumab may also cause liver injury within a week of starting the drug. Other less serious side effects may include headache, fatigue, urinary tract infections, joint and limb pain, rash, and infusion reactions.
| Adverse Reactions (Preferred Term) | TYSABRI n=627 Percentage |
Placebo n=312 Percentage |
| General | ||
| Headache | 38% | 33% |
| Fatigue | 27% | 21% |
| Arthralgia | 19% | 14% |
| Chest discomfort | 5% | 3% |
| Acute hypersensitivity reactions** | 4% | < 1% |
| Other hypersensitivity reactions** | 5% | 2% |
| Seasonal allergy | 3% | 2% |
| Rigors | 3% | < 1% |
| Weight increased | 2% | < 1% |
| Weight decreased | 2% | < 1% |
| Infection | ||
| Urinary tract infection | 21% | 17% |
| Lower respiratory tract infection | 17% | 16% |
| Gastroenteritis | 11% | 9% |
| Vaginitis* | 10% | 6% |
| Tooth infections | 9% | 7% |
| Herpes | 8% | 7% |
| Tonsillitis | 7% | 5% |
| Psychiatric | ||
| Depression | 19% | 16% |
| Musculoskeletal/Connective Tissue Disorders | ||
| Pain in extremity | 16% | 14% |
| Muscle cramp | 5% | 3% |
| Joint swelling | 2% | 1% |
| Gastrointestinal | ||
| Abdominal discomfort | 11% | 10% |
| Diarrhea NOS | 10% | 9% |
| Abnormal liver function test | 5% | 4% |
| Skin | ||
| Rash | 12% | 9% |
| Dermatitis | 7% | 4% |
| Pruritus | 4% | 2% |
| Night sweats | 1% | 0% |
| Menstrual Disorders* | ||
| Irregular menstruation | 5% | 4% |
| Dysmenorrhea | 3% | < 1% |
| Amenorrhea | 2% | 1% |
| Ovarian cyst | 2% | < 1% |
| Neurologic Disorders | ||
| Somnolence | 2% | < 1% |
| Vertigo | 6% | 5% |
| Urinary incontinence | 4% | 3% |
| Urinary urgency/frequency | 9% | 7% |
| Injury | ||
| Limb injury NOS | 3% | 2% |
| Skin laceration | 2% | < 1% |
| Thermal burn | 1% | < 1% |
| *Percentage based on female patients only. | ||
Fontolizumab
is an antibody to IFN-gamma that has provided significantly better clinical response rates and remission than placebo. The effect was most prominent in patients with objective evidence of inflammation as defined by elevated CRP (Hommes D et al, 2006Hommes DW, Mikhajlova TL, et al. Fontolizumab, a humanised anti-interferon gamma antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn's disease. Gut. 2006 Aug;55(8):1131-7.; Reinisch W et al, 2010Reinisch W, de Villiers W, et al. Fontolizumab in moderate to severe Crohn's disease: a phase 2, randomized, double-blind, placebo-controlled, multiple-dose study. Inflamm Bowel Dis. 2010 Feb;16(2):233-42).