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A third approach is an attempt to reduce autoantibodies with immunomodulating drugs. Immunotherapies either amplify an immune response or reduce or suppress the immune system. There are several immunomodulating drugs that have been prescribed for SPS, but they are not without risk.
1. Dalakas MC. B cells as therapeutic targets in autoimmune neurological disorders. Nat Clin Pract Neurol. 2008 Oct;4(10):557-67. doi: 10.1038/ncpneuro0901. Epub 2008 Sep 23. Link to article
1. Azathioprine, Azasan, Imuran, Azamun, Imurel
Azathioprine belongs to the chemical class of purine analogues. It has been widely used as an immunosuppressant for more than 50 years. Azathioprine most strongly affects proliferating cells, such as the T cells and B cells of the immune system. The main adverse effect of azathioprine is bone marrow suppression, which can be life-threatening, especially in people with a genetic deficiency of the enzyme thiopurine S-methyltransferase. It is also listed by the International Agency for Research on Cancer as a Group 1 carcinogen (carcinogenic to humans). Azathioprine is sometimes used in systemic lupus erythematosus patients who require a maintenance dose of 15 mg or higher of prednisone and those who experience recurrent flares. It is used as an adjuvant in the oral steroid therapy of pemphigus and myasthenia gravis, as a "steroid-sparing" agent for reducing the dose of corticosteroids. It was widely used for the treatment of multiple sclerosis until the first half of the 1990s. Concerns about increased risk of malignancy has led to a decreased use, yet it is still used in maintenance treatment for patients who frequently relapse. Drugs.com
Cyclophosphemide is used to treat cancers and autoimmune disorders. As a prodrug, it is converted in the liver to active forms that have chemotherapeutic activity. Cyclophosphamide has severe and life-threatening adverse effects, including acute myeloid leukemia, bladder cancer, hemorrhagic cystitis, and permanent infertility, especially at higher doses. For autoimmune diseases, doctors often substitute less-toxic methotrexate or azathioprine after an acute crisis. Drugs.com
3. Cyclosporine, Ciclosporine, Cyclosporin, CsA, Neurostat, Sandimmune
Cyclosporine is an immunosuppressant drug widely used in organ transplantation to prevent rejection. It reduces the activity of the immune system by interfering with the activity and growth of T cells. Drugs.com
4. Mycophenolate mofetil, CellCept
CellCept is an immunosuppressant and prodrug of mycophenolic acid, used extensively in transplant medicine. It is also used in the treatment of autoimmune diseases, such as Behçet's disease, pemphigus vulgaris and lupus. Suppressing T cells and B cells stops them from attacking healthy cells, but also weakens their ability to defend against infections. Among the most common side-effects of this drug are high blood sugars and increased blood cholesterol levels. Other changes in blood chemistry such as hypomagnesemia, hypocalcemia, hyperkalemia, and an increase in BUN are regularly noted. Other serious side effects may occur. Drugs.com.
1. Rossi S, Ulivelli M, Malentacchi M, et al. Effects of immunotherapy on motor cortex excitability in Stiff Person Syndrome. J Neurol. 2010 Feb;257(2):281-5. doi: 10.1007/s00415-009-5331-z. Epub 2009 Oct 10. Link to article
5. Rituximab, Rituxin, MabThera
Rituximab is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of immune system B cells (this should not be confused with pancreatic β- or beta cells). Rituximab destroys B cells and is therefore used to treat diseases which are characterized by excessive numbers of B cells, overactive B cells, or dysfunctional B cells. This includes many lymphomas, leukemias, transplant rejection, and autoimmune disorders. Rituximab was recently shown to give symptomatic and serological remission in patients with otherwise refractory SPS. Rituximab is widely used off-label to treat difficult cases of multiple sclerosis, systemic lupus erythematosus, and autoimmune anemias. The most dangerous, although among the most rare, side effect is progressive multifocal leukoencephalopathy (PML) infection, which is usually fatal. However, only a very small number of cases have been recorded occurring in autoimmune diseases. A subset of the plasma cells become long-lived forming the humoral memory of the human immune system, which may persist over decades. Since plasma cells do not express the B cell surface marker CD20 they are not removed by treatment with monoclonal antibodies like rituximab, which is depleting all CD20+ B cells through mechanisms including antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and apoptosis. B cell depletion has little effects on the long-term humoral memory against these antigens. Drugs.com
1. Fekete R, Jankovic J. Childhood Stiff-Person Syndrome Improved with Rituximab. Case Report. Neurol. 2012;4(20):92-96. doi: 10.1159/000339446 Link to article
2. Rommer PS, Patejdl R, Zettl UK. Monoclonal antibodies in the treatment of neuroimmunological diseases. Curr Pharm Des. 2012;18(29):4498-507. Review. Link to article
3. Amato AA. Stiff person syndrome and rituximab. Muscle Nerve. 2012 Oct;46(4):612; author reply 612-3. doi: 10.1002/mus.23486.
4. Bacorro EA, Tehrani R. Stiff-person syndrome: persistent elevation of glutamic acid decarboxylase antibodies despite successful treatment with rituximab. J Clin Rheumatol. 2010 Aug;16(5):237-9. doi: 10.1097/RHU.0b013e3181e931fa.
“The baclofen was discontinued and the diazepam was tapered. However, 6 months after the rituximab treatment, despite continued clinical improvement, the patient had persistently elevated titers of antibody to glutamic acid decarboxylase. We postulate that rituximab was associated with clinical improvement through mechanisms other than antibody depletion.”
5. Baker MR, Das M, Isaacs J, Fawcett PR, Bates D. Treatment of stiff person syndrome with rituximab. J Neurol Neurosurg Psychiatry. 2005 Jul;76(7):999-1001. Link to article
“Treatment with rituximab induced a lasting clinical remission.”
6. Dupond JL, Essalmi L, Gil H, et al. Rituximab treatment of stiff-person syndrome in a patient with thymoma, diabetes mellitus, and autoimmune thyroiditis. J Clin Neurosci 2010;17:389. Link to article
“The patient experienced a partial improvement following a thymectomy and the administration of prednisone, intravenous immunoglobulins and mycophenolate mofetil. Treatment with rituximab was followed by a complete sustained remission and the disappearance of serum anti-amphiphysin antibodies.”
7. Ibrahim H, Dimachkie MM, Shaibani A. A review: the use of rituximab in neuromuscular diseases. J Clin Neuromuscul Dis. 2010 Dec;12(2):91-102. doi: 10.1097/CND.0b013e3181ff49f3. Review.
“Among these agents, rituximab has shown promise in some of the neuromuscular disorders with minimal side effects. Rituximab is a genetically engineered antibody that depletes CD20+ B-cells and is Food and Drug Administration- approved for treatment of non-Hodgkin lymphoma, CD20+ CLL, and rheumatoid arthritis.”
8. Katoh N, Matsuda M, Ishii W, Morita H, Ikeda S. Successful treatment with rituximab in a patient with stiff-person syndrome complicated by dysthyroid ophthalmopathy. Intern Med. 2010;49(3):237-41. Epub 2010 Feb 1. Link to article
“Therapeutic efficacy of plasmapheresis and high-dose intravenous immunoglobulin was transient. After starting administration of rituximab, the patient showed obvious improvement of muscle spasms due to stiff-person syndrome and ophthalmoplegia following quick depletion of CD20-positive cells in peripheral blood. The anti-GAD and anti-thyroid antibodies decreased slowly.”
9. Lobo ME, Araújo ML, Tomaz CA, Allam N. Stiff-person syndrome treated with rituximab. BMJ Case Rep. 2010 Dec 13;2010. pii: bcr0520103021. doi: 10.1136/bcr.05.2010.3021.
“The authors present a case report of a 41-year-old female patient diagnosed with SPS who was treated with rituximab in a public hospital in Brasília, Brazil, showing a good and safe response to the treatment so far.”
10. Qureshi A, Hennessy M. Stiff person syndrome (SPS) complicated by respiratory failure: successful treatment with rituximab. J Neurol. 2012 Jan;259(1):180-1. doi: 10.1007/s00415-011-6123-9. Epub 2011 Jun 7. Link to article
11. Venhoff N, Rizzi M, Salzer U, et al. Monozygotic twins with stiff-person syndrome and autoimmune thyroiditis: rituximab inefficiency in a double-blind, randomised, placebo controlled crossover study. Ann Rheum Dis;68:1506. Link to article
12. Murinson B. Stiff-person syndrome. Johns Hopkins.School of Medicine. Link to article
6. Sirolimus, Rapamycin
Sirolimus is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. It prevents activation of T cells and B cells by inhibiting their response to interleukin-2 (IL-2). Sirolimus works, in part, by eliminating old and abnormal white blood cells. Sirolimus is effective in mice with autoimmunity and in children with a rare condition called autoimmune lymphoproliferative syndrome (ALPS). Sirolimus may increase the risk that you will develop an infection or cancer, especially lymphoma or skin cancer. Sirolimus inhibits a protein kinase complex known as mTORC1, and this appears to provide most of the beneficial effects of the drug (including life-lengthening in animal studies). Sirolimus also acts on a related complex known as mTORC2. Disruption of mTORC2 produces the diabetes-like symptoms of decreased glucose tolerance and insensitivity to insulin also associated with sirolimus. Drugs.com
Tacrolimus is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection. It is also used in a topical preparation in the treatment of atopic dermatitis (eczema), severe refractory uveitis after bone marrow transplants, exacerbations of minimal change disease, and the skin condition vitiligo. It reduces interleukin-2 (IL-2) production by T-cells. Drugs.com.