Systemic Lupus Erythematous Emergence in a
Multiple Sclerosis Patient Treated with Fingolimod
Multiple Sclerosis and Neuro-Immunology Research Center, Isfahan University of medical sciences, Iran
Submission: April 26, 2017; Published: June 19, 2017
*Corresponding author: Amir Neshatfar, Multiple Sclerosis and Neuro-Immunology Research Center, Isfahan University of medical sciences, Iran,Tel: 00989131254246; Email: email@example.com
How to cite this article: Amir N. Systemic Lupus Erythematous Emergence in a Multiple Sclerosis Patient Treated with Fingolimod. Glob J Pharmaceu Sci. 2017; 2(5) : 555600. DOI: 10.19080/GJPPS.2017.02.555600
Fingolimod (FIN) is a novel therapy in multiple sclerosis with some side effects. There have been some studies in which the potential risk of consequent exacerbation of autoimmune diseases after use of fingolimod has been discussed. According to our knowledge our study is the only one investigating a case of fingolimod causing systemic lupus erythematous. We report a case of multiple sclerosis with no history of any rheumatologic disorder who experienced arthritis within two weeks after initiation of fingolimod therapy, which can be a potential consequence of dysregulation of immune system and its impact on regulatory T cells. Finally we concluded that fingolimod therapy can potentially cause autoimmune disorders in patients with clear history of such diseases.
Multiple Sclerosis (MS) is a chronic disease that affects central nervous system. MS is thought to be an autoimmune disease. In MS, the body’s immune system produces cells and antibodies that attack myelin. For many years many studies investigated application of different possible therapeutic profiles for this disorder. The damage to myelin and nerve fibers, is caused by over-active T cells. FIN was the first oral drug approved to treat relapsing forms of MS. FIN is a sphingosine 1-phosphate receptor modulator that binds to lymphocytes preventing their migration from peripheral lymphoid tissue in to the blood stream [1,2]. There have been several studies on how fIN administration can be helpful despite all possible side effects such as: Immune reconstitution inflammatory syndrome (IRIS), exacerbation of other auto-immune disorders or like what occurred in our case, causing a new autoimmune disease. In this study, we discuss a case of a female patient with MS who experienced arthritis and SLE presentation after FIN treatment.
A 27-year old female MS case was referred to our clinic with complain of arthritis predominant in PIP, DIP and knees after one week of treatment with FIN in May 2015. On 2005, after her multiple sclerosis was diagnosed, she started treatment with interferon B-1a after two attacks of optic neuritis and paresthesia in lower limbs. Also, Magnetic resonance imaging (MRI) showed multiple T2 weighted hyper intensities in juxtacortical and periventricular areas of brain. The cerebrospinal fluid examination showed positive oligoclonal bands. At that time all laboratory tests, including: antiphospholipid anti body, ANA, anti dsDNA was negative. During nine years she had not any attack and was stable, both clinically and from imaging point of view. Her EDSS score was 1.
In April 2015, she was presented with lower limb weakness. After one month treatment of corticosteroid, Gilenya (Fingolimod) started for her because of clinical and radiological disease reactivations. After ten days of treatment with FIN, she presented with fatigue, arthritis and rashes on her face and also on her hands. After this statement, workup for vasculitis tests was done and ANA and dsDNA was highly positive. (>1/320) After cessation of fingolimod therapy Patients symptoms resolved completely but SLE serologic tests remained positive for almost 1 year follow up.
The exact patho-etiology of systemic lupus erythematosus (SLE) remains elusive. An extremely complicated and multifactorial interaction among various genetic and environmental factors is probably involved. Defective immune regulatory mechanisms, such as the clearance of apoptotic cells and immune complexes, are important contributors to the development of SLE. The loss of immune tolerance, increased antigenic load, excess T cell help, defective B cell suppression, and the shifting of T helper 1 (Th1) to Th2 immune responses leads to B cell hyperactivity and the production of pathogenic autoantibodies. B cell activation is abnormal in patients with SLE. The number of B cells at all stages of activation is increased in the peripheral blood of patients with active SLE .
These B cell abnormalities can precede the development of SLE. Activated lupus B cells have higher intracytoplasmic calcium responses than controls . There is also evidence that B cells in patients with SLE are more sensitive to the stimulatory effects of cytokines such as IL-6 than non-SLE B cells . Moreover, the phenomenon of epitope spreading has been demonstrated in both human and murine SLE . Thus, it appears that B cells in patients with SLE are more prone to polyclonal activation by antigens, cytokines, and other stimuli. Abnormalities in T cell function are also evident in patients with SLE. The total number of peripheral blood T cells is usually reduced, probably because of the effects of anti-lymphocyte antibodies .
In SLE, same as neuromyelitisoptica, B cell lymphocytes are predominant and therapies designed to reduce humoral immune activity [8,9]. Studies have reported poor efficacy or worsening disease following treatment with approved MS therapies such as beta-interferon [10-12], natalizumab [13,14] and Fingolimod . But in our case, the patient was presented with arthritis early after fingolimod treatment without past history of SLE. Fingolimod agonizes the S1P (Sphingosine-1- phosphate) receptor . S1P is recognized as a major regulator of trafficking of T and B cells and inhibition of S1P receptors was shown to be critical for immunomodulation.
Fingolimod interferes with T and B lymphocyte egress from secondary lymphatic tissue and reduce relapses in MS [17,19]. Fingolimod, has been shown to have anti-inflammatory properties [20,21]. While, data remain sparse on acting fingolimod on regulatory T cells. Evidence exists that fingolimod may inhibit T-regulatory cell proliferation . Another article showed that, effector memory T cells which are capable of down-regulating their surface CCR7 do not depend on S1P signaling and can therefore freely migrate through lymph nodes and then might result autoimmune reaction [23,24]. Fingolimod inhibited T regulatory cell proliferation without directly affecting immunosuppressive T regulatory function in- vitro . However, a mechanism by which fingolimod might influence T regulatory function was provided by Liu et al.  who showed that S1P1 induces selective activation of the Akt- mTOR pathway in regulatory T cells.
At this point, it is not clear how these contradictory reports can be explained. There are no data on acting fingolimod on other regulatory cells such as regulatory B-cells or NK cells. Fingolimod exerts on action upon the immune system not yet fully understood but it associated with immunological dysregulation and imbalance of T cells . This could imply that initiation of fingolimod in patients might result exacerbation of autoimmune disease by inhibiting regulatory T cells. Because of dysregulation of immune system and impacting on regulatory T cells tumo affective demyelinating lesion in relapsing-remitting MS might be presented on fingolimod treatment [28-31].
The authors relied on genetic systems rather than pharmacological modulation to clarify the function of S1P1 because of very complex interaction between fingolimod and S1P1 and other receptors, which are still not fully understood. This complexity might explain contradictory findings of drug's influence on regulatory T cell function. The majority of reports, however, suggest that fingolimod promotes T regulatory activity. Because of the paucity of available data, a possible association of Fingolimod and autoimmune disease flare up is still speculative. Further studies are warranted to evaluate this issue and clarify FIN mechanism of action in immune system predominant in T-cell regulatory.