Iranian Journal Review Article of Neurology Iran J Neurol 2018; 17(3): 129-36 Induction or aggravation of other Received: 25 Feb. 2018 immune-mediated disorders by Accepted: 07 May 2018 disease-modifying therapy in treatment of multiple sclerosis Seyed Mohammad Baghbanian1, Mohammad Ali Sahraian2 1 Bualicina Hospital, Mazandaran University of Medical sciences, Sari, Iran 2 Multiple Sclerosis Research Centre, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran Keywords system which, in over 85% of circumstances, Interferon-Beta; Glatiramer Acetate; Autoimmune initially presents as relapsing neurological Disease; Multiple Sclerosis disability followed by remission phases.1-3 The disease affects young adults and is more common among women.4 There is no cure for MS, and treatment concentrates on treating relapses, Abstract diminishing the progression of disability and Interferon beta (IFN-β) and glatiramer acetate (GA) secondary symptom management. Interferon beta are the primary therapeutic immunomodulatory (IFN-β) and glatiramer acetate (GA) are the agents that interfere with relapsing-remitting primary therapeutic immunomodulatory agents multiple sclerosis (RRMS), and the most commonly- used drugs as well. Induction or aggravation of other that interfere with relapsing-remitting multiple immune-mediated diseases has been reported sclerosis (RRMS), and the most commonly-used 5 following INF-β administration. We have reviewed drugs as well. the reported cases to notify the treating physicians Isaacs and Lindenmann,6 the discovers of INF, about these rare adverse events. Although co-morbid use this term to explain the antiviral replication autoimmune disorders have been reported in properties of these biologically-active substances. patients with MS, the pro-inflammatory role of It features an acceptable risk profile, is well disease-modifying drugs, especially INF-β, could tolerated, and is effective in decreasing the affect and enhance this co-occurrence. Clinical or activity of RRMS. This makes INF the first choice laboratory autoimmunity histories suggest the use of for disease-modifying therapy in MS. GA over INF-β as the treatment of choice. GA is a synthetic polypeptide composed of four amino acids in a mixture resembling myelin basic Introduction protein.7 Many trials have shown that GA can Multiple sclerosis is an inflammatory reduce the relapse rate, disability progression and demyelinating disease of the central nervous ameliorate the course of the disease as indicated by Iranian Journal of Neurology © 2018 Corresponding Author: Seyed Mohammad Baghbanian Email: [email protected] Email: [email protected] http://ijnl.tums.ac.ir 06 July Autoimmune disorders aggravation by disease-modifying treatment of MS MRI findings.8 GA is one of the most prescribed histopathology from arcuate and polycyclic disease-modifying-therapies for multiple sclerosis.9 erythematous scaly plaque on the face, trunk, and Injection site reaction is the most frequent side upper extremities of a 43-year-old woman with effect of IFN and GA. Other side effects include a RRMS under treatment with intramuscular (IM) flu-like syndrome, lymphopenia caused by IFN as INF-b1a who presented with interface well as hepatic failure, hepatitis and elevated liver dermatitis.15 Lupus erythematosus profundus enzymes. These have been reported for both (lupus panniculitis) was diagnosed when a treatments, although they are more common for 19-year-old woman with RRMS under treatment IFN.10 Induction or aggravation of other immune with INF-β1b presented with painful nodules on mediated diseases have been reported following the face, both shoulders, and upper limbs; a skin INF beta administration. Here we have reviewed biopsy suggested lobular panniculitis.16 Two cases the reported cases to notify the treating physicians of lupus-like reaction to INF at the injection site about these rare adverse events. In many were reported in patients with MS being treated instances continuation of INF following with INF-β1b.17 SLE induced by INF-b1 therapy appearance of a new autoimmune disease may was reported in a 34-year-old patient with RRMS aggravate the condition and INF therapy should who developed myalgia associated with wrist be promptly stopped to prevent further damage. synovitis with no skin involvement.18 Psoriasis: Case reports have shown an Review of case reports association between psoriasis and MS. In most Arthritis: A 37-year-old woman with MS cases, the psoriasis presented before MS, and it presented with isolated temporomandibular joint appeared possible to define co-morbidity, but INF- arthritis two weeks after starting IFN-β1a therapy. induced psoriasis was not excluded.19 Exacerbation It resolved completely shortly after IFN of cutaneous psoriasis and psoriatic arthritis has discontinuation, and did not recur after switching been reported in patients with MS.20-22 treatment to GA.11 A 38-year-old woman with Inflammatory bowel disease (IBD): Severe RRMS presented with left pre-patellar bursitis colitis caused by Crohn’s disease was reported in with no particular involvement three months after a patient with MS treated with IFN-β.23 initiation of IFN-β1a.11 A 29-year-old woman with Aggravation and development of ulcerations was RRMS presented with severe acute-onset reported after treatment with IFN-β1a.24,25 A case arthralgia, swelling of both knees, and of rapid-onset ulcerative colitis was reported one inflammatory synovial fluid reaction three weeks week after INF-β1a therapy. The time of onset of after beginning treatment with IFN-β1b. The ulcerative colitis was from one day after IFN condition disappeared a few days after initiation to one week after discontinuation of the discontinuation of IFN.12 Seropositive therapy.26 Celiac disease was reported in a 36-year polyarthritis with high erythrocyte sedimentation old woman with RRMS after one month of rate (ESR), elevated C-reactive protein (CRP), and treatment with IFN-β1b.27 MS concomitant with high rheumatic factor (RF) titer was reported in a celiac disease has been recently diagnosed more 42-year-old woman with RRMS after 30 months of often than expected.27 A 27-year-old woman with treatment with INF-β1b.12 Animal experiments RRMS treated with GA for 2 years presented with have shown that GA could exacerbate abdominal pain, diarrhea, fever, and weight loss. autoimmune arthritis. These findings suggest that A colonoscopy showed diffuse right-sided colitis GA should be used with great caution in patients and ileitis, and the biopsy was compatible with with MS and other autoimmune complications.13 Crohn’s disease. This report emphasized that Systemic lupus erythematosus (SLE): A Crohn’s disease might be an adverse event related 43-year-old woman with RRMS under treatment to treatment with GA.28 with INF-β1a was diagnosed with drug-induced Sarcoidosis: IFN-β has been reported to induce SLE (DILE) four weeks after developing synovitis, sarcoidosis. The duration of IFN-β treatment at fever, myalgia, and facial edema. Laboratory test the time of diagnosis varied from results were positive for antinuclear antibodies 8 months to three years. The most common (ANA) and anti-double stranded DNA antibody presentation included pulmonary manifestations, (anti-dsDNA). After discontinuation of INF, the although hepatic, and bone involvement. symptoms resolved completely.14 A diagnosis of Transbronchial, mediastinal, and paratracheal cutaneous SLE was confirmed by lesional skin lymph node and skin biopsies confirmed the 130 Iran J Neurol, Vol. 17, No. 3 (2018) http://ijnl.tums.ac.ir 06 July S.M. Baghbanian and M.A. Sahraian diagnoses.29,30 Cutaneous and pulmonary patients presented with generalized urticaria, sarcoidosis with erythema nodosum in the lower nausea, and hypotension upon the first limbs, breast abscesses, and unilateral pulmonary administration of GA. In a third patient, after six adenopathy were reported in a 33-year-old woman months of GA interruption, an immediate with RRMS treated with INF-β1b for 2.5 years.31 reaction presented with eyelid edema 20 minutes Susac syndrome: Exacerbation of Susac after GA administration.46 syndrome retinopathy has been reported in a Autoimmune hepatitis (AIH): Features of 23-year-old man misdiagnosed with MS who was autoimmune liver disease and primary biliary treated with IFN-β1a for 15 months. Two weeks cirrhosis after 33 months of administration of IFN- after IFN-β discontinuation, the visual field and β was reported in a 42-year-old woman with fluorescein angiography indicated complete RRMS. The strong positivity of antimitochondrial recovery.32 antibodies was consistent with primary biliary Scleromyxedema: Scleromyxedema was reported cirrhosis and positive ANA along with elevated in a 37-year-old woman with RRMS under aspartate aminotransferase (AST) and alanine treatment with IFN-β1a for three years. The patient aminotransferase (ALT) were suggestive of AIH; recovered after discontinuation of IFN-β1a but clinical symptoms of acute liver injury did not treatment.33 present.47 A 20-year-old woman and a 47-year-old Dermatomyositis: A violaceous skin eruption man with RRMS treated with IFN-β1a presented associated with periorbital edema and proximal with elevated liver function tests. The first patient muscle weakness presented in a 57-year-old man presented with asthenia, progressive jaundice, with RRMS under treatment with IFN-β1a. Skin nausea, and abdominal discomfort along with re- biopsy diagnosed it as dermatomyositis. Clinical elevated liver