Myasthenia gravis onset during rheumatic disease: a new paradoxical effect of anti‐TNF alpha therapy?

Abstract

Anti-TNF biological drugs are largely used for treatment of different rheumatic (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis) and non-rheumatologic diseases (psoriasis, inflammatory bowel diseases). Since high TNF-alpha levels have been detected also in Myasthenia gravis (MG) patients, anti-TNF alpha therapy has been suggested in those patients who failed conventional therapies.1 In detail, etanercept therapy has been found to be effective in these patients.2 However, two cases of MG onset during etanercept therapy for rheumatoid arthritis (RA) were reported,3, 4 suggesting a paradox effect of anti-TNF alpha therapy like to what observed for either psoriatic arthritis or Crohn's disease. Hereby, we report the case of a RA patient who developed MG during long-term etanercept therapy. A 51-year old male patient, with diabetes and hypertension, was diagnosed with psoriasis at 40 years and psoriatic arthritis 6 years later involving hands, elbows, and foots with typical radiological features and 6.1 Disease Activity Score (DAS28). Methotrexate therapy (10 mg/week) was started, but an intolerance with asthmatic crises required treatment interruption. Therefore, anti-TNF-alpha therapy with etanercept (25 mg twice week) was introduced, following negative results of screening for tuberculosis and viral hepatitis. A rapid clinical benefit was observed, and the DAS28 decreased to 2.6. The psoriatic arthritis remained in remission during the following 4 years with the same therapy. On November 2012, a symptomatology including difficulty to chew, swallowing impairment, and dysarthria developed. The search for anti-AChR antibodies was positive (20 nmol/L; normal values: < 0.15) and the electromiografic study was compatible with MG. Both thoracic CT and cerebral NMR were negative. A pyridostigmine (60 mg thrice daily) was started, and etanercept therapy was continued to control the psoriatic arthritis. Two months later, the muscular asthenia persisted and respiratory difficulty occurred, so that etanercept therapy was stopped and prednisone therapy (50 mg/day) introduced. Despite such a therapy, a severe respiratory insufficiency developed, so that the admission in a Intensive Care Unit was required for patient intubation. Several plasmaphereses were performed with respiratory function recover. Therefore, a therapy with i.v. immunoglobulin and oral mofetil mycophenolate was started, whilst pyridostigmine dose was increased until to 60 mg six times daily. At 1 year follow-up, the MG symptomatology improved, although did not disappear. Anti-TNF-alpha therapy may cause important side-effects, including tuberculosis reactivation, autoimmune diseases, and neurologic manifestations. A paradox effect of this therapy has been also reported, i.e. the onset of a disease for which anti-TNF-alpha therapy is effective. For instance, psoriasis may develop in either RA or inflammatory bowel disease (IBD) patients receiving anti-TNF-alpha therapy, as well as an IBD may onset in RA patients during such a therapy.5, 6 This phenomenon has been attributed to an imbalance between TNF-alpha and IFN-alpha. In detail, the neutralization (or inhibition) of TNF-alpha induced by anti-TNF-alpha therapy would increase IFN-alfa levels triggering autoimmune diseases.7 Myasthenia gravis is an autoimmune disease characterized by presence of either anti-AChR antibodies or anti-muscle-specific receptor tyrosine kinase autoantibodies (anti-MuSK), detectable in near 80% and 10% of cases, respectively.8, 9 In our case, anti-AChR antibodies onset during etanercept therapy occurred. Such a phenomenon was not unexpected, various auto-antibodies (Antinuclear antibodies, Anti-double-strained DNA, Antiphospholipid antibodies, etc.) being produced in course of anti-TNF-alpha therapy, although a disease rarely develops. More recently, an important role of TNF-alpha in MG pathogenesis has been suggested, the high levels of such a inflammatory cytokine suggesting a potential role of anti-TNF-alpha therapy in these patients.10 Therefore, the onset of MG during anti-TNF-alpha therapy would appear a paradoxical effect. To our knowledge, two cases of MG development in patients receiving anti-TNF-alpha therapy have been reported.3, 4 Of note, in both previous cases as well as in our patient, MG developed during a long-term etanercept therapy in for either RA (two previous cases) or psoriatic arthritis (our case), whilst no cases were reported following other biologic therapies. Differently from the previous two cases, in our patient removal of etanercept therapy was not followed by a prompt improvement of MG symptoms, and an intensive therapy was required. The lacking of improvement of MG following anti-TNF-alpha therapy withdraw would question on the actual role of etanercept therapy in MG development in our patient. However, it was evident that such a therapy failed to prevent MG onset, and this should be considered in clinical practice. In conclusion, the onset of neurological manifestation during anti-TNF-alpha therapy for rheumatic diseases should alert for a potential MG which may require not only etanercept discontinuation, but also a long-term appropriate therapy.