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Long-term treatment in MG – A review

Long-term treatment in MG – A review. Amelia Evoli Neuroscience Department Catholic University, Roma, Italy a.evoli@rm.unicatt.it. Myasthenia gravis. MG is currently considered a syndrome rather than a single disease

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Long-term treatment in MG – A review

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  1. Long-term treatment in MG – A review Amelia Evoli Neuroscience Department Catholic University, Roma, Italy a.evoli@rm.unicatt.it

  2. Myasthenia gravis MG is currently considered a syndrome rather than a single disease Clinical presentation, response to therapeutic modalities and disease outcome vary in different patient populations. • MG management is a graded approach, from anticholinesterases (AChE) for mild weakness to immunosuppressive therapy for disabling symptoms • Thymectomy is reserved for selected patients • Though current treatment has limitations, MG prognosis has much improved during the past decades: • Mortality rate <5% • Satisfactory control of symptoms in >80% of patients

  3. Myasthenia gravis: clinical forms

  4. MGFA clinical classification Jaretzki, 2000 Maximum disease severity

  5. Treatment in patientswithprolonged follow-up An appraisal of treatment efficacy in MG includes: • Quantification of the therapeutic response (P.I.S.) • Analysis of its time duration • Evaluation of unwanted effects Long-term treatment or long-term effects of treatment ? • These parameters were evaluated in patients treated in our Institution

  6. Population Patients treated for MG in our center with a follow-up ≥ 2 years Patients thymectomized for thymoma in other hospitals and referred to us for MG Exclusion of: Pts diagnosed/thymectomized in our hospital and treated elsewhere/ incomplete follow-up data • Treatment • ACHE: as first-line treatment in all patients • Thymectomy: in thymoma cases and in early-onset generalized MG • IS therapy: in patients with disabling symptoms: • prednisone (max dosage: 100 mg e.o.d. in generalized, 50 mg e.o.d. in ocular MG) • immunosuppressants as steroid-sparing agents: • - azathioprine, cyclosporine, MMF, tacrolimus, rituximab • Plasma-exchange/IVIG: MG exacerbations and in preparation for thymectomy Side effects Serious side effects of IS therapy:diabetes, glaucoma, severe osteoporosis, systemic infections, ulcerative gastritis, IS-related cancer (skin tumors, melanoma, lymphoma)

  7. N. patients

  8. Ocular Myasthenia In 12-15% of patients MG remains confined to extrinsic ocular muscles

  9. Ocular myasthenia ACHE Unsatisfactory response Diagnosis of thymoma Prednisone (25-50mg e.o.d.) Thymectomy Progressive dose reduction to the “minimum effective dose” or withdrawal Unsatisfactory response or (more commonly) high maintenance doses Consider the association with immunosuppressants

  10. Ocular myasthenia – 120 patients Follow-up: 2-33 yrs (10.7) <5 yrs: 38 patients 5-10: 29 10-15: 18 15-20: 14 20-25: 11 >25: 10 76 M/44 F age of onset: 4-79 years (mean 42) IS therapy in 89/120 pts (74%) 13 underwent thymectomy (thymectomized patients) prednisone was finally withdrawn in 8 pts Serious side effects from IS therapy in 16/89 pts (18%)

  11. Generalized myasthenia mild MG – indication for thymectomy (thymoma, “early-onset” MG) Satisfactory control of symptoms ACHE, thymectomy Disabling symptoms IS therapy moderate/severe MG – indication for thymectomy ACHE, IS therapy plasma-exchange, IVIG thymectomy IS therapy When thymectomy is not indicated (“late-onset” MG, MuSK-MG) ACHE in patients with mild disease IS therapy in cases with disabling symptoms Plasma-exchange, IVIG in treating disease exacerbations

  12. Early-onset AChR+ generalized MG: 350 patients Disease severity 68 M/282 F age of onset: 4-50 years (mean 26.3) Follow-up yrs: 1-35 (12.8) <5 yrs: 75 pts 5-10 : 69 10-15: 67 15-20: 53 20-25: 45 >25: 41 • Thymectomy: 309/350 • extended transcervical + sternal split in 8 pts • extended transsternal in all the other pts • Immunosuppressive (IS) therapy: 219/350 (62.6%) • -191/309 thymectomized pts (61.8%) • - 28/41 unthymectomized pts (68.3%) • - finally withdrawn in 57 • Serious side effects of IS therapy in 24/219 pts (11%)

  13. Response to therapy in early-onset MG Complete Stable Remission (CSR) in 120/350 patients - 34%

  14. ……after thymectomy 26 pts (irrespective of MG status) developed other autoimmune diseases: SLE (5) vitiligo (3) alopecia areata (3) myositis (1) thyroid disease (7) ulcerative colitis (1) psoriasis (1) autoimmune thrombocytopenia (1) MS (1) autoimmune hepatitis (1) IDDM (1) RA (1) Patients who had achieved CSR (mostly 2-5 years after thymectomy) maintained it for the whole length of follow-up 10 pts complained, 10-28 years after thymectomy, of transient ocular signs

  15. 1500 1000 500 Before After BAFF serum levels do not decline after thymectomy While they are markedly reduced by immunosuppressive treatment Mean BAFF levels measured 5-33 years after thymectomy in patients without IS therapy Serum BAFF levels in serial samples before and after thymectomy p=0.008 Thymectomized pts Controls

  16. Late-Onset MG: 190 patients Disease severity 129 M/61 F age of onset: 51-88 years (mean 67) Follow-up: 1-25 years (7.7) < 5 yrs: 70 patients 5-10: 54 10-15: 38 15-20: 21 > 20 : 7 Immunosuppressive (IS) therapy in 174/190 (91%) Thymectomy in 23 21/23 thymectomized pts received IS therapy

  17. Late-onset MG: response to therapy Immunosuppressive therapy was finally withdrawn in 16 cases 45/174 patients (26%) complained of serious side effects

  18. Thymoma-associated MG: 240 patients 120 M/120 F age of onset: 8-83 years (mean 47) 135 invasive/105 non invasive thymomas Disease severity Follow-up: 1-34 years (11.5) <5 yrs: 46 patients 5-10: 66 10-15: 57 15-20: 36 20-25: 19 >25: 16 All patients underwent thymectomy Immunosuppressive therapy in 202/240 pts (84.2%)

  19. Thymoma-MG: response to therapy thymoma-related deaths: 10 IS therapy was suspended in 20 pts; serious side effects in 44/202 pts (22%)

  20. Seronegative MG – 73 patients 29 M/44 F age of onset: 7-82 years (mean 36.7) follow-up: 2-33 yrs (8.3) IS therapy in 49 (67%), thymectomy in 32 Side effects from IS therapy in 8 (16%) Prednisone withdrawn in 8 pts

  21. anti-MuSK+ MG: 71 patients 13M/58F age of onset: 6-68 years (mean 36.8) follow-up: 1-30 years (11) Thymectomy in 17 pts IS therapy in 67/71 (94%) Serious side effects in 8 (12%) Dramatic response to Rituximab in one patient

  22. MG treatment: cumulative results

  23. The present treatment for MG is very effective in most cases. However, many patients remain dependent on treatment and suffer from severe side effects. We need more specific treatment. In the meantime, we can try to reduce unwanted effects through: • tailored treatment • prevention and monitoring of complications

  24. P. Tonali A.P. Batocchi Neuroscience Department F. Scuderi E. Bartoccioni General Pathology Department P. Granone G. Cusumano Thoracic Surgery Department

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