CASE OF THE MONTH ABSTRACT: Tacrolimus (FK-506) is a calcium-calcineurin inhibitor, suc-cessfully used in transplant recipients. We report the successful use of tac-rolimus as a single immunosuppressant in a patient who had developedmyasthenia gravis (MG) during interferon alpha treatment. In this case, thecoexistence of hepatitis C and type 2 diabetes mellitus contraindicated theuse of both steroids and azathioprine, and cyclosporine A, although effec-tive, had induced renal failure. Tacrolimus proved to be effective in thetreatment of MG, was not significantly hepatotoxic, and was less nephrotoxicthan cyclosporine.

© 2002 John Wiley & Sons, Inc. Muscle Nerve 25: 111–114, 2002

SUCCESSFUL TREATMENT OF MYASTHENIAGRAVIS WITH TACROLIMUS

AMELIA EVOLI, MD, CHIARA DI SCHINO, MD, FRANCESCA MARSILI, MD, and

CHIARA PUNZI, MD

Institute of Neurology, Catholic University, L. go F. Vito 1, 00168 Rome, Italy

Accepted 28 August 2001

Myasthenia gravis (MG) is an immune-mediateddisorder of neuromuscular transmission caused usu-ally by antibodies against muscle acetylcholine recep-tors (AChR).5 Its current treatment includes severalimmunosuppressive agents such as corticosteroids,azathioprine, cyclosporine A, and mycophenolatemofetil.2,12 As MG is a chronic disease, patients gen-erally require long-term treatment, which is very ef-fective but also has a number of serious side effects.For this reason, the immunosuppressive regimenshould be individualized, taking into account the pa-tient’s clinical history and associated conditions.

Tacrolimus (FK-506) is a macrolide molecule ofthe same immunosuppressant class as cyclosporine.It acts through the inhibition of the calcium-calcineurin pathway and exerts its immunosuppres-sive effect by reducing the proliferation of activatedT cells. Tacrolimus has proven to be a valid alterna-tive to cyclosporine in the treatment of transplantrecipients17 and has been effective in treating differ-ent immune-mediated diseases.6,13,21 We now report

the successful treatment of a patient with MG usingtacrolimus as the sole immunosuppressive agent.

CASE REPORT

A 56-year-old man first complained, in February1996, of intermittent ptosis, diplopia, and difficultyin chewing and swallowing after 3 months therapywith interferon-alpha 2b (Intron A, 3 million unitssubcutaneously three times each week) for hepatitisC (HCV genotype 1 b). He was also affected by type2 diabetes mellitus that was managed with metfor-min.

Neuromuscular symptoms persisted after inter-feron had been discontinued, and limb weakness de-veloped in the ensuing weeks. MG was diagnosed onthe basis of a positive response to edrophonium in-jection, 15% decrement of the compound muscleaction potential (CMAP) of the deltoid muscle atlow-rate (3 HZ) repetitive nerve stimulation, and el-evated serum AChR antibodies (4.2 nM/L). The pa-tient was given pyridostigmine 180 mg/day with re-sulting benefit.

In April 1996, the patient was admitted to ourhospital with worsening myasthenic symptoms. Clini-cal examination revealed bilateral ptosis, diplopiadue to paresis of left lateral rectus muscle, facialweakness, mild dysphagia and dysarthria, weaknessof both upper limbs and fatiguability (arms out-stretched for 30 s), corresponding to a quantitativeMG (QMG) score19 of 14. Vital capacity was withinthe normal limits. Blood glucose levels were within

Abbreviations: ACE, angiotensin-converting enzyme; AChR, acetylcho-line receptor; CMAP, compound muscle action potential; GAD, glutamicacid decarboxylase; GGT, gamma-glutamyltranspeptidase; HCV, hepa-titis C virus; MG, myasthenia gravis; QMG score, quantitative myastheniagravis scoreKey words: cyclosporine; diabetes mellitus; HCV infection; myastheniagravis; tacrolimusCorrespondence to: A. Evoli; e-mail: a.evoli@vsb.it

© 2002 John Wiley & Sons, Inc.DOI 10.1002/mus.10018

MG Treatment with Tacrolimus MUSCLE & NERVE January 2002 111

the normal range with metformin treatment (500mg twice daily); blood biochemical screening testswere normal apart from a serum gamma-glutamyl-transpeptidase (GGT) of 84 U/L (normal range:4–45); serum HCV RNA levels measured by reversetranscription–polymerase chain reaction assay were600,000 copies/ml; histological evaluation of a liverbiopsy specimen was consistent with chronic hepati-tis; thyroid antibody and hormone levels were nor-mal. As increased doses of pyridostigmine did notproduce additional benefit, cyclosporine A wasstarted at a dose of 250 mg/day (3.3 mg/kg), withgood clinical response.

In the following months, the patient’s status im-proved to pharmacological remission19 (apart frommild weakness of eyelid closure); cyclosporine Adosage was maintained at 150 to 200 mg/day, cor-responding to blood levels between 100 and 130ng/ml.

In December 1998, the patient underwent trans-sternal thymectomy. Histological examinationshowed an involuted thymus with predominance ofadipose tissue, without evidence of lymphoid fol-licles. At that time, AChR antibody titer was 1.7nM/L and HCV RNA levels were 1,190,000 copies/ml. Treatment remained unaltered after surgery.

In April 1999, the patient was found to have ar-terial hypertension (180/110 mmHg); laboratorytests were consistent with mild nephropathy (bloodurea nitrogen 36 mg/dl, serum creatinine 1.6 mg/dl, serum potassium 5.5 mEq/L). He was placed ona low-protein and low-sodium diet, and antihyperten-sive treatment with angiotensin-converting enzyme(ACE) inhibitors was started. In order to reducenephrotoxicity, the cyclosporine dosage was gradu-ally reduced to 100 mg/day, but had to be increasedagain to 200 mg/day owing to worsening MG, withptosis, constant diplopia, and weakness of neck andlimb muscles (QMG score: 15).

In September 1999, the patient, who had ne-glected his dietary restrictions and antidiabetictherapy, was readmitted to hospital complaining ofincreased weakness, weight loss, recurrent head-aches, and visual flashes. He was found to have de-compensated diabetes, arterial hypertension, andmild renal failure (blood urea nitrogen 50 mg/dl,serum creatinine 1.7 mg/dl, serum potassium 5.5mEq/L). Antidiabetic therapy was changed to gliq-uidone (45 mg/day); a calcium antagonist wasadded as antihypertensive drug and the cyclosporinedosage was maintained unaltered.

In November 1999, the patient was reevaluated ashis MG signs had not significantly improved but theblood indices of nephropathy had increased further

(blood urea nitrogen 60 mg/dl, serum creatinine 2.2mg/dl, serum potassium 5.8 mEq/L); diabetes andblood pressure were under control. Cyclosporinewas discontinued and the patient was placed on tac-rolimus 2 mg twice daily (approximately 0.05 mg/kg) with unaltered pyridostigmine dosage. Myas-thenic symptoms began to improve after 2 weeks oftherapy.

In December 1999, clinical examination showedonly fatiguability of upper limb muscles and mildweakness of orbicularis oculi muscles (QMG score:3). Tacrolimus blood level was 11.5 ng/ml (recom-mended range 5–15 ng/ml). Renal function indiceswere improved (blood urea nitrogen 37 mg/dl, se-rum creatinine 2.1 mg/dl, and serum potassiumwithin the normal range); blood pressure was undercontrol, but normalization of glucose levels requiredan increase in gliquidone dosage to 90 mg/day. Inthe ensuing months, tacrolimus dosage was reducedto 1 mg twice daily without exacerbating his MGsymptoms.

At the last follow-up evaluation, in February 2001,the patient appeared in pharmacological remis-sion19: clinical examination showed isolated weak-ness of eyelid closure, absence of ptosis and diplopiawith normal function of extra-ocular muscles, nobulbar signs, and neither weakness nor fatiguabilityof limb muscles. Tacrolimus blood level was 9.6 ng/ml. Biochemical screening showed blood glucoselevels within the normal range, blood urea nitrogenof 30 mg/dl, and serum creatinine of 1.6 mg/dl,potassium of 4.8 mEq/L, and GGT 71 U/L; antihy-pertensive therapy was reduced to just the ACE in-hibitor, and antidiabetic treatment was maintainedunaltered. At that time, serum AChR antibody titerwas 3 nM/L and HCV RNA levels were 1,700,000copies/ml.

Anti–islet cell and anti-glutamic acid decarboxyl-ase (anti-GAD) antibodies were assayed before andafter tacrolimus treatment by indirect immunofluo-rescence22 and by immunohystochemistry,10 respec-tively; they were both absent.

DISCUSSION

In our patient, MG occurred during interferon-alpha 2b treatment and persisted after interferondiscontinuation. Both development and deteriora-tion of immune-mediated disorders during suchtreatment for malignant diseases and viral hepatitishave been previously described.7,9 We previously re-ported the occurrence of MG 1 and this has subse-quently been confirmed by other authors.14,20

In the present case, the presence of disablingweakness required immunosuppressive treatment,

112 MG Treatment with Tacrolimus MUSCLE & NERVE January 2002

but the concomitant presence of diabetes mellitusand hepatitis were contraindications to the use ofboth steroids and azathioprine. The patient re-sponded well to cyclosporine A, but this treatmentwas complicated by the occurrence of significantnephrotoxicity. This encouraged us to use tacroli-mus, which although acting in a similar fashion tocyclosporine, is reportedly less nephrotoxic.4

Tacrolimus has proven effective in both preven-tion and treatment of acute rejection after organtransplantation.8,15 It exerts its immunosuppressiveeffect through binding to its immunophilin calledFK-506–binding protein; this complex, in turn, in-hibits the events mediated by calcineurin, a calcium-dependent serine/threonine protein phosphataserequired for cell signalling in T lymphocytes. Likecyclosporine, tacrolimus interferes with both the ac-tivation and the nuclear import of the nuclear factorof activated T cells, required for the expression ofcytokine genes involved in T-cell activation.3 Al-though tacrolimus and cyclosporine act in a similarfashion, the potency of tacrolimus appears to be 10to 100 times greater than that of cyclosporine.13

Tacrolimus has been used successfully in thetreatment of autoimmune disorders such as systemiclupus erythematosus, connective tissue diseases, au-toimmune hepatitis, and enteropathy.6,13,21 It hasnot been previously employed in the treatment ofMG, although it prevents the induction of experi-mental autoimmune MG through decrease in anti-gen-specific T-cell response.23 In the present case,tacrolimus was as effective in controlling MG as cy-closporine, even though at a dosage of 1 mg twice aday it was less efficient in reducing AChR antibodylevels.

Hyperglycemia is a well-recognized complicationof immunosuppression with tacrolimus16; this side-effect appears to be dose-related and less severe thanthat induced by steroids, inasmuch as tacrolimus ispart of steroid-free immunosuppressive regimens intransplant recipients.18 It has also been suggestedthat this drug may induce autoimmune diabetes insubjects at risk for immune-mediated disorders.11

We confirm the diabetogenic effect of tacrolimus, asincreased doses of antidiabetic drugs were requiredin the present case to control a preexisting type 2diabetes. However, we did not find any evidence ofautoimmune diabetes as, although our patient waspredisposed to autoimmunity, both anti–islet celland anti-GAD antibodies remained negative duringtacrolimus treatment.

Serial assays of HCV RNA levels revealed a steadyincrease of viral replication during the follow-up pe-riod. This finding, which was not associated with

worsening of liver function indices, can be nonspe-cifically related to immunosuppressive therapyrather than to any specific drug.

In conclusion, in the patient here reported, ta-crolimus at low doses was effective in the treatmentof MG, was not significantly hepatotoxic, and was lessnephrotoxic than cyclosporine. It should be consid-ered as an alternative treatment for patients withdisabling MG that is not responsive to conventionalimmunosuppressants, or when these other agentsare contraindicated.

The authors thank Dr. B. Giometto for testing for anti-GAD anti-bodies.

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