. 2015 Mar;8(2):92–103. doi: 10.1177/1756285615571873

Table 2.

Prospective trials of tacrolimus in myasthenia gravis.

Clinical situation	Study	Design	Population	Dosage	Duration	Efficacy measures	Results^‡	Adverse effects (% of patients)
Steroid-sparing effects	Shimojima et al. [2006]	Open-label, single center	n = 7	3 mg/day	6–32 months	Mean ∆ QMGS at 3, 6 months	↓4.2^,↓5.0^	No notable adverse effects
						Mean ∆ MG-ADL at 3, 6 months	↓1.3^,↓2.0^
						∆ Anti-AChR AB	↓^¶
	Nagaishi et al. [2008]	Open-label, single center	n = 10	3 mg/day	1–5 years	Mean ∆ MG-ADL at 1, 6 months	↓3 (1-4), ↓5.8 (4–12)^§	No serious adverse effects
						PSC-MGFA	1 PR, 4 MM, 2 exacerbations ^§	2 discontinuations after 1 month due to new diabetes mellitus and diarrhea
	Tada et al. [2006]	Open-label, single center	n = 9	3 mg/day	24–46 months	QMGS ∆ at 3, 6, 12 months	↓2.6^*, ↓3.0^$, ↓3.2^$	No serious adverse effects
						3 point ↓ in QMGS at 3, 6 monthsMean ∆ Anti-AChR AB at 6 months	66.7%, 77.8% of patients^§↓51.6 nM^*	Hemoglobin A1C increase and lymphocyte reduction (33%)
	Konishi et al. [2003]	Open-label, multicenter	n = 19	3 mg/day	16 weeks	Median ∆ in MG score at 16 weeks	↓4^$	No serious adverse effects
						MG-ADL score ∆ at 12, 16 weeks3 point ↓ in MG score	↓^*¶37% of patients^§	Increased neutrophil count and decreased lymphocyte count (37%)
						1 point ↓ in ADL score	42% of patients^§
						Median ∆ Anti-AChR AB at 12, 16 weeks	↓2.8 nM^, ↓2.1 nM^
						Median ∆ IL-2 production at 16 weeks	↓8.5 U/ml ^$
	Konishi et al. [2005]	Open-label extension	n = 12	2–4.5 mg/day	2 years	3 point ↓ in MG score1 point ↓ in MG-ADL score	41.7% of patients^§50% of patients^§	Minor (66.7%), increased neutrophil count and decreased lymphocyte count (33%)
						Mean ∆ Anti-AChR ABMean ∆ prednisolone dose	↓7.5 nM^$↓37% (8.3–57.0%)^§	Drug held for headache/eye pain in 1 patient, later resumed
	Zhao et al. [2011]	Open-label, multicenter pilot study	n = 47	3 mg/day	24 weeks	Median ∆ QMGSMedian ∆ MMT scoreMedian ∆ MG-ADLMedian ∆ prednisone dose	↓5.34 ±4.79^$↓14.7 ±14.02^$↓4.75 ±4.30^$↓11.8 mg/day^$	Hyperlipidemia (18%), hyperglycemia (12%), diarrhea (12%), respiratory infection (12%) 1 death due to MG exacerbation 9 days into study, not attributed to tacrolimus
	Yoshikawa et al. [2011]	Randomized, double-blind, placebo-controlled, multicenter	n = 80	3 mg/day	28 weeks	Mean prednisolone dose, ITTMean prednisolone dose, PPQMGS	4.91±4.04 versus 6.51±4.89 mg/day4.45±3.44 versus 6.19±4.77 mg/day^4.4±3.62 versus* 5.8±5.09	Nasopharyngitis (25 versus 30%), WBC elevation (12.5 versus 5%), URI (12.5 versus 5%), A1C increase (10 versus 2.5%), muscle spasm (10 versus 0%)
						MG-ADLMean ∆ Anti-AChR AB	1.2±1.33 versus 2.3±3.0No ∆^¶	2 serious events: 1 appendicitis and 1 hearing loss which resolved with treatment
						Mean ∆ IL-2 production	No ∆^¶	2 discontinuations for appendicitis and insomnia
Corticosteroid with cyclosporine failure	Ponseti et al. 2005a	Open-label, single center	n = 13	0.1 mg/kg/day	1 year	Median ∆ QMGSMean ∆ Anti-AChR AB	↓20.93^$↓6.6 nM^*	No notable adverse effects
						PSC-MGFA	13 PR^§
						Mean ∆TEMS	↑26.53^$
	Ponseti et al. 2005b	Open-label, single center	n = 79	0.1 mg/kg/day	2.5 years	Mean ∆ prednisolone doseWithdrawal of steroidsMean ∆ QMGSMean ∆ Anti-AChR ABPSC-MGFA, % of patientsMean ∆ TEMS	↓56.5 mg/day. ^§77 patients. ^§↓20.2^$↓34.8 nM. ^$CSR 5.1%, PR 88.6%, MM 6.4%↑26.8^$	3 new malignancies, included 2 patients with lung cancer and 1 with renal cancer (after 4 to 6 months of treatment)
Postoperative thymectomy	Ponseti et al. [2006]	Open-label, single center	n = 49	0.1 mg/kg/day	6–60 months	Withdrawal of steroids at 1, 2 yearsMean ∆ prednisone doseMean ∆ QMGSMean ∆ Anti-AChR ABPSC-MGFA, % of patientsMean ∆ TEMS	93.7%, 100% of patients^§↓80.7 mg/day^§↓20.7^$↓20.8 nM^§CSR 33%, PR 62.6%, MM 4%^§↑24^§	Hypomagnesemia (23.7%), paresthesia (5.3%), tremor (5.3%)
De novo diagnosis	Nagane et al. [2005]	Randomized, controlled, single center	n = 34	3 mg/day	1 year	Early phase:Number of PLEX + HMP treatmentsMean oral prednisolone doseFollow-up phase:Number of PLEX + HMP treatmentsHMPMean oral prednisolone dose	1.3±1.5 versus 3.1±2.3^5.1±4.1 versus* 6.7±3.0 mg/day0.2±0.5 versus 1.1±1.6^0.4±0.9 versus* 1.8±2.7^4.6±4.1 versus* 8.1±2.6 mg/day^*	No significant adverse effectsSerum creatine increased from 0.4–1.1 mg/dl to 1.4–1.5 mg/dl in 1 patient
Presence of thymoma	Mitsui et al. [2007]	Open-label, controlled, single center	n = 10	3 mg/day	3 months	∆ QMGS at 1, 3 monthsBaseline anti-AChR ABAnti-AChR AB at 1moAnti-AChR AB at 3 months	↓^\|\|,¶68.16±36.4 versus* 16.5±7.8 nM53.8±30.9 versus 16.5±8.3 nM79.2±53.9 versus 15.25±5.2 nM	No notable adverse effects

Anti-AChR AB= anti-nicotinic acetylcholine receptor antibody titer; CSR= complete stable remission; HMP= high dose intravenous methylprednisolone; IL-2= interleukin-2; ITT= intention to treat; MG= myasthenia gravis; MG-ADL= Myasthenia Gravis Activities of Daily Living; MM= minimal manifestation; MMT= Manual Muscle Testing; PLEX= plasma exchange; PP= per protocol; PR= pharmacologic remission; PSC-MGFA= Post-Intervention Status Criteria, Myasthenia Gravis Foundation of America; QMGS= Quantitative Myasthenia Gravis Score; TEMS= Test to Evaluate Muscle Strength; URI= upper respiratory inflammation.

p < 0.05

p ⩽ 0.01

^‡

For comparisons of tacrolimus versus placebo or, if no comparator used, for final results versus baseline.

^§

p values not reported.

^||

Thymoma versus nonthymoma group

^¶

Specific values not reported.