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Tacrolimus-Associated myositis: a case report in a renal transplant patient
Tacrolimus-Associated Myositis: A Case Report in a Renal Transplant Patient V. Orlandi, C. Campieri, G. Mosconi, G.L. D’Arcangelo, G. Feliciangeli, M.P. Scolari, and S. Stefoni ABSTRACT A 55-year-old Caucasian man who had received a second kidney graft in July 1993, was switched from cyclosporine to tacrolimus in June 2000 due to deterioration of renal function. Thereafter, he began to complain of muscle cramps in both quadriceps with an increased CPK and EMG findings of polyneuropathy. A muscle biopsy demonstrated acute myositis. Prednisone was administered with amelioration of the patient’s symptoms, but with persistently increased CPK and myoglobin levels. In February 2001, mycophenolate mofetil was introduced and tacrolimus tapered to 3 mg daily to seek a toxic role of this immunosuppressant, since there was no other cause of myositis. A sudden decrease in CPK was observed, but the complete normalization took place only after its withdrawal in September 2002. This case represents a tacrolimus-associated myositis.
T
ACROLIMUS-BASED THERAPY produces a significantly reduced risk of graft failure.1 It has also been employed as rescue therapy for a sudden increase in serum creatinine.2 Although tacrolimus has been advocated as an agent for treatment of myositis,3,4 we herein report a case of a transplanted patient with a histologically proven myositis associated with tacrolimus given as a rescue therapy. This myositis was cured by tacrolimus tapering and resolved by its withdrawal. CASE REPORT A 55-year-old Caucasian man received a second renal graft in July 1993. The previous graft had lasted from January 1987 to May 1990. The only evident comorbidities were hypertension and a HCV-associated hepatitis that had been treated with Ribavirin from September 1999, and subsequently tapered due to anemia and discontinued thereafter in July 2000. His antihypertensive treatment included daily doses of doxasozin (4 mg) and nifedipine (30 mg). He never received statins for abnormal lipid values. His immunosuppressive treatment initially included prednisone (5 mg), cyclosporine (250 mg) and azathioprine (50 mg). The last agent was withdrawn in July 1999 due to leukopenia. In August 1999, he experienced deterioration in renal function (serum creatinine peaking at 2.7 mg/dL from a baseline value of 1.7 mg/dL) associated with 24-hour proteinuria of 2.2 g and gum hypertrophy, leading to prescription of tacrolimus (5 mg) to replace cyclosporine. In September 1999, tacrolimus was tapered to 4 mg daily due to high serum levels (14 ng/mL). In June 2000 (Fig 1) the patient began to complain of bilateral quadriceps pain with difficulties walking and standing. Over 3 weeks the CPK levels increased from 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.03.018 708
300 to 420 U/L. A neurological evaluation performed in August recommended an EMG, which showed a reduction in voltage amplitude (Fig 2a), and a muscle biopsy, which revealed small infiltrates constituted with lymphocytes and monocytes around apparently normal muscular fibers as well as focally within the fibers (see arrows in Fig 3a, hematoxylin and eosin staining) accompanied by atrophy of type 2B fibers (Fig 3b, ATPase staining). These findings are both diagnostic of myositis. Prednisone was increased to 25 mg daily for 3 weeks and then tapered to 12.5 mg for another 3 weeks with a mild improvement in the muscular symptoms but a persistently increased CPK (400 U/L). In February 2001, tacrolimus was tapered to 3 mg daily and mycophenolate mofetil was introduced at 1000 mg daily to test a possible toxic role of tacrolimus in the genesis of the myositis (see Fig 1). In March 2002, a further reduction of tacrolimus to 2 mg daily was accompanied by a decrease in CPK (238 U/L). However, there was a persistent elevation of myoglobin levels (367 g/L). Only withdrawal of tacrolimus in September 2002 was followed by myoglobin levels within normal values. At present the patient is asymptomatic and in good general condition with a serum creatinine of 1.8 mg/dL. The last EMG (May 2003) also demonstrated that the polyneuropathy had improved (Fig 2b).
From the Nephrology, Dialysis, and Renal Transplantation Unit, S. Orsola, Malpighi University Hospital, Bologna, Italy. Address reprint requests to C. Campieri, Nephrology, Dialysis, and Renal Transplant Unit, S. Orsola, Malpighi University Hospital, Via Massarenti 9, 40138 Bologna, Italy. E-mail: [email protected] © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36, 708 –710 (2004)
TACROLIMUS-ASSOCIATED MYOSITIS
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Fig 1. The course of CPK and myoglobin levels parallels the tapering of tacrolimus. EMG, biopsy, and muscle enzymes helped in the diagnosis of myositis and in the follow-up to recovery.
CONCLUSIONS
The neurotoxic effects of tacrolimus are well documented,5 particularly in kidney transplant patients.6 They may be triggered by hypertension, liver failure, hypomagnesemia, or acyclovir treatment.5 Even if a therapeutic role in the treatment of myositis has been suggested, up to now, no
case of tacrolimus-associated myositis has been reported in the PubMed selected literature. This case seems to fulfill the criteria for a tacrolimus-associated myositis. In fact, in years preceeding the use of tacrolimus, symptoms of myositis had never been reported in this patient. The symptoms were manifested 10 months after inception of tacrolimus
Fig 2. (a) Electromyography (August 2000). Reduction of voltage amplitude (as demonstrated by arrows) after stimulation of peroneal nerve. This finding is compatible with a neuropathy. (b) Electromyography (May 2003). Significant improvement of voltage amplitude of the peroneal nerve demonstrating an improved neuropathy.
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ORLANDI, CAMPIERI, MOSCONI ET AL
Fig 3. (a) Muscle biopsy (hematoxylin and eosin stain). Small infiltrates constituted of lymphocytes and monocytes around the apparently normal muscular fibers and focally within the fibers (see arrows). (b) Muscle biopsy (ATPase stain). Type 2B fibers appear atrophied (see arrows).
treatment. During the same interval, no other drug with a probable myotoxic effect was administered. The tapering of tacrolimus was followed in parallel by a decrease in enzymatic abnormalities of myositis. Only complete withdrawal of tacrolimus led to a normalization of CPK or myoglobin levels. The time during which tacrolimus was tapered and discontinued lasted about 20 months; during this time recovery was proportional to the decrease in the daily dosage of tacrolimus (Fig 1). Finally, no infection was detected during this time. We therefore suggest the role of tacrolimus in the onset and reversal of myositis. We cannot exclude that other mechanisms, as already described for the neurotoxic effects, which could have acted synergistically with tacrolimus to produce myositis. This patient in fact was hypertensive, had mild HCV-related hepatitis, and persistent mild hypomagnesemia. Thus this clinical picture, may be termed tacrolimus-associated myositis.
REFERENCES 1. Vincenti F, Jensik SC, Filo RS, et al: A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: evidence for improved allograft survival at five years. Transplantation 73:775, 2002 2. Jang HJ, Kim SC, Han DJ: Tacrolimus for rescue theraphy in refractory renal allograft rejection. Transplant Proc 32:1765, 2000 3. Oddis CV, Shurba FC, Elmagd KA, et al: Tacrolimus in refractory polymiositis with interstitial lung disease. Lancet 353: 1762, 1999 4. Ueda M, Makinodan R, Matsumura M, et al: Successful treatment of amyopathic dermatomyositis with topical tacrolimus. Br J Dermatol 148:595, 2003 5. Bechstein WO: Neurotoxicity of calcineurin inhibitors: impact and clinical management. Transpl Int 13:313, 2000 6. Veroux P, Veroux M, Puliatti C, et al: Tacrolimus-induced neurotoxicity in kidney transplant recipients. Transplant Proc 34:3188, 2002
T
ACROLIMUS-BASED THERAPY produces a significantly reduced risk of graft failure.1 It has also been employed as rescue therapy for a sudden increase in serum creatinine.2 Although tacrolimus has been advocated as an agent for treatment of myositis,3,4 we herein report a case of a transplanted patient with a histologically proven myositis associated with tacrolimus given as a rescue therapy. This myositis was cured by tacrolimus tapering and resolved by its withdrawal. CASE REPORT A 55-year-old Caucasian man received a second renal graft in July 1993. The previous graft had lasted from January 1987 to May 1990. The only evident comorbidities were hypertension and a HCV-associated hepatitis that had been treated with Ribavirin from September 1999, and subsequently tapered due to anemia and discontinued thereafter in July 2000. His antihypertensive treatment included daily doses of doxasozin (4 mg) and nifedipine (30 mg). He never received statins for abnormal lipid values. His immunosuppressive treatment initially included prednisone (5 mg), cyclosporine (250 mg) and azathioprine (50 mg). The last agent was withdrawn in July 1999 due to leukopenia. In August 1999, he experienced deterioration in renal function (serum creatinine peaking at 2.7 mg/dL from a baseline value of 1.7 mg/dL) associated with 24-hour proteinuria of 2.2 g and gum hypertrophy, leading to prescription of tacrolimus (5 mg) to replace cyclosporine. In September 1999, tacrolimus was tapered to 4 mg daily due to high serum levels (14 ng/mL). In June 2000 (Fig 1) the patient began to complain of bilateral quadriceps pain with difficulties walking and standing. Over 3 weeks the CPK levels increased from 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.03.018 708
300 to 420 U/L. A neurological evaluation performed in August recommended an EMG, which showed a reduction in voltage amplitude (Fig 2a), and a muscle biopsy, which revealed small infiltrates constituted with lymphocytes and monocytes around apparently normal muscular fibers as well as focally within the fibers (see arrows in Fig 3a, hematoxylin and eosin staining) accompanied by atrophy of type 2B fibers (Fig 3b, ATPase staining). These findings are both diagnostic of myositis. Prednisone was increased to 25 mg daily for 3 weeks and then tapered to 12.5 mg for another 3 weeks with a mild improvement in the muscular symptoms but a persistently increased CPK (400 U/L). In February 2001, tacrolimus was tapered to 3 mg daily and mycophenolate mofetil was introduced at 1000 mg daily to test a possible toxic role of tacrolimus in the genesis of the myositis (see Fig 1). In March 2002, a further reduction of tacrolimus to 2 mg daily was accompanied by a decrease in CPK (238 U/L). However, there was a persistent elevation of myoglobin levels (367 g/L). Only withdrawal of tacrolimus in September 2002 was followed by myoglobin levels within normal values. At present the patient is asymptomatic and in good general condition with a serum creatinine of 1.8 mg/dL. The last EMG (May 2003) also demonstrated that the polyneuropathy had improved (Fig 2b).
From the Nephrology, Dialysis, and Renal Transplantation Unit, S. Orsola, Malpighi University Hospital, Bologna, Italy. Address reprint requests to C. Campieri, Nephrology, Dialysis, and Renal Transplant Unit, S. Orsola, Malpighi University Hospital, Via Massarenti 9, 40138 Bologna, Italy. E-mail: [email protected] © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36, 708 –710 (2004)
TACROLIMUS-ASSOCIATED MYOSITIS
709
Fig 1. The course of CPK and myoglobin levels parallels the tapering of tacrolimus. EMG, biopsy, and muscle enzymes helped in the diagnosis of myositis and in the follow-up to recovery.
CONCLUSIONS
The neurotoxic effects of tacrolimus are well documented,5 particularly in kidney transplant patients.6 They may be triggered by hypertension, liver failure, hypomagnesemia, or acyclovir treatment.5 Even if a therapeutic role in the treatment of myositis has been suggested, up to now, no
case of tacrolimus-associated myositis has been reported in the PubMed selected literature. This case seems to fulfill the criteria for a tacrolimus-associated myositis. In fact, in years preceeding the use of tacrolimus, symptoms of myositis had never been reported in this patient. The symptoms were manifested 10 months after inception of tacrolimus
Fig 2. (a) Electromyography (August 2000). Reduction of voltage amplitude (as demonstrated by arrows) after stimulation of peroneal nerve. This finding is compatible with a neuropathy. (b) Electromyography (May 2003). Significant improvement of voltage amplitude of the peroneal nerve demonstrating an improved neuropathy.
710
ORLANDI, CAMPIERI, MOSCONI ET AL
Fig 3. (a) Muscle biopsy (hematoxylin and eosin stain). Small infiltrates constituted of lymphocytes and monocytes around the apparently normal muscular fibers and focally within the fibers (see arrows). (b) Muscle biopsy (ATPase stain). Type 2B fibers appear atrophied (see arrows).
treatment. During the same interval, no other drug with a probable myotoxic effect was administered. The tapering of tacrolimus was followed in parallel by a decrease in enzymatic abnormalities of myositis. Only complete withdrawal of tacrolimus led to a normalization of CPK or myoglobin levels. The time during which tacrolimus was tapered and discontinued lasted about 20 months; during this time recovery was proportional to the decrease in the daily dosage of tacrolimus (Fig 1). Finally, no infection was detected during this time. We therefore suggest the role of tacrolimus in the onset and reversal of myositis. We cannot exclude that other mechanisms, as already described for the neurotoxic effects, which could have acted synergistically with tacrolimus to produce myositis. This patient in fact was hypertensive, had mild HCV-related hepatitis, and persistent mild hypomagnesemia. Thus this clinical picture, may be termed tacrolimus-associated myositis.
REFERENCES 1. Vincenti F, Jensik SC, Filo RS, et al: A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: evidence for improved allograft survival at five years. Transplantation 73:775, 2002 2. Jang HJ, Kim SC, Han DJ: Tacrolimus for rescue theraphy in refractory renal allograft rejection. Transplant Proc 32:1765, 2000 3. Oddis CV, Shurba FC, Elmagd KA, et al: Tacrolimus in refractory polymiositis with interstitial lung disease. Lancet 353: 1762, 1999 4. Ueda M, Makinodan R, Matsumura M, et al: Successful treatment of amyopathic dermatomyositis with topical tacrolimus. Br J Dermatol 148:595, 2003 5. Bechstein WO: Neurotoxicity of calcineurin inhibitors: impact and clinical management. Transpl Int 13:313, 2000 6. Veroux P, Veroux M, Puliatti C, et al: Tacrolimus-induced neurotoxicity in kidney transplant recipients. Transplant Proc 34:3188, 2002