EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Drug-induced toxic myopathy is a complication of familial Mediterranean fever in patients who receive colchicine, especially when combined with cyclosporine. Protracted febrile myalgia syndrome is a severe form of familial Mediterranean fever. A 34-year-old man who had familial Mediterranean fever for > 15 years developed kidney failure because of secondary amyloidosis. He received living-unrelated-donor kidney transplant that functioned normally. He was on colchicine prophylaxis that was continued after transplant, and he received immuno-suppression induction with antithymocyte globulin and maintenance with prednisolone, mycophenolate mofetil, and cyclosporine. After 2 months, he presented with severe myopathy and elevated creatine kinase. Muscle biopsy showed evidence of drug-induced toxic myopathy, most likely caused by cyclosporine in combination with colchicine. Cyclosporine was replaced with sirolimus and colchicine was stopped. Symptoms partially improved and creatine kinase decreased to normal. The prednisolone dosage was reduced gradually to 5 mg daily. At 8 months after transplant, he was readmitted because of severe arthralgia, prolonged fever, pleuritic chest pain, diffuse abdominal pain, purpuric rash, macroscopic hematuria, proteinuria, and diarrhea. The C-reactive protein and erythrocyte sedimentation rate were elevated. The clinical diagnosis was recurrent familial Mediterranean fever presenting as protracted febrile myalgia syndrome. Despite the history of toxic myopathy, he was restarted on colchicine (0.5 mg, twice daily), and colchicine was well tolerated. There was marked improvement of most symptoms within several days. Follow-up 5 years later showed normal kidney graft function and no familial Mediterranean fever activity on colchicine prophylaxis. In summary, familial Mediterranean fever reactivation and protracted febrile myalgia syndrome after kidney transplant may be treated with colchicine and modulation of immunosuppressive therapy.

Key words : Amyloidosis, Colchicine, Cyclosporine, Immunosuppression, Myopathy

Familial Mediterranean fever (FMF) is a disorder characterized by sporadic, paroxysmal attacks of fever and serosal inflammation.^1,2 Acute attacks of FMF are accompanied by elevation in serum markers of systemic inflammation.^3,4 The disorder is inherited as an autosomal recessive trait and has been described in several ethnic groups primarily in the Mediterranean region: Sephardic Jews, Armenians, Turks, North Africans, Arabs, Greeks, and Italians.1 However, the disease is not restricted to these groups.¹

Amyloidosis, a common long-term complication of FMF, can be delayed by colchicine prophylaxis.^5-9 Amyloid involvement of an allograft is expected after transplant in patients who have maintenance colchicine dosage reduced to 0.5 mg daily.⁹ It may be preferable to modulate immunosuppressive drugs to enable giving an adequate prophylactic dosage of colchicine that may prevent amyloid involvement of the allograft.⁹

Myalgias, reported in 25% patients who have FMF, may be part of a spontaneous, exercise-induced, or protracted febrile myalgia syndrome (PFMS).^2-4 Colchicine-induced myotoxicity is well-described but a rare adverse event.² Neuromyopathy caused by colchicine can occur in patients who have an acute overdose or chronically administered therapeutic doses.^6,7 The pathogenesis of colchicine neuro-myopathy is unknown, but the major risk factor may be increased plasma colchicine levels associated with chronic kidney disease.⁸ The risk of colchicine neuromyopathy is increased in organ transplant recipients who are treated with cyclosporine, especially when the patient receives other drugs that are known to cause neuromyopathy.^9-11 Myopathy is a frequent adverse event in kidney transplant recipients who are treated with cyclosporine and colchicine because cyclosporine impairs the metabolism of colchicine.^9-11 The clinical improve-ment that is associated with discontinuation of colchicine supports a central role of this drug as a cause of myopathy.^10,11

The syndrome PFMS is a form of myalgia that may occur in patients who have FMF, and is characterized by severe paralyzing myalgia, high fever, abdominal pain, diarrhea, arthritis or arthralgia, and transient vasculitic rashes mimicking Henoch-Schönlein purpura.^12-20 The earliest description of PFMS in patients who have FMF was in 1994, and PFMS has been reported in sporadic case reports and 11% patients who have FMF.^12,14

The 5 Mediterranean fever gene (MEFV) mutations of the M694V gene may cause FMF and frequently occur in Arabs.¹⁵ Patients who have FMF and who develop amyloidosis and PFMS frequently are homozygous for the M694V gene.¹⁵

A review of the literature showed no previous report of a kidney transplant recipient who had FMF and PFMS. We treated a patient who had FMF, developed drug-induced toxic myopathy, and developed PFMS after discontinuing colchicine prophylaxis. Immunosuppressive drug modulation and resuming colchicine were successful in maintaining long-term remission of FMF and normal graft function.

A 34-year-old Lebanese Arab man had FMF for > 15 years and M694V gene mutation. He developed renal failure because of amyloidosis secondary to FMF. He was on hemodialysis for 6 months until he received a living-unrelated-donor kidney transplant that functioned normally. He was on colchicine prophylaxis that was continued after transplant, and he had no acute attacks of FMF for 3 years before transplant. The immunosuppressive regimen included induction with antithymocyte globulin and maintenance therapy with prednisolone, mycophenolate mofetil, and cyclosporine.

At 2 months after transplant, he presented with severe myalgia and was diagnosed with severe myopathy because of high creatine kinase level (32.6 μkat/L [1950 U/L]) and myopathic changes on electromyography and nerve conduction studies. He was not taking any statin drugs and his serum electrolytes were normal. Muscle biopsy showed vacuolar changes in muscle cells that were seen best on frozen section, and evaluation with special stains and electron microscopy confirmed that the vacuoles originated from lysosomes. The clinical impression was that the myopathy was caused by cyclosporine given with colchicine. The cyclosporine and colchicine were discontinued, and sirolimus was started. The creatine kinase level returned to normal, but the residual mild chronic myalgia persisted and he required oral analgesics. The dosage of prednisolone was reduced gradually to 5 mg daily.

At 8 months after transplant, he was readmitted to the hospital because of severe arthralgia, prolonged fever, pleuritic chest pain, diffuse abdominal pain, purpuric rash, macroscopic hematuria, proteinuria, and diarrhea. The white blood cell count (12 × 10⁹/L), creatine kinase level (33.7 μkat/L [2019 U/L]), C-reactive protein (1829 nmol/L [192 mg/L]), and erythrocyte sedimentation rate were elevated (120 mm/h). Other tests for infection, malignancy, hyperparathyroidism, and rheumatic diseases were negative. The clinical diagnosis was acute attack of FMF presenting as PFMS because he was not receiving colchicine for 6 months. Despite the history of toxic myopathy 6 months earlier, he was treated with increased doses of steroids and colchicine (0.5 mg, twice daily). The colchicine was well tolerated and there was marked improvement of most symptoms within several days. Follow-up for 5 years showed that the kidney graft function remained normal and he had no additional FMF attacks.

The syndrome PFMS is characterized by severe paralyzing myalgia, high fever, abdominal pain, diarrhea, arthritis, arthralgia, and transient vasculitic rashes mimicking Henoch-Schönlein purpura.^14-20 It is associated with acute attacks of FMF and elevation of serum markers of systemic inflammation such as leukocytosis with predominant neutrophils and elevated erythrocyte sedimentation rate, β2-microglobulin, C-reactive protein, serum amyloid protein, and fibrinogen levels. The PFMS may persist for several weeks and involve the abdominal muscles.¹⁹ Vasculitis may occur including polyarteritis nodosa and Henoch-Schönlein purpura.^12,13,20 Kidney involvement is common. Steroid treatment may shorten the course of PFMS, but PFMS may recur despite colchicine prophylaxis.⁴

Secondary amyloidosis, a common long-term complication of FMF, may be delayed by colchicine prophylaxis. Amyloid involvement of an allograft may occur after transplant in patients who have colchicine dosage reduced to 0.5 mg daily.⁹ The development of amyloidosis of the kidney graft in patients who have FMF usually is preventable with colchicine at a dosage ≥ 1.5 mg/d.⁵ Patients who are resistant to colchicine may need treatment with an interleukin 1 inhibitor (anakinra), which may be effective in patients who have FMF, secondary amyloidosis, kidney transplant, and resistance to colchicine treatment.^21-22

Colchicine-induced myotoxicity is well described but is a rare adverse event.² Neuromyopathy with colchicine may occur in patients who have acute overdose or chronic administration of therapeutic doses.^6,7 The patient who has chronic colchicine neuromyopathy typically will have been treated with daily low-dose colchicine (0.5-1.0 mg/d) for several months to years, but myopathy has occurred in 1 reported patient within 2 weeks after starting colchicine therapy (0.6 mg, 3 times daily).¹⁶

The pathogenesis of colchicine neuromyopathy is unknown. However, the effect of colchicine on microtubule function may cause impaired axonal transport in peripheral nerves and changes in the muscle cytoskeleton that may impair normal movement of lysosomes in the cell.⁶ Chronic kidney disease may cause increased plasma colchicine levels and is a major risk factor for neuromyopathy.⁸The risk also is increased in organ transplant recipients who are treated with cyclosporine, which impairs the metabolism of colchicine. Affected patients typically present with proximal muscle weakness, often more prominent in the lower than upper extremities. Creatine kinase levels usually are elevated 10 to 20 times that of normal levels. Electromyography and nerve conduction studies may show myopathic changes and axonal polyneuropathy that usually is asymptomatic or may cause mild sensory symptoms and diminished deep tendon reflexes. Myotonic discharges may be noted and may correlate with clinical findings of myotonia.^17,18 Muscle biopsy may shows vacuolar changes in muscle cells that are seen best on frozen section because the vacuoles may be damaged by paraffin fixation. Special stains and electron microscopy may confirm that the vacuoles originate from lysosomes.^6,7 Muscle weakness may resolve and creatine kinase levels may return to normal within several days to weeks after discontinuing colchicine, but the neuropathy may resolve more slowly.

Colchicine neuromyopathy may be confused with polymyositis. Distinguishing features include the presence of neuropathy by electrodiagnostic testing and the appearance of vacuoles and absence of inflammation in the muscle biopsy of patients treated with colchicine. In addition, rapid resolution of the myopathy after withdrawal of colchicine may support the diagnosis and help avoid the unnecessary use of glucocorticoids that are indicated for polymyositis.

Cyclosporine neuromyopathy may be associated with other myotoxic drugs that may cause muscular symptoms.^10,11 Myopathy is a frequent adverse event in kidney transplant recipients who receive both cyclosporine and colchicine.^10,11 Discontinuing colchicine usually causes clinical improvement and confirms the effect of colchicine in causing myopathy.^10,11 The incidence of 3 clinical patterns of myalgia identified in FMF is 8% in the spontaneous pattern, 81% in the exercise-induced pattern, and 11% in patients who have PFMS.¹² The 3 patterns differ in the severity of pain and fever and duration of the episode. In 33 children who had exercise-induced myalgia in whom response to colchicine could be reliably assessed, a favorable response was achieved in 97% patients. A marked response to corticosteroids was observed in 3 children who had PFMS.¹² An 11-year-old Turkish girl had a second PFMS attack before being diagnosed with FMF, and this illustrates the importance of myalgia in the diagnosis of FMF despite the absence of other symptoms.¹³ In 14 patients who had FMF and who were admitted because of an attack of severe disabling myalgia, fever, high erythrocyte sedimentation rate, and hyperglobulinemia that persisted for 6 weeks, a prompt response to corticosteroid therapy was observed.¹⁴ A 30-year-old pregnant Turkish woman who had known FMF and was receiving colchicine prophylaxis developed severe myalgia for 8 weeks; this emphasizes the importance of a different clinical pattern of PFMS even in the absence of other symptoms.³

The 5 MEFV mutations of the M694V gene that may cause FMF occur frequently in Arabs. In a study of 407 patients, 12 patients developed PFMS and 5 patients (42%) were homozygous for the M694V gene. The M694V gene is the most common gene mutation in Arab patients who have FMF and may be associated with the development of amyloidosis and PFMS.¹⁵ The present patient was an Arab who had the M694V gene mutation, FMF, and secondary amyloidosis, and he had good response to colchicine prophylaxis before transplant. The combination of cyclosporine and colchicine after transplant precipitated toxic myopathy that was confirmed with a muscle biopsy and responded to discontinuation of both drugs. The FMF was reactivated in the absence of colchicine for 6 months and presented with PFMS. This case demonstrates the unfavorable combination of cyclosporine and colchicine and the need to modulate immunosuppressive drugs to maintain remission for patients who have FMF and kidney transplant. In the present patient, drug-induced toxic myopathy was precipitated by the combination of cyclosporine and colchicine and not cyclosporine or colchicine alone. We successfully treated him again with colchicine after replacing cyclosporine with sirolimus. The patient responded well to steroids and restarting colchicine and recovered within several weeks. Literature review showed no previous patient who had kidney transplant and who was successfully treated again with colchicine for PFMS after discontinuation for 6 months because of documented drug-induced myopathy. Therefore, cyclosporine treatment in the presence of colchicine may precipitate toxic myopathy, and colchicine may be restarted despite a history of toxic myopathy or PFMS. The present patient did not have an exacerbation of FMF or severe myopathy during 5 years after cyclosporine was replaced with sirolimus and colchicine was resumed. The modulation of immunosuppression enabled the resumption of colchicine prophylaxis, despite the history of toxic myopathy, to avoid recurrence of FMF.

In summary, FMF reactivation after kidney transplant may be treated with colchicine and immunosuppressive drug modulation. The present patient presented with PFMS and responded to restarting colchicine despite the history of drug-induced toxic myopathy. Discontinuation of cyclosporine enabled maintenance of adequate colchicine prophylaxis.

Volume: 13 Issue: 2 April 2015

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