Myalgia: an uncommon or underestimated side effect of mycophenolate mophetil after transplantation?

Sir,

Mycophenolate mophetil (MMF) is widely used after transplantation and in several autoimmune disorders. Because of its recent introduction and its use in combination with other drugs, uncommon or overlapping side effects, such as severe myalgia, may be difficult to detect.

According to a systematic search on Medline and Embase (to 2003, week 38; combining Mesh-Emtree and free terms related to MMF and to muscle-myalgia), only four of the 317 titles retrieved described myalgia as a severe or common MMF side effect. These four papers dealt with autoimmune diseases (uveitis, psoriasis and Wegener granulomatosis) [14]; a further report suggested a facilitating effect on myalgia during quinupristin-dalfopristin therapy [5].

Even if myalgia is considered among the side effects of MMF in clinical trials, its severity is usually minor and it is not considered among the common causes of drop-out from MMF [6].

We would like to bring attention to this uncommon side effect, by reporting on two patients who developed severe, invalidating myalgia, presumably linked to MMF, after kidney and pancreas grafts.

Case 1. A 42-year-old type 1 diabetic woman underwent a successful pancreas graft, in the presence of laser-treated retinopathy, neuropathy, and biopsy-proven diabetic nephropathy. Chronic immunosuppressive therapy consisted of tacrolimus (levels 10–15 ng/ml in the first 2 months, 8–12 ng/ml at 3–12 months), MMF 2 g, methylprednisone tapered at 5 mg/day at 6 months.

Before transplantation, during a tacrolimus-challenge test to assess her renal reponse, her tacrolimus levels reached 42 ng/ml, and remained above 20 ng/ml for a week (presumably because of the interaction with bioflavones contained in herbal teas). During this episode, she experienced all main tacrolimus side effects, including nausea, vomiting, anxiety, insomnia, restless leg syndrome and lower limb neuropathy. The symptoms progressively disappeared with tacrolimus clearance.

Since the early post-transplant period, she complained of muscular pain, particularly in the lower limbs, which was exacerbated by exercise, but present also at rest. The symptoms were reported as completely different from those experienced during tacrolimus challenge. Three months after transplantation, the myalgia was severe enough to impair her daily activities.

Renal function was in the normal range (serum creatinine 0.8 mg/dl, creatinine clearance 96 ml/min, physiological proteinuria). Tacrolimus levels were in the prescribed range; support therapy consisted in thrimetoprim-sulphametoxazole, acetylsalycilate and omeprazole.

Viral, immunological and metabolic-endocrinologic tests were normal; therefore, the myalgia was hypothesized as pharmacological, but unrelated to tacrolimus, and unresponsive to corticosteroid tapering. Consequently, an adverse effect of MMF seemed the most likely explanation. MMF kinetic was tested (2 months after graft: basal level 1.8 µg/ml, second hour 9 µg/ml; 5 months after graft: basal level 2.2 µg/ml, second hour 11.3 µg/ml); even though the ‘ideal levels’ were not yet fully defined in the literature, MMF was reduced from 2 to 1.5 g/day; the symptoms improved in few days and disappeared in 3 weeks.

Case 2. A 57-year-old man, a recipient of a renal graft 12 years before (serum creatinine 1.2 mg/dl, creatinine clearance 102 ml/min, microalbuminuria, normal blood count and liver tests), was switched from azathioprine to MMF because of severe gouty arthritis, to allow allopurinol therapy. Further therapy (cyclosporin A 200 mg/day, felodipine, acetylsalycilate and isosorbide mononitrate) was unchanged. A few days after starting MMF (1 g/day), he complained of diffuse arthromyalgic aches, mainly in the lower limbs, fatigue and ankle oedema. The myalgia was severe enough to require a return to azathioprine, 2 weeks later. Rapid improvement was observed, with complete recovery within 1 week.

During the short period of MMF therapy, cyclosporin A levels were in the prescribed range (basal prescribed range 80–120 ng/ml; levels 84, 121 ng/ml), and support therapy was unchanged.

Interestingly, in both cases, the usual adverse effects of MMF were not recorded: gastrointestinal symptoms and leucopoenia were both absent, and serum immunoglobulins were in the normal range in case 1, in which they were periodically tested. Case 1, however, was severely anaemic (haemoglobin nadir 7 g/dl, with slow response to darbopoietin alpha). Even if less common than isolated leucopenia, anaemia is also reported as side effect of immunosuppressive regimens containing MMF, in particular in the first phases after transplantation.

As it occurs in the case of relatively new drugs, the pharmacological interactions are only partially known and a role of concomitant therapies cannot be excluded. However, the two patients did not share any immunosuppressive agent, nor any support therapy, with the exception of acetylsalicylate at low doses, and the calcineurin inhibitors (tacrolimus in case 1 and cyclosporin A in case 2), known to interfere with MMF metabolism, were in the usual ranges in both, thus suggesting an individual predisposition in the development of this unusual problem.

Even if only an MMF challenge could definitely prove the role of the drug, the myalgia was severe enough to avoid proposing such a trial to these two patients.

Solid organ transplants are the most common worldwide indication for MMF. The concomitant use of corticosteroids, known to induce myopathy, and of calcineurin inhibitors, whose side effects include neuropathic pain, may mask the presence of this occasionally severe MMF side effect.

Higher awareness may lead to its precise quantification in transplantation medicine.

Conflict of interest statement. None declared.

Giorgina B. Piccoli, Maura Rossetti, Cesare Guarena, Valentina Consiglio, Elisabetta Mezza, Giorgio Soragna, Giorgio Grassi1, Manuel Burdese, Massimo Gai, Piero Marchetti2, Ugo Boggi3 and Giuseppe Paolo Segoloni

University of Torino1 Diabetic Care Outpatient Unit University of Torino, Italy2 Endocrinology and Metabolism Department University of Pisa, Italy3 UO General and Transplantation Surgery University of Pisa, Italy Email: gbpiccoli{at}hotmail.com or gbpiccoli{at}yahoo.it

References

  1. Greiner K, Varikkara M, Santiago C, Forrester JV. Efficiency of mycophenolate mofetil in the treatment of intermediate and posterior uveitis. Ophthalmologe 2002; 99: 691–694[CrossRef][ISI][Medline]
  2. Mahe E, Meyer O, Descamps V, Picard-Danhan C, Crickx B. Early severe and transient arthralgia induced by mycophenolate mophetil in a patient with erythrodermal psoriasis. Ann Dermatol Vener 2002; 129: 1054–1055[ISI]
  3. Geilen CC, Arnold M, Orfanos CE. Mycophenolate mofetil as a systemic antipsoriatic agent: positive experience in 11 patients. Br J Dermatol 2001; 144: 583–586[CrossRef][ISI][Medline]
  4. Maes B, Oellerich M, Ceuppens JL et al. A new acute inflammatory syndrome related to the introduction of mycophenolate mofetil in patients with Wegener's granulomatosis. Nephrol Dial Transplant 2002; 17: 923–926[Abstract/Free Full Text]
  5. Carver PL, Whang E, Kauffman CA, Malani PN. Risk factors for arthralgias or myalgias associated with quinupristin-dalfopristin therapy. Pharmacotherapy 2003; 23: 159–164[ISI][Medline]
  6. de Sevaux RG, Gregoor PJ, Hene RJ et al. A controlled trial comparino two doses of cyclosporine in conjunction with mycophenolate mofetil and corticosteroids. J Am Soc Nephrol 2001; 12: 1750–1757[Abstract/Free Full Text]




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