Colchicine myopathy in a patient with familial mediterranean fever and normal renal function
Arthritis & Rheumatism (Arthritis Care & Research)Vol. 49, No. 4, August 15, 2003, pp 614 – 616DOI 10.1002/art.11185 2003, American College of Rheumatology
Colchicine Myopathy in a Patient With Familial Mediterranean Fever and Normal Renal Function EUGENE Y. KISSIN,1 JOSEPH C. CORBO,2 FRANCIS A. FARRAYE,1 AND PETER A. MERKEL1 Introduction
trexate, and infliximab. At the time of her presentation
Patients with familial Mediterranean fever (FMF) rou-
with weakness, the Crohn’s disease was under good con-
tinely take large daily doses of colchicine to both prevent
trol with balsalazide alone. Other medical conditions in-
and abort acute attacks (1,2) and to reduce the risk of
cluded gastroesophageal reflux disease and irritable bowel
developing amyloidosis (3). Unfortunately, colchicine can
syndrome. In October 2001 her medications included ome-
also cause a number of toxic side effects, including neu-
prazole (20 mg/day), balsalazide (2.25 gm 3 times per day),
romyopathy. Almost all cases of colchicine neuromyopa-
colchicine (1.8 mg/day), calcium carbonate (500 mg 3
thy previously described have been associated with renal
times per day), and amitriptyline (50 mg/day).
insufficiency (4). We report the first case of biopsy-con-
Physical examination revealed a weight of 48 kg, blood
firmed myopathy due to chronic colchicine administration
pressure of 100/70 mm Hg and pulse of 80 beats/minute.
in an adult with FMF and normal renal function.
Neurologic examination revealed 5–/5 strength in theproximal upper extremity muscle groups and 4ϩ/5strength in the proximal lower extremity muscle groups
bilaterally. She had great difficulty performing 1 deep knee
A 38-year-old woman with FMF and Crohn’s disease pre-
bend (squat). Distal muscle groups had normal strength.
sented in October 2001 for evaluation of worsening muscle
Deep tendon reflexes were absent in the biceps, triceps,
weakness over the previous 3 years. She had difficulty
knees, and ankles bilaterally. Sensation to light touch, gait,
walking up stairs or doing overhead work. She reported no
and cranial nerve examination were normal. The results of
muscle pain, rash, fevers, Raynaud’s phenomenon, joint
the remainder of her physical examination were normal.
The patient’s laboratory studies were notable for the
The patient has carried the diagnosis of FMF (homozy-
following values: creatine phosphokinase (CPK) enzyme
gous for mutation V726A) since childhood. She had recur-
level 889 U/liter (normal 30 –250 U/liter), aldolase 9.5
rent attacks every 3– 4 weeks lasting 24 – 48 hours accom-
U/liter (normal 1.2–7.6 U/liter), white cell count 4,200/
panied by fevers to 40°C and abdominal or chest pains. Her
mm3, hematocrit 31%, platelet count 161,000/l, blood
symptoms had responded to treatment with 1.8 –2.4 mg of
urea nitrogen 6 mg/dl, creatinine 0.3 mg/dl, albumin 4.0
colchicine daily and she has been maintained on this
gm/dl (normal 3.5– 4.8 gm/dl), urinalysis results were nor-
dosage since her teenage years. She had not had any at-
mal. Abdominal fat aspirate was negative for amyloid.
Nerve conduction and electromyography studies re-
In 1997 the patient developed diarrhea and was diag-
vealed moderately severe denervation in the proximal
nosed with Crohn’s disease for which she was treated with
muscles of the upper and lower extremities, as well as
combinations of mesalamine, oral glucocorticoids, metho-
absent superficial peroneal sensory responses and low am-plitude sural sensory responses.
Muscle biopsy of the right quadriceps revealed central
Dr. Merkel is supported in part by a Mid-Career Develop-
rimmed vacuoles and endomysial fibrosis (Figure 1). There
ment Award in Clinical Investigation (NIH-NIAMS: K24
was marked variability of fiber size with atrophic fibers
AR-2224-01A1). 1Eugene Y. Kissin, MD, Francis A. Farraye, MD, MSc,
and few basophilic regenerating fibers. There was a noted
Peter A. Merkel, MD, MPH: Boston University School of
absence of necrotic fibers and a paucity of inflammatory
Medicine, Boston, Massachusetts; 2Joseph C. Corbo, MD,
infiltrate. Electron microscopy showed central longitudi-
PhD: Children’s Hospital and Harvard Medical School, Bos-
nal autophagic vacuoles containing aggregates of cellular
degradation products and exhibiting areas of myofibrillar
Address correspondence to Peter A. Merkel, MD, MPH, Arthritis Center E5, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118. E-mail: pmerkel@
Colchicine was discontinued following the muscle bi-
opsy in early November 2001 and no other medication
Submitted for publication August 8, 2002; accepted in
changes occurred. By March 2002 her strength gradually
revised form December 6, 2002.
improved, but her CPK enzyme level had only decreased
cause bone marrow failure and death (5). Myopathy andneuropathy are well recognized but rare toxicities of treat-ment with oral colchicine. Colchicine may lead to myop-athy by causing a toxic accumulation of lysosomal andautophagic vacuoles in myocytes through disruption of thecytoskeletal network by which these vacuoles are excreted(6).
Colchicine is bound by tissues in the extravascular
space because its volume of distribution is greater thantotal body water (7). Studies in mice have determined that,4 hours after intravenous administration, significantamounts of colchicine accumulate in the intestines, kid-neys, and spleen but not in blood, the brain, or muscles (8). However, colchicine concentrations in these tissues werenot evaluated at later time points. Others have found leu-kocytes to contain significant concentrations of colchicine10 days following intravenous administration (9). Colchi-cine and its metabolites are cleared through the bile (10)and urine (11), thus renal or hepatic dysfunction may leadto elevation of plasma colchicine levels and increase therisk of toxicity (12). Interestingly, the mean elimination
Figure 1. Conventional histology of muscle biopsy from right thigh. Hematoxylin-eosin stain a,b and trichrome stain c,d dem-
half-life for colchicine in patients with FMF is more than
onstrate variation in muscle fiber size (double arrow), centraliza-
twice as long as in healthy individuals, despite normal
tion of nuclei (small arrow), endomysial fibrosis (white arrow),
renal function and no evidence of amyloidosis (13).
and central vacuoles (arrowhead) in several myofibers. There is a
Kuncl et al described the characteristic features of col-
paucity of inflammatory cells and no necrosis of myofibrils.
chicine neuromyopathy in 12 patients (4). These features
to 482 U/liter. Normalization of CPK (138 U/liter) and
include proximal weakness, an elevation of creatine ki-
return of normal strength occurred by June 2002, 8 months
nase, proximal myopathic changes on electromyography,
after discontinuation of colchicine. The patient has not
axonal polyneuropathy on nerve conduction velocities,
had any attacks of FMF over these 8 months.
and vacuolar myopathy on muscle biopsy, all of which ourpatient exhibited. However, unlike the patients presented
by Kuncl et al, our patient had persistently normal renal
Our patient presented with an insidious onset of muscle
function. Furthermore, our patient’s CPK levels did not
weakness, CPK elevation, peripheral neuropathy, and a
return to normal for 8 months following discontinuation of
vacuolar myopathy on muscle biopsy. The resolution of
the offending drug, while normalization typically occurs
her symptoms with normalization of CPK enzymes follow-
ing discontinuation of colchicine further implicates col-
Three prior cases of colchicine-associated neuromyopa-
chicine as the cause of her myopathy. Colchicine is well
thy in patients with normal renal function have been re-
known for its toxic side effects. Even at low doses it can
ported (14,15). Two of these cases occurred in children
commonly cause gastrointestinal distress. When given via
with FMF. However, neither of these cases had evidence of
the intravenous route in doses greater than 2 mg, espe-
muscle involvement, with symptoms consisting only of
cially to patients with renal or hepatic insufficiency, it can
neuropathy. The third case occurred in a patient onchronic suppressive therapy for gout who, similar to ourpatient, also required a prolonged, 4-month period forresolution of myopathic toxicity (14).
Treatment of patients with FMF after the development
of colchicine myopathy is problematic. Over 9 years, 49%of patients with FMF will develop proteinurea due to renalamyloidosis if colchicine is not used, compared with just1.7% in patients compliant with colchicine therapy (3). One report of 10 patients describes interferon alfa beingused in an effort to abort attacks of FMF instead of colchi-cine (16). However, it is unknown whether interferon alfawill prevent the development of amyloidosis. As there issome evidence that colchicine can reverse or stabilizerenal amyloidosis, the risks of colchicine could potentially
Figure 2. Electron microscopy of muscle biopsy from right thigh.
be avoided until proteinuria first develops. Patients with
a, There are numerous autophagic vacuoles centrally located
previous myopathy could be then rechallenged with a
within the muscle fibers and containing heterogeneous material.
lower dose of colchicine (0.6 mg/day). This case illustrates
b, Numerous autophagic vacuoles produce extensive myofibrillar disarray.
the importance of continued clinical monitoring for col-
chicine toxicity in patients on long-term treatment, even
8. Back A, Walaszek E, Uyeki E. Distribution of radioactive
when renal and hepatic function is normal.
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