Coichicine myoneuropathy and renalLettersto theeditor I The cooperating clinics committee of the...
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Letters to the editor I The cooperating clinics committee of the American Rheumatism Association. A seven- day variability study of 499 patients with peripheral rheumatoid arthritis. Arthritis Rheum 1965; 8: 302-34. 2 Thompson P W, Silman A J, Kirwan J R, Currey H L F. Articular indices of joint inflammation in rheumatoid arthritis. Arthritis Rheum 1987; 30: 618-23. 3 Hench P S. The ameliorating effect of pregnancy on chronic atrophic (infectious rheumatoid) arthritis, fibrosis, and intermittent hydrarth- rosis. Proc Mayo Clin 1938; 13: 161-8. 4 Cecere F A, Persellin R H. The interaction of pregnancy and the rheumatic diseases. Clin Rheum Dis 1981; 7: 747. S Persellin R H. The effect of pregnancy on rheumatoid arthritis. Bull Rheum Dis 1976-7; 27: 922. 6 Granier L W. Clinical response of rheumatoid arthritis to postpartum plasma. JAMA 1951; 146: 995-7. 7 Josephs C. Observations on the treatment of rheumatoid arthritis by transfusions of blood from pregnant women. BMJ 1954; ii: 134-5. 8 Neustadt D H, Geiger J, Steinbrocker 0. Effect of postpartum plasma in rheumatoid arthritis. Ann Rheum Dis 1954; 13: 131-5. 9 Stimson W H. Studies on the immunosuppressive properties of a pregnancy-associated alpha-2 macroglobulin. Clin Exp Immunol 1975; 25: 199-206. 10 Persellin R H, Rhodes J. Inhibition of human monocyte Fc receptor and HLA-DR antigen expression by pregnancy alpha-2 glycoprotein. Clin Exp Immunol 1981; 46: 350-4. 11 Ostensen M, Schoultz Bvon, Husby G. Com- parison between serum alpha-2 pregnancy- associated globulin and activity of rheumatoid arthritis and ankylosing spondylitis during pregnancy. ScandjRheumatol 1983; 12: 315-8. 12 Unger A, Kay A, Griffin A J, Panayi G S. Disease activity and pregnancy-associated alpha-2 glycoprotein in rheumatoid arthritis during pregnancy. BMJ 1983; 286: 750-2. 13 Nicholas N S, Panayi G S, Norri A M E. Human pregnancy serum inhibits interleukin-2 production. Clin Exp Immunol 1984; 58: 587-95. 14 Nicholas N S, Panayi G S. Immunosuppressive properties of pregnancy serum on the mixed lymphocyte reaction. Brj Obstet Gynecol 1986; 93: 1251-5. 15 Arkwright P, Rademacher T, Marshall J, et al. Glycoprotein glycosylation and the immuno- suppressive effects of human pregnancy serum. J Reprod Immunol 1992; 21: 97-102. Coichicine myoneuropathy and renal dysfunction* Sir: Colchicine has been used in the treatment of gout and other diseases for over 200 years. Unusually high dosing regimens have resulted in multiorgan toxicity affecting the haemo- poietic, renal, nervous, dermatological, and musculoskeletal systems.' 2 Recently, a myoneuropathy has been noted in elderly patients taking low doses of colchicine over months to years.3 All patients had underlying chronic renal insufficiency, which is considered an important component of the syndrome. We report the development of colchicine myo- neuropathy in a woman with a transient prerenal illness. A 75 year old woman presented with a three week history of progressive proximal muscle weakness. The onset of her symptoms followed a 10 day diarrhoeal illness that spontaneously resolved. Her medical history included long- standing hypertension, degenerative joint disease, and suspected calcium pyrophosphate deposition disease, for which she had been treated with oral colchicine, 0-6 mg twice daily, over the preceding 16 months. Other drugs included a thiazide diuretic taken three times daily. Physical examination showed an elderly woman weighing 61-4 kg who appeared well. Motor testing disclosed weakness of the shoulder and pelvic girdle muscles with normal distal strength, and results of a neuro- logical examination were normal. Laboratory studies showed a creatine kinase of 646 IU/I (normal range 0-170 IU/l), and a Westergren sedimentation rate of 10 mm/h. Blood urea was 13-2 mmol/l and serum creatinine 132-6 iLmol/l. Renal function studies six months earlier had been within normal limits: blood urea 6-4 mmol/l and serum creatinine 106 1 Itmol/l. Electromyography showed myopathic changes characterised by resting membrane instability, positive sharp waves, fibrillations, and decreased amplitude and duration of potentials in proximal muscles. Nerve conduction studies were consistent with a mild polyneuropathy of the legs. A muscle biopsy showed vacuolation of 30% of myofibres without necrosis, inflammatory infiltrates, atrophy, or inclusion bodies (figure). Treat- ment with colchicine and diuretic was dis- continued. Ten days later her motor strength had returned to normal and the serum creatine kinase was 35 IU/I. Blood urea was 6-1 mmol/l and serum creatinine 114-9 ,tmol/l. In the nervous system colchicine interferes with neurotubule assembly causing a disruption of axonal transport.4 This probably accounts for the mild polyneuropathy seen in affected patients; however, the mechanism of injury in muscle, is less clear. In rat skeletal muscle an accumulation of 'large sarcoplasmic mem- branous bodies'-with presumed autophagic activity-appears two to three days after the intraperitoneal injection of colchicine and is coincident with clinical weakness.5 In the arterial smooth muscle cells of rats colchicine causes structural and functional changes, including the increased appearance of auto- phagic vacuoles and lysosomes.6 In humans electron microscopy of proximal skeletal muscle from patients with colchicine myopathy shows abnormal accumulation of lysosomes and autophagic vacuoles.3 An anatomical linkage between lysosomes and microtubules has been demonstrated in cultured fibroblast studies.7 It seems likely that colchicine disrupts the microtubular cytoskeleton that directs the movement and function of intracellular organelles including lysosomes and autophagic vacuoles. Ironically, however, microtubules have not been clearly shown in human adult skeletal muscle. Whether colchicine exerts its myotoxic effects through intracellular micro- tubular disruption or by a yet undisclosed mechanism remains to be shown. This case of colchicine myoneuropathy was thought to arise in a patient with normal renal function who had transient prerenal azotaemia resulting from diuretic abuse superimposed on a diarrhoeal illness. A more careful analysis of her renal function by the Cockcroft-Gault equation,8 9 however, showed an underlying creatinine clearance of only 46 ml/min, which decreased to 16 ml/min during her prerenal state. It is unclear whether a transient decrease in the renal clearance of colchicine precipitated the development of symptomatic colchicine toxicity. It does suggest, however, that the risk of colchicine myoneuropathy may extend beyond the patient with obvious renal insuffi- ciency to include any elderly patient with normal or near normal serum creatinine concentrations who may be prone to episodes of decreased renal perfusion. Because of partial dependence on hepatic metabolism, underlying liver disease may also predispose to colchicine toxicity. ' Given the increasing application of oral colchicine in a variety of rheumatic and non-rheumatic diseases, increased awareness of its potential toxi- cities-even in the presence of a 'normal' serum creatinine-should not be overlooked. STEVEN A OLDER Rheumatology Service Department of Medicine Brooke Army Medical Center San Antonio, TX 78234, USA DAVID S FINBLOOM Division of Cytokine Biology Food and Drug Administration Bethesda, MD, USA GHOLAM H PEZESHKPOUR Neuromuscular Section Armed Forces Institute of Pathology Washington DC, USA Correspondence to: Dr Older. *The opinions contained herein are those of the authors and do not necessarily reflect the views of the Department of the Army, Department of Defense, or the United States Government. I Naidus R M, Rodvien R, Mielke C H. Colchicine toxicity, a multisystem disease. Arch Intern Med 1977; 137: 394-6. 2 Riggs J E, Schochet S S, Gutmann L, Crosby T W, DiBartolomeo A G. Chronic human colchicine neuropathy and myopathy. Arch Neurol 1986; 43: 521-3. 3 Kuncl R W, Duncan G, Watson D, Alderson K, Rogawski M A, Peper M. Colchicine myopathy and neuropathy. N Engl J Med 1987; 316: 1562-8. Colchicine myopathy. Note the vacuoles and absence of inflammation. (Haematoxylin and eosin.) 1343 on January 28, 2020 by guest. Protected by copyright. http://ard.bmj.com/ Ann Rheum Dis: first published as 10.1136/ard.51.12.1343 on 1 December 1992. Downloaded from
Transcript of Coichicine myoneuropathy and renalLettersto theeditor I The cooperating clinics committee of the...
Letters to the editor
I The cooperating clinics committee of theAmerican Rheumatism Association. A seven-day variability study of 499 patients withperipheral rheumatoid arthritis. ArthritisRheum 1965; 8: 302-34.
2 Thompson P W, Silman A J, Kirwan J R,Currey H L F. Articular indices of jointinflammation in rheumatoid arthritis. ArthritisRheum 1987; 30: 618-23.
3 Hench P S. The ameliorating effect of pregnancyon chronic atrophic (infectious rheumatoid)arthritis, fibrosis, and intermittent hydrarth-rosis. Proc Mayo Clin 1938; 13: 161-8.
4 Cecere F A, Persellin R H. The interaction ofpregnancy and the rheumatic diseases. ClinRheum Dis 1981; 7: 747.
S Persellin R H. The effect of pregnancy onrheumatoid arthritis. Bull Rheum Dis 1976-7;27: 922.
6 Granier L W. Clinical response of rheumatoidarthritis to postpartum plasma. JAMA 1951;146: 995-7.
7 Josephs C. Observations on the treatment ofrheumatoid arthritis by transfusions of bloodfrom pregnant women. BMJ 1954; ii: 134-5.
8 Neustadt D H, Geiger J, Steinbrocker 0. Effectof postpartum plasma in rheumatoid arthritis.Ann Rheum Dis 1954; 13: 131-5.
9 StimsonW H. Studies on the immunosuppressiveproperties of a pregnancy-associated alpha-2macroglobulin. Clin Exp Immunol 1975; 25:199-206.
10 Persellin R H, Rhodes J. Inhibition of humanmonocyte Fc receptor and HLA-DR antigenexpression by pregnancy alpha-2 glycoprotein.Clin Exp Immunol 1981; 46: 350-4.
11 Ostensen M, Schoultz Bvon, Husby G. Com-parison between serum alpha-2 pregnancy-associated globulin and activity of rheumatoidarthritis and ankylosing spondylitis duringpregnancy. ScandjRheumatol 1983; 12: 315-8.
12 Unger A, Kay A, Griffin A J, Panayi G S.Disease activity and pregnancy-associatedalpha-2 glycoprotein in rheumatoid arthritisduring pregnancy. BMJ 1983; 286: 750-2.
13 Nicholas N S, Panayi G S, Norri A M E. Humanpregnancy serum inhibits interleukin-2production. Clin Exp Immunol 1984; 58:587-95.
14 Nicholas N S, Panayi G S. Immunosuppressiveproperties of pregnancy serum on the mixedlymphocyte reaction. Brj Obstet Gynecol 1986;93: 1251-5.
15 Arkwright P, Rademacher T, Marshall J, et al.Glycoprotein glycosylation and the immuno-suppressive effects of human pregnancy serum.J Reprod Immunol 1992; 21: 97-102.
Coichicine myoneuropathyand renal dysfunction*Sir: Colchicine has been used in the treatmentof gout and other diseases for over 200 years.Unusually high dosing regimens have resultedin multiorgan toxicity affecting the haemo-poietic, renal, nervous, dermatological, andmusculoskeletal systems.' 2 Recently, amyoneuropathy has been noted in elderlypatients taking low doses of colchicine overmonths to years.3 All patients had underlyingchronic renal insufficiency, which is consideredan important component of the syndrome. Wereport the development of colchicine myo-neuropathy in a woman with a transientprerenal illness.A 75 year old woman presented with a three
week history of progressive proximal muscleweakness. The onset ofher symptoms followeda 10 day diarrhoeal illness that spontaneouslyresolved. Her medical history included long-standing hypertension, degenerative jointdisease, and suspected calcium pyrophosphatedeposition disease, for which she had beentreated with oral colchicine, 0-6 mg twicedaily, over the preceding 16 months. Otherdrugs included a thiazide diuretic taken threetimes daily. Physical examination showed anelderly woman weighing 61-4 kg who appearedwell. Motor testing disclosed weakness ofthe shoulder and pelvic girdle muscles withnormal distal strength, and results of a neuro-logical examination were normal. Laboratory
studies showed a creatine kinase of 646 IU/I(normal range 0-170 IU/l), and a Westergrensedimentation rate of 10 mm/h. Blood ureawas 13-2 mmol/l and serum creatinine 132-6iLmol/l. Renal function studies six monthsearlier had been within normal limits: bloodurea 6-4 mmol/l and serum creatinine 106 1Itmol/l. Electromyography showed myopathicchanges characterised by resting membraneinstability, positive sharp waves, fibrillations,and decreased amplitude and duration ofpotentials in proximal muscles. Nerveconduction studies were consistent with a mildpolyneuropathy of the legs. A muscle biopsyshowed vacuolation of 30% of myofibreswithout necrosis, inflammatory infiltrates,atrophy, or inclusion bodies (figure). Treat-ment with colchicine and diuretic was dis-continued. Ten days later her motor strengthhad returned to normal and the serum creatinekinase was 35 IU/I. Blood urea was 6-1 mmol/land serum creatinine 114-9 ,tmol/l.
In the nervous system colchicine interfereswith neurotubuleassembly causing a disruptionof axonal transport.4 This probably accountsfor the mild polyneuropathy seen in affectedpatients; however, the mechanism of injury inmuscle, is less clear. In rat skeletal muscle anaccumulation of 'large sarcoplasmic mem-branous bodies'-with presumed autophagicactivity-appears two to three days after theintraperitoneal injection of colchicine and iscoincident with clinical weakness.5 In thearterial smooth muscle cells of rats colchicinecauses structural and functional changes,including the increased appearance of auto-phagic vacuoles and lysosomes.6 In humanselectron microscopy of proximal skeletalmuscle from patients with colchicine myopathyshows abnormal accumulation of lysosomesand autophagic vacuoles.3 An anatomicallinkage between lysosomes and microtubuleshas been demonstrated in cultured fibroblaststudies.7 It seems likely that colchicine disruptsthe microtubular cytoskeleton that directs themovement and function of intracellularorganelles including lysosomes and autophagicvacuoles. Ironically, however, microtubuleshave not been clearly shown in human adultskeletal muscle. Whether colchicine exerts itsmyotoxic effects through intracellular micro-tubular disruption or by a yet undisclosedmechanism remains to be shown.
This case of colchicine myoneuropathy was
thought to arise in a patient with normal renalfunction who had transient prerenal azotaemiaresulting from diuretic abuse superimposed ona diarrhoeal illness. A more careful analysis ofher renal function by the Cockcroft-Gaultequation,8 9 however, showed an underlyingcreatinine clearance of only 46 ml/min, whichdecreased to 16 ml/min during her prerenalstate. It is unclear whether a transient decreasein the renal clearance ofcolchicine precipitatedthe development of symptomatic colchicinetoxicity. It does suggest, however, that therisk of colchicine myoneuropathy may extendbeyond the patient with obvious renal insuffi-ciency to include any elderly patient withnormal or near normal serum creatinineconcentrations who may be prone to episodesof decreased renal perfusion. Because ofpartial dependence on hepatic metabolism,underlying liver disease may also predispose tocolchicine toxicity. ' Given the increasingapplication of oral colchicine in a varietyof rheumatic and non-rheumatic diseases,increased awareness of its potential toxi-cities-even in the presence of a 'normal'serum creatinine-should not be overlooked.
STEVEN A OLDERRheumatology Service
Department of MedicineBrooke Army Medical Center
San Antonio, TX 78234, USA
DAVID S FINBLOOMDivision of Cytokine Biology
Food and Drug AdministrationBethesda, MD, USA
GHOLAM H PEZESHKPOURNeuromuscular Section
Armed Forces Institute of PathologyWashington DC, USA
Correspondence to: Dr Older.*The opinions contained herein are those of theauthors and do not necessarily reflect the views of theDepartment of the Army, Department of Defense,or the United States Government.
I Naidus R M, Rodvien R, Mielke C H. Colchicinetoxicity, a multisystem disease. Arch InternMed 1977; 137: 394-6.
2 Riggs J E, Schochet S S, Gutmann L, CrosbyT W, DiBartolomeo A G. Chronic humancolchicine neuropathy and myopathy. ArchNeurol 1986; 43: 521-3.
3 Kuncl R W, Duncan G, Watson D, Alderson K,Rogawski M A, Peper M. Colchicine myopathyand neuropathy. N Engl J Med 1987; 316:1562-8.
Colchicine myopathy. Note the vacuoles and absence ofinflammation. (Haematoxylin and eosin.)
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Letters to the editor
4 Paulson J C, McClure W 0. Inhibition ofaxoplasmic transport by colchicine, podo-phyllotoxin, and vinblastine: an effect onmicrotubules. Ann NY Acad Sci 1975; 253:517-27.
5 Markand 0 N, D'Agostino A N. Ultrastructuralchanges in skeletal muscle induced by col-chicine. Arch Neurol 1971; 24: 72-82.
6 Nilsson J, Ksiazek T, Thyberg J. Effects ofcolchicine on DNA synthesis, endocytosis, andfine structure of cultivated arterial smoothmuscle cells. Exp Cell Res 1983; 143: 367-75.
7 Collot M, Louvard D, Singer S J. Lysosomes areassociated with microtubules and not withintermediate filaments in cultured fibroblasts.Proc Natl Acad Sci USA 1984; 81: 788-92.
8 Cockcroft D W, Gault M H. Prediction ofcreatinine clearance from serum creatinine.Nephron 1976; 16: 31-41.
9 Wallace S L, Singer J Z, Duncan G J, WigleyF M, Kuncl R W. Renal function predictscolchicine toxicity: guidelines for the prophy-lactic use of colchicine in gout. J Rheumatol1991; 18: 264-9.
10 Besana C, Comi G, Baldini V, Ciboddo G,Bianchi R. Colchicine myoneuropathy. Lancet1987; ii: 1272-3.
Polyarteritis nodosa andacute interstitial pneumoniaSir: Although about eight reports of patientswith polyarteritis nodosa associated with inter-stitial pneumonia have been published,'interstitial pneumonia has not been consideredto be a complication of polyarteritis nodosa.Of the eight cases with this association, onlytwo cases have been recorded in Englishpublications.' Thus we present one case ofpolyarteritis nodosa associated with acuteinterstitial pneumonia.A 71 year old man was admitted to the
hospital on 2 October 1990. He had complainedof fatigue, weight loss, fever, and cough fortwo months before admission. His temperaturewas 39°C and oedema of the legs was noted.Abnormal laboratory data included a whiteblood cell count of 14 5 x10/l (normal range4-8x 109/l) with neutrophilia, haemoglobinconcentration 103 g/l (140-180g/1), erythrocytesedimentation rate 31 mm/h (1-7 mm/h),C reactive protein + 5, and serum complement(CH50) 18-8 U/ml (30-40 U/ml). Bothrheumatoid factor and antinuclear antibodywere positive. Hepatitis B surface antigen andantibodies were negative. Cryoglobulins werenegative. A chest radiograph was normal. Thepatient was clinically diagnosed as possiblepolyarteritis nodosa and was treated withcorticosteroids (prednisolone 60 mg/day).Two months later both rheumatoid factor andantinuclear antibody were negative, and CH50had returned to normal.On 4 January 1991 he complained of dys-
pnoea. Arterial blood gas analysis at room airshowed a partial pressure of oxygen (Pao2) of32 mmHg, partial pressure of carbon dioxide(PaCo2) 32-7 mmHg, bicarbonate 23-4 mmol/l,and pH 7-5. The chest radiograph showed adiffuse reticular pattern in both lungs (fig 1).Although he was treated with a large dose ofcorticosteroids (1 g of prednisolone a day forsix days) based on the clinical diagnosis ofacute interstitial pneumonia, he died ofrespiratory failure on 15 January 1991.Necropsy showed polyarteritis nodosa
affecting multiple organs, including the lung,oesophagus, stomach, intestine, liver, spleen,kidney, pancreas, and testis. In the lung thebronchial andpulmonary arteries were affected.Most marked were the changes in the stomach.The arteries along the greater and lessercurvatures of the stomach contained numerousnodules, often arranged in chains like a stringof pearls. Moreover, many nodules produced
protuberances of the gastric mucosa so thatthe inner surface of the stomach appearednodular. Histologically, the affected arteriesrepresented the scar stage of necrotisingarteritis according to our classification.8Collapse of the alveolar sacs and dilatation ofthe alveolar ducts could be seen in all lobesof both lungs (fig 2). Hyaline membraneformation, fibroblast proliferation, and chronicinflammatory cell infiltrate were present inthe alveolar septae. Moreover, cuboidalisationof the alveolar lining cells and thickened pul-monary arteries were noted. These findingscorrespond to acute interstitial pneumonia.9There was no correlation between interstitialpneumonia and arteritis.
Although interstitial pneumonia associatedwith collagen vascular diseases has beendescribed, it was believed that polyarteritisnodosa is not complicated with interstitialpneumonia. Recently, Carratala and coworkerspresented two cases of polyarteritis nodosaassociated with interstitial pneumonia, andsuggested that reports of new cases wereneeded to determine whether or not thisassociation is real.7Our case represents classic polyarteritis
nodosa, indicated by nodule formation, withhistological evidence of arteritis of polyarteritisnodosa type. Nodules were originally des-cribed, hence the term polyarteritis nodosa,but these nodules are infrequently seen today,either clinically or pathologically. In the
Figure 1 Chest radiograph showing a diffusereticular pattern in both lungs.
present case the arteritis represented the scarstage.8 On the other hand, the interstitialpneumonia corresponded to the acute stage.9Thus we think that interstitial pneumoniaoverlapped the pre-existing polyarteritisnodosa in this case.A nationwide research team was organised
under the auspices of the Ministry of Healthand Welfare of Japan in 1973 to investigatepolyarteritis nodosa. The research teamanalysed 56 patients with polyarteritis nodosa,of whom 10 (18%) clinically had interstitialpneumonia.'0 Moreover, our own experienceof three patients with polyarteritis nodosa (thepresent one and two previously reported5)showed that two had interstitial pneumonia.These findings indicate that polyarteritisnodosa associated with interstitial pneumoniais apparently morecommon than has previouslybeen recognised. Thus during treatment ofpolyarteritis nodosa it may be necessary totreat overlapping interstitial pneumonia.
T MATSUMOTOM OKADA
N KUWABARAFirst Department of Pathology
Juntendo UniversitySchool of Medicine
Tokyo, Japan
S HOMMAT SUZUKI
S KIRADepartment of Respiratory Medicine
Juntendo UniversitySchool of Medicine
Tokyo, JapanT UEKUSA
S SAIKIDepartment of Pathology
St Luke's Intemational HospitalTokyo, J7apan
Correspondence to: Dr Toshiharu Matsumoto, FirstDepartment of Pathology, Juntendo University,School of Medicine, Hongo 2-1-1, Bunkyo-ku,Tokyo, 113 Japan.
1 Gherman G, Niculescu I, Serban A L, Caluser I.Uber einen Fall von Periarteriitis nodosa mitinterstitielier, diffuser Lungenfibrose undparietaler fibroser Endokarditis. Z Gesamte InnMed 1%3; 18: 827-9.
2 Turiaf J, Basset F, Battesti J P. Fibrose inter-stitielle diffuse de la periarterite noueuse.Societe' Medicale des Hospitaux de Paris 1%5;116: 1149-60.
3 De Biasio R, Stanisic M, Reutter F W. DiffuseLungenfibrose bei Panarteriitis nodosa. SchweizMed Wochenschr 1973; 103: 1540-3.
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Figure 2 Acute interstitial pneumonia. Note collapse of the alveolar sacs and dilatation of the alveolarducts. (Elastic van Gieson stain.)
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