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.

9','V..

., *>.s9¶:,

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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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