Ann. rheum. Dis. (1965), 24, 432.

POLYMYALGIA RHEUMATICAA BIOPSY AND FOLLOW-UP STUDY

BY

F. M. ANDREWS*From the Oxford Regional Rheumatic Diseases Research Centre, Stoke Mandeville Hospital, Aylesbury

The name "polymyalgia rheumatica" has beenused to designate a syndrome which has beendescribed by several authors under many titles.Table I lists these authors and the names suggested,and shows also the numbers of cases in each report.Although detailed consideration of these reportssuggests that many authors have not been describingclinically homogeneous groups, the existence of asyndrome satisfying the broad criteria applied in thepresent investigation is now generally accepted. Nospecific histopathological lesion has been linked withthe clinical syndrome, though some have postulateda close relationship to giant-cell arteritis. Thishypothesis will be examined in this report.The earliest account of this syndrome seems to be

that ofBruce (1888), who described "senile rheumaticgout" in three patients. This disease was an acutesevere rheumatic illness with recovery in about 2years occurring in the elderly. The five patientsof Holst and Johansen (1945) with "peri-extra-articular rheumatism" were aged between 40 and 61years and had pain mainly round the shoulders andin the buttocks, transient fever, and raised erythro-cyte sedimentation rates (E.S.R.)-estimated by* Arthritis and Rheumatism Council Fellow.

Westergren's technique-of up to 100 mm. in thefirst hour during the acute phase. All five improvedconsiderably during the 2 years after the onset.Meulengracht (1945) and Meulengracht andSchwartz (1952) described 22 patients with "peri-arthrosis humeroscapularis", who had similar symp-toms and a similar benign outcome, as did thethirteen very similar patients described by Kersley(1951) under the purely descriptive title of "a myalgicsyndrome of the elderly with systemic reaction".Kersley's patients responded well to cortisone or tocorticotrophin. The name "anarthritic rheumatoiddisease" was applied by Bagratuni (1953, 1963) to agroup of patients who shared the clinical featuresdescribed above, but in some instances had inaddition headaches, gastro-intestinal symptoms, andtransient abnormalities of the chest radiographs.The term "polymyalgia rheumatica" was suggestedby Barber (1957) when he described twelve morecases, and this was adopted by Gordon (1960) in hisclassical paper. The report of Alestig and Barr(1963) entitled "Giant-cell Arteritis, a Biopsy Studyof Polymyalgia Rheumatica including a Case ofTakayasu's Disease" is important for its suggestionof a specific pathological lesion in polymyalgia

TABLE I

AUTHORS, NAMES SUGGESTED, AND NUMBERS OF CASES REPORTED

Author Date Name Suggested No. of Cases

Bruce 1888 Senile rheumatic gout 3

Meulengrachtand Schwartz 1952 Periarthrosis humeroscapularis 20Holst and Johansen 1945 Peri-extra-articular rheumatism 5

Kersley 1951 Myalgic syndrome of the elderly with systemic reaction 13

Forestier and Certonciny 1953 Pseudo-polyarthrite rhizom6lique 25

1953 7Bagratuni 1963 Anarthritic rheumatoid disease 21

Barber 1957 Polymyalgia rheumatica 12

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POL YMYALGIA RHEUMATICArheumatica, a relationship earlier postulated byPaulley and Hughes (1960) on clinical grounds.However, not all the cases in this series are acceptableas examples of polymyalgia rheumatica. The onecase of Takayasu's syndrome presented with absentperipheral pulses, and only at follow-up 2 years later,was a history ofmyalgia obtained; four other patientshad symptoms whose distribution differed fromthose of polymyalgia rheumatica, and of the re-maining five examples, two had histological evidenceof giant-cell arteritis. Hamrin, Jonsson, and Land-berg (1964) described 23 further cases which wouldseem acceptable as "polymyalgia rheumatica",although the diagnostic criteria are not stated;twelve of these patients had histological evidence ofgiant-cell arteritis. Chalmers, Alexander, andDuthie (1964) emphasized the diagnostic difficultiesin patients presenting with muscle pain. Theydivided their patients among four diagnostic groups,the first consisting of eight subjects whose sympto-matology seems similar to polymyalgia rheumatica.Specific electromyographic (E.M.G.) changes werenot found in the six patients of this group who weretested. Three of their patients showed a highcreatine excretion, but since both sex and age alterthe normal range of creatine excreted (Howell,1956; Taussky and Brahen, 1961), it is possible thatthese three instances of "raised" excretions may infact be within the normal range for the age and sexof the subjects. In this series the Waaler-Rose titrewas 1/32 or greater in six and 1/16 in the remainingtwo patients.

It was felt, therefore, that a further review of thissyndrome should be undertaken, especially in orderto examine once again the possibility that it may beprimarily a disease of muscle, and to examine itsrelationship both to giant-cell arteritis and, byfollow-up studies, to rheumatoid arthritis, and byradiographs and biopsy studies to seek evidence fora possible central polyarthritis.

Methods and MaterialCriteriaThe diagnosis of polymyalgia rheumatica was made in

all patients presenting with pain and stiffness confinedto the limb girdles and with evidence of systemic disturb-ance. Fever, unintentional weight loss, raised E.S.R.,or anaemia, or any combination of these was taken asevidence of systemic disturbance. The criteria weredeliberately allowed to be wide.

PatientsTen cases fulfilling these criteria presented in 1963.

Before January 1, 1961, 34 other cases had presented;of these two could not be traced and two refused re-examination.

Investigations

All acute cases presenting during 1963 were examinedfully and investigated by means of radiographs, muscle-enzyme assays, and creatine excretion as well as byroutine haemoglobin (Hb), erythrocyte sedimentationrate (E.S.R.) by the Westergren technique, white bloodcorpuscle count (W.B.C.), and Waaler-Rose testing.Evidence was also sought for the presence of malignantdisease and brucellosis. Further, save for those referredelsewhere or who refused admission, all were submittedto biopsy. Biopsies were taken under general anaes-thesia from a tender acromio-clavicular joint and a tendermuscle (usually deltoid). To ensure that each musclebiopsy included a piece of muscular septum electricalstimulation of the motor-point was used. With thistechnique the septum appears as a groove betweencontracting muscle bundles. Biopsy of a vessel wasperformed only when tendemess was elicited along itscourse. Serum glutamic oxalo-acetic transaminase(S.G.O.T.) and serum aldolase were estimated in allcases. Aldolase was estimated by the Boehringer test-combination method and results were expressed in Brunsunits (normal range 3-8 units) (Bruns, 1954). Aldolaseis present in red corpuscles at high concentration so thatminor degrees of haemolysis may raise the serum con-centration grossly. Raised serum aldolase levels weretherefore checked by estimation of the serum phospho-creatine-kinase, again using the Boehringer test-combina-tion method. Phospho-creatine kinase is an enzymetroublesome to estimate but is not present in redcorpuscles.The following radiographs were taken routinely:

postero-anterior view of chest; antero-posterior views ofpelvis, hands, and feet; antero-posterior and lateral viewsof lumbar spine; antero-posterior and flexed lateral viewsof cervical spine. In one pre-menopausal woman thepelvic x ray was omitted. Radiographs of the follow-upcases were compared, with the exception of the pelvicfilms, with radiographs matched for age and sex obtainedfrom a random sample of the population of Watfordduring a survey by the field unit of the Arthritis andRheumatism Council. The pelvic films were comparedwith similarly matched x rays taken from a series as-sembled from the "preliminary" films of intra-venouspyelograms of mobile but otherwise unselected casesattending Stoke Mandeville Hospital in the years 1962/63.

Radiographs from patients and from the matchedcontrols were admixed, read, and marked independentlyby two observers according to the "Atlas of StandardRadiographs of Arthritis".

Results

The following points emerge from the history andexamination of the newly-diagnosed cases and fromperusal of the notes and re-examination of thosefollowed up (44 cases in all).

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(i) The onset was abrupt in twenty cases. Severalpatients could not only give the date their illnessstarted but could also specify the time of day.

(ii) The degree of early morning stiffness was

greater than is usual in rheumatoid arthritis. Tenpatients could not rise unaided and thirteen othershad to roll from bed. Although this stiffnesslessened as the day progressed, all patients hadinitially some stiffness persisting throughout the day.

(iii) Night sweats, often so severe as to enforce a

change of nightwear, occurred in 32 patients.(iv) Severe depression was present before treat-

ment in six patients and depression was mentionedspontaneously by seventeen others. Some of thesehad been treated in the psychiatric clinic for depres-sive symptoms immediately before their referral tothe unit.

(v) The maximum E.S.R. was over 100 mm./hr infifteen cases and between 50 and 100 mm./hr in 23others.

(vi) There were thirteen men and 31 women in thewhole series.

Cases presenting during 1963.-There were tenpatients in whom the diagnosis was made during theyear. The main facts are summarized in Table II.

One patient had a clinically unsuspected broncho-genic carcinoma. This man had no involvement ofskin and no radiographic evidence of bony meta-stases or pulmonary osteo-arthropathy. Biopsieswere not obtained since he had to be transferred

elsewhere for radiotherapy. One other patient whorefused admission had a generalized macular rashwhich remitted as his myalgic symptoms improved;his creatine excretion was, however, normal. Twosera showed a raised level of aldolase, which was

discounted since the phospho-creatine-kinase wasnot increased. Muscle-enzyme studies were other-wise normal. The Waaler-Rose test was initiallynegative in all cases. None of those admitted hadfever exceeding 990 F. during their 2-week period inhospital, though four had a spike of fever to this levelon the day after biopsy.The biopsy results are given in Table III. Only

one acromioclavicular joint was normal, the re-

maining six showed evidence of arthrosis and oneshowed in addition pannus (Fig. 1, opposite). Themuscle biopsies were all normal as were the musclevessels in the six cases in which they were seen.

There were no inflammatory cells in the intra-muscular septa and the two temporal arteries studiedwere normal.

Cases followed up.-Of the 34 patients in whomthe diagnosis had been made before January 1, 1961,27 attended for re-examination, blood tests, andx rays. Two refused to attend for re-examination,two could not be traced, and three had died. Thecause of death was ascertained from the patients'general practitioner and confirmatory autopsyreports were available in two cases.

TABLE I I

MAIN FEATURES IN TEN ACUTE CASES

Case No. Age* (yrs) Sex ESRm.(Westergren) Urinary Creatine Serum Aldolase Serum S.G.O.T. Remarks

60 Male 60 20 4 10 Bronchogenic2 52 Male 80 30 3 5 carcinoma3 76 Female 70 40 6 - Rash4 68 Female 102 18 5 205 55 Female 68 12 5 1 56t 55 Female 53 32 10 107 54 Male 27 36 6 88 55 Male 40 14 4 59t 74 Male 72 42 12 1 610 70 Female 28 24 3 12

t Phospho-creatine kinase normal.* Average age 61 9 yrs.

TABLE Ill

RESULTS OF BIOPSIES

Case No. Acromio-clavicular Joint Muscle Muscle Septum Muscle Vessel Temporal Artery

4 Fissuring and pannus Normal No cellular infiltrate Normal Normal5 Arthrosis Normal No cellular infiltrate None seen6 Arthrosis Normal No cellular infiltrate Normal7 Arthrosis Normal No cellular infiltrate Normal8 Normal Normal No cellular infiltrate Normal9 Advanced arthrosis Normal No cellular infiltrate Normal Normal10 Arthrosis Normal No cellular infiltrate Normal

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Fig. 1.-Biopsy from Case 4 showing fissuring and pannus formation. Haematoxylin and eosin. x 150.

One patient died of coronary thrombosis and atautopsy was said to have "rheumatoid arthritis of thehands" but the joints were not opened. The histologyof the coronary vessels of this patient showed no evidenceof giant-cell arteritis. One patient died as the result of ableeding duodenal ulcer, which was confirmed as benignat autopsy. No histological examination was made.The third death was certified as due to heart failuresecondary to chronic bronchitis but no autopsy wasperformed.

The mean age at onset was 66 years (range 24-79).The most striking feature of the follow-up was

that 26 of the patients referred to their acute rheu-matic illness as an episode of the past, distinct fromany of the symptoms of degenerative joint diseasewhich most had at re-examination. Negative find-ings common to the whole group were the normalmuscle enzyme levels and the lack of evidence ofbrucella infection (two patients, both farm workers,had weakly-positive brucellin skin tests, but in eachcase the agglutination titres were below 1/30 bothbefore and one week after brucellin injection). Noneof these patients had positive Waaler-Rose tests at

follow-up, but two had had positive titres, up to1/64, during their illness. None had evidence ofretinal vessel obstruction or ophthalmoplegia, andall had normal temporal, occipital, and peripheralpulses.The one patient whose rheumatic illness has not

remitted appears to have a central sero-negativepolyarthritis with anaemia, but he has no radio-graphic evidence of sacro-iliitis. Three patientshad developed peripheral acrosclerosis since theirfirst attendance. None of these had had Raynaud'sphenomenon when first seen and none had otherevidence to suggest scleroderma. One of the threehad minimal early morning stiffness. One patienthad psoriasis, without locomotor symptoms, andone other had Parkinsonism.Table IV (overleaf) summarizes the locomotor

symptoms found among the 26 patients whose diseasehad remitted. Symptoms, when present, were al-ways sharply distinguished from those of their earlieracute illness. Additionally, one patient had anearly "senile" cataract and grade I or II hyper-tensive changes were found in the retina in six.

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ANNALS OF THE RHEUMATIC DISEASESTABLE IV

RHEUMATIC FEATURES AT FOLLOW-UP(All distinguished by the subjects from their "past rheumatic illness")

Morning Stiffness (lasting less than 30 min.) .. .. 5

Painful and stiff.Hands Heberden's nodes. I

Paraesthesiae I

Shoulders Painful andstiff. 7

Knees Crepitant andpainful.5Crepitantonly. 7

Hips Painful and stiff. 4

Neck Painful I

X ray of the Follow-up Cases.-No abnormalityof the hilar shadows or lung fields were seen in thechest radiographs. Ten of the x rays showed minordegrees of aortic-arch unfolding and seven of thesealso showed evidence of left ventricular hypertrophy.No significant differences were found between the

x rays of hands and feet of the patient and controlgroups. Similarly, no statistically significant differ-ence was found between the lumbar radiographs ofthe two groups (Table V).The results of the cervical spine radiographs are

shown in Table VI. Again, the differences betweenthe groups are not significant; there was, however, a

TABLE V

X RAYS OF LUMBAR SPINE-GRADE OF DISKDEGENERATION

Grade 0 1 2 3 4

Patients* .. .. 6 6 10 5 0Controlst .. .. 6 4 10 6 1

* Two patients' x rays showed spondylolisthesis of L4 and L5,both apparently of long standing.t One control showed a similar spondylolisthesis and one an oldcrush fracture of L4.

greater incidence of changes in the sacro-iliac jointsamong patients than among controls. Thesechanges (a typical example of which is shown in Fig.2, opposite) had not been present in x-rays taken atthe time of original diagnosis (Table VIl).

Discussion

In this series, one of ten new patients with theclinical syndrome of polymyalgia rheumatica had abronchogenic carcinoma, and one other had histo-logical evidence of rheumatoid arthritis in anacromio-clavicular joint. No patient showed evid-ence of giant-cell arteritis, but only two acute cases

TABLE VI

X RAYS OF CERVICAL SPINE

Grade.0 2 3 4

Disk Degeneration Patients.2 4 8 12Controls.4 5 9 7 2

Apophyseal Arthritis Patients.7 8 8 4 0Controls. 9 6 8 3 1

Note: The X rays of one patient showed atlanto-axial laxity. No other evidence of cervical R.A. was seen, and there was no evidenceof ankylosing spondylitis.

TABLE VIl

X RAYS OF SACRO-ILIAC JOINTS

Grade 0 2 3 4

Bilateral I.... 4 2 0Patients 11

Unilateral J .. . . 3 3 1

Bilateral .. .. 3 0 0 0Controls 22

Unilateral J *... 0 0 0 0

Since Grade 1 means "doubtfully abnormal', those with a Normal x ray or Grade I change have been contrasted with those witha Grade 2, 3, or 4 change.

Grade Nornial or 2, 3, and 4 Total

Patients. 16 11 27Controls .25 27

Total 41 13 54

Z2 6 48; df =- 1; P 1 percent.

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POLYMYALGIA RHEUMATICA

S :-.:F 4 <,

k D W :. .* ............................. :. ... ... . . ::. ... :. . .t..' z ..°' v:: .............. .: .:. ... . . . . .. . .... ..S

t..yoF. ................... ... .... ...:: .::: ...

;.....

........

................

... ...........

..._ ..

Fig. 2.-Typical example of loss of space in left sacro-iliac joint.

had temporal artery biopsies; it would seem, how-ever, that the clinical course of giant-cell arteritisdiffers from that of "polymyalgia rheumatica".Ross Russell (1959) found fever in 29 of 35 cases ofgiant-cell arteritis and Alestig and Barr (1963) showthe temperature chart of "a typical case" whichshows fever up to 380 C. and mention "characteristictemperature curves which for long periods remainaround 380 C. Sixteen of Ross Russell's 35 casesof giant-cell arteritis had visual disturbance (fiveprogressing to complete blindness) and two had aperipheral neuropathy. None of the present serieshad evidence of retinal vasculitis (although one hada "senile" cataract) nor of peripheral neuropathy,and none had evidence of arteritis elsewhere. Simi-larly, in this series, no evidence of giant-cell arteritisinvolving muscle vessels was found, again in contrastto the single case of proved giant-cell arteritis21

reported by Ross Russell (1962) which later showedarteritis of the small vessels of a muscle biopsiedwhen muscle pain, stiffness, and tendernessdeveloped. The presence of peripheral acrosclerosishas not been reported in studies of giant-cell arteritis,but three of 27 cases had developed this lesionduring the years of the follow-up.No evidence was found of primary muscle disease

nor of brucellosis. This study has confirmed thebenign nature of this syndrome. Only one of thefollow-up cases has notable disability and the deathof three of 32 patients in a group of this mean age isabout that to be expected statistically. The re-maining 26 patients re-examined are leading livesof at least average activity for their years.

Perhaps polymyalgia rheumatica is a syndromethat can be produced by several pathologicalprocesses, including bronchogenic carcinoma and

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ANNALS OF THE RHEUMATIC DISEASES

rheumatoid arthritis in the present series. Theremay be other types of "central arthritis" which canproduce this clinical picture and, although noevidence of this was found in this series, there maybe an association with giant-cell arteritis.

SummaryA study of acute cases of the syndrome called

polymyalgia rheumatica and a 3-year follow-upstudy of the same syndrome is reported. Thesyndrome was found to be associated with a broncho-genic carcinoma in one case and with rheumatoid-like histology in a second. The follow-up casesincluded a single example of progressive, sero-negative, central polyarthritis, and three examplesof peripheral acrosclerosis. The syndrome wasassociated with a favourable outcome in 26 of thirtycases followed. The findings and possible causesare discussed.

My thanks are due to the Arthritis and RheumatismCouncil for very generous financial support; to Dr. AlanHill for much advice and encouragement; to Dr.Brownell of the Department of Neuropathology at theRadcliffe Infirmary, Oxford, for the reports on musclebiopsies; to Dr. Spalding Smith for his generous helpwith the x rays of these patients; to Dr. Colin Tribe ofthe Department of Pathology, Stoke Mandeville Hospital;to Dr. J. S. Lawrence of the Arthritis and RheumatismCouncil Field Unit for the loan ofx rays, and to all thoseothers, nurses, technicians, and secretaries, who havehelped in so many ways. Especially my thanks are dueto the patients,

REFERENCESAlestig, K., and Barr, J. (1963). Lancet, 1, 1228.Bagratuni, L. (1953). Ann. rheum. Dis., 2, 98.- (1963). Brit. med. J., 1, 513.

Barber, H. S. (1957). Ann. rheum. Dis., 16, 230.Bruce, W. (1888). Brit. med. J., 2, 811.Bruns, F. (1954). Biochem. Z., 325, 156.Chalmers, T. M., Alexander, W. R. M., and Duthie,

J. J. R. (1964). Ann. rheum. Dis., 23, 123.Forestier, J., and Certonciny, A. (1953). Rev. Rhum.,

20, 854.

Gordon, I. (1960). Quart. J. Med., 29, 473.Hamrin, B., Jonsson, N., and Landberg, T. (1964).

Lancet, 1, 397.Holst, J. E., and Johansen, E. (1945). Acta med. scand.,

122, 258.Howell, T. H. (1956). J. Geront., 11, 61.Kersley, G. D. (1951). Proc. II Cong. Europ. Rheum.

(Barcelona), p. 388.Meulengracht, E. (1945). Nord. Med., 27, 1569.

and Schwartz, M. (1952). Acta med. scand., 143,350.

Paulley, J. W., and Hughes, J., P. (1960). Brit. med. J.,2, 1562.

Russell, R. W. Ross (1959). Quart. J. Med., n.s. 28,471.(1962). Ann. rheum. Dis., 21, 171.

Taussky, H. H., and Brahen, L. (1961). In "StandardMethods of Clinical Chemistry", ed. D. Seligsen,vol. 3, p. 99. Academic Press, New York.

Polymialgia rheumatica-Etude biopsique etpost-hospitaliere

RtsuMFOn rapporte sur une etude des cas aigus du syndrome

appelle polymyalgia rheumatica et sur les r6sultatsd'observation pendant 3 ans de malades atteints de cesyndrome. Ce syndrome se trouvait associ6 avec uncarcinome bronchogene dans un cas et avec une histologierhumatolde dans un autre. Les cas suivis comprenaientun seul exemple de polyarthrite centrale, sero-n6gative etprogressive et trois exemples d'acrosclerose peripherique.L'evolution etait favorable chez 26 sur 30 cas suivis. Ondiscute ces resultats et l'6tiologie de la maladie.

Polymialgia rheumatica-Investigaci6n biopsica ypost-hospitalaria

SUMARIOSe relata una investigaci6n de casos agudos del sin-

drome llamado polymyalgia rheumatica y los resultadosde observaci6n durante 3 afios de enfermos con estesindrome. En un caso el sindrome se vio asociado conun carcinoma bronqui6geno y en un otro con unahistologfa de tipo reumatoide. Los casos seguidoscomprendieron un solo ejemplo de pohiartritis central,seronegativa y progresiva y tres ejemplos de acrosclerosisperiferica. La evolucion fue favorable en 26 de los 30casos seguidos. Se discuten estos resultados y laetiologfa de la enfermedad.

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