Musculoskeletal Manifestations in Hyperlipidaemia: a Controlled Study

44 Annals ofthe Rheumatic Diseases 1993; 52: 44 48

Musculoskeletal manifestations in hyperlipidaemia: Ann Rheum Dis: first published as 10.1136/ard.52.1.44 on 1 January 1993. Downloaded from a controlled study

P Klemp, Anne M Halland, F L Majoos, Krisela Steyn

Abstract arthritis, and oligoarthritis. '-' The reported Eighty eight patients with hyperlipidaemia (81 prevalence of these manifestations varies widely white patients from South Africa and seven from study to study because of differences in patients of mixed race from the West Cape classification of the hyperlipidaemias, patient area) were studied. Forty eight had adult selection, and study design. Interpretation of familialhypercholesterolaemia, 16had juvenile the findings, none of which included control familial hypercholesterolaemia, and 24 had patients, is difficult especially where prevalence mixed hyperlipidaemia (increased cholesterol figures are low. Migratory polyarthritis appears and triglycerides). They were interviewed and to be particularly associated with homozygous examined and their musculoskeletal mani- familial hypercholesterolaemia.' There are, festations compared with 88 controls with however, other uncontrolled studies which normal lipid profiles, and matched for age, show no specific associations between hyper- sex, and race for each group of patients. The lipidaemia and rheumatic disorders.' '1 foliowing manifestations were significantly In the one controlled study the only difference increased inthepatients: (a) tendon xanthomas between patients with hypercholesterolaemia particularly of the tendo Achiflis in patients and controls was that pain, particularly of the with adult familial hypercholesterolaemia and ankles and feet, was significantly more severe in mixed hyperlipidaemia; (b) tendo Achillis the patients." There was no difference in the tendinitis in patients with adult familial hyper- duration of morning stiffness, analgesic use, or cholesterolaemia and mixed hyperlipidaemia; effect on lifestyle. This study cannot be com- and (c) oligoarthritis in patients with mixed pared with others, however, as specific entities hyperlipidaemia but not in those with adult such as xanthomas and migratory polyarthritis familial hypercholesterolaemia. Migratory were not reported. polyarthritis and transient tendo Achillis pain We documented the musculoskeletal system were rare. Thirty eight per cent of patients manifestations of 88 patients with hyper- with juvenile familial hypercholesterolaemia lipidaemia and compared them with 88 age and http://ard.bmj.com/ had musculoskeletal system manifestations sex matched controls. The patients were sub- none of which was significantly increased divided into groups with different lipid profiles. compared with controls. There was a signi- The onset of the manifestations in relation to ficant association between tendon xanthomas the diagnosis of hyperlipidaemia and the effect and tendo Achillis tendinitis. There was a oflipid lowering treatment on the manifestations in pretreatment chole- were also investigated. significant difference on October 2, 2021 by guest. Protected copyright. sterol levels in the patients with adult familial hypercholesterolaemia and musculoskeletal system manifestations compared with those Patients and methods without and in ali three groups combined. The Eighty eight consecutive patients with hyper- study confmms an association between hyperlipidaemia attending the lipid clinic at Tygerberg lipidaemia and tendon xanthomas, tendo Hospital were studied. They were interviewed Achillis tendinitis, and to a lesser extent with a detailed questionnaire and examined, oligoarthritis but not migratory polyarthritis and the following information was recorded: Rheumatology Unit, or tendo Achillis as in age, sex, family history of hyperlipidaemia or Department of transient pain reported Internal Medicine, other studies. It also shows that musculo- ischaemic heart disease, musculoskeletal system University of skeletal system manifestations antedated the manifestations past or present, cholesterol and Stellenbosch Medical of in 24/39 triglyceride levels in patients with and without School, diagnosis hyperlipidaemia (62%) Tygerberg Hospital, patients and that the manifestations improved musculoskeletal system manifestations, the Cape Town, or resolved completely in 19/30 (63%) patients effect of lipid lowering treatment on musculo- South Africa after receiving lipid lowering treatment. It is skeletal system manifestations, and whether the P Klemp A M Halland therefore important to recognise the asso- onset of musculoskeletal system disorders F L Majoos ciation between musculoskeletal system antedated or followed the diagnosis of hyper- Lipid Clinic, manifestations and hyperlipidaemia for lipidaemia. Particular attention was paid to a Tygerberg Hospital, diagnostic and therapeutic reasons. history of migratory polyarthritis, oligoarthritis, 7505 Tygerberg, tendo Achillis tendinitis, and transient tendo South Africa K Steyn (Ann Rheum Dis 1993; 52: 414 48) Achillis pain. Correspondence to: P Klemp, A number of studies suggest that there is an Queen Elizabeth Hospital, association between hyperlipidaemia and CLASSIFICATION OF HYPERLIPIDAEMIA Rotorua, New Zealand. tendo Achillis Patients were classified as follows. (a) Hyper- Accepted for publication tendon xanthomas, tendinitis, 20 August 1992 transient tendo Achillis pain, migratory poly- cholesterolaemia without hypertriglyceridaemia Musculoskeletal manifestations in kvperlipidaemnia 45

in patients at least 16 years old if(i) pretreatment sterol less than the 50th centile for age'2 and total cholesterol was greater than or equal to 6-5 normal triglyceride levels (<2-0 mmol/l). The mmol/l, (ii) normal triglyceride levels (-2 0 normal range for cholesterol and triglyceride Ann Rheum Dis: first published as 10.1136/ard.52.1.44 on 1 January 1993. Downloaded from mmol/l), (iii) strong family history of ischaemic levels is the same in the two race groups. heart disease or familial hypercholesterolaemia. This group of patients was considered to have type Ila adult familial hypercholesterolaemia. LIPID ANALYSIS (b) Hypercholesterolaemia without hypertrigly- The plasma was stored at 4°C and analysed ceridaemia in patients younger than 16 years if within 24 hours. The total cholesterol and high (i) pretreatment total cholesterol was greater density lipoprotein cholesterol levels were than or equal to 6-5 mmol/l, and (ii) and (iii) as measured on a Gilford autoanalyser using the for adult familial hypercholesterolaemia. These Boehringer Mannheim CHOD-PAP enzymatic patients are referred to as having juvenile method. High density lipoprotein cholesterol familial hypercholesterolaemia. (c) Mixed was measured after precipitation of the apo- hyperlipidaemia if (i) total cholesterol was protein B containing lipoproteins with man- greater than or equal to 6 5 mmol/l, and (ii) ganese heparin. The non-fasting triglyceride triglyceride levels were greater than or equal to levels were determined by the Boehringer 2-0 mmol/l. A family history of hyperlipidaemia Mannheim enzymatic Peridochrom method. In or ischaemic heart disease was not considered in each instance the Gilford autoanalyser was this group. calibrated against Preciset Cholesterol. Control Of the 88 patients 81 were white South serum samples used were Precinorm L as an Africans and seven were patients of mixed race external control and a pooled plasma as an from the West Cape area. Forty eight patients internal control. had adult familial hypercholesterolaemia, aged 19-68 years (mean 41), of whom 30 (63%) were women; 16 had juvenile familial hyperchole- STATISTICS sterolaemia, aged 5-16 years (mean 11), with The x2 test was used to compare the groups equal sex distribution; and 24 had mixed unless less than five manifestations per group hyperlipidaemia, aged 19-69 years (mean 48), were present when Fisher's exact test was used. of whom 16 (67%) were men. For the three In determining the difference in cholesterol and groups the mean cholesterol levels were adult triglyceride levels in patients with musculo- familial hypercholesterolaemia 9172, juvenile skeletal system manifestations and those familial hypercholesterolaemia 7-81, and mixed without, logarithmic transformations were hyperlipidaemia 8'69 mmol/l, and the mean applied to remove positive skewness apparent in triglyceride levels were adult familial hyper- cholesterol and triglyceride levels. cholesterolaemia 1 07, juvenile familial hypercholesterolaemia 0-77, and mixed hyperlipidaemia 4-32 mmol/l. Results http://ard.bmj.com/ ALL MUSCULOSKELETAL SYSTEM MANIFESTATIONS Overall 65 (74%) patients and 50 (57%) controls CONTROLS had one or more musculoskeletal system mani- The controls, interviewed and examined in the festations (p=0 026). The manifestations same way as the patients, were 88 normal included those which previous studies have volunteers matched for age in decades, sex, and shown to be associated with hyperlipidaemia race for each group of patients. They had and others such as osteoarthritis, rotator cuff on October 2, 2021 by guest. Protected copyright. normal fasting lipid profiles with total chole- syndrome, epicondylitis, and meniscal tears. Three patients aged 10-18 years and none of the controls were hypermobile (a score of 4 or more n= lc on Beighton's 9 point scale'3). None had features 80r- of the hypermobility syndrome. Gout was Patients 70 n - 32 present in four patients with mixed hyper- k- ZI Controls u~~~~~~~~~~~~~~~~~~~~~~~~~~~ lipidaemia and in none of the other patient 60 t- groups or controls.

50 F-- MUSCULOSKELETAL SYSTEM MANIFESTATIONS % 40 - AND HYPERLIPIDAEMIA Fifty seven (65%) of the 88 patients and 10 30 - (1 1%) controls had one or more of the musculo- 20 H n = 9 skeletal system manifestations claimed to be associated with hyperlipidaemia (p<0001), 10 L- namely tendon xanthomas, tendo Achillis n= 1 tendinitis, transient Achilles tendon pain, oligo- :::::::::::: f - 0 0 L-.. arthritis and migratory polyarthritis. One or AFH JFlH MH p 00010 more of these manifestations occurred in NS pc 0001 significantly more patients with adult familial Selected musculoskeletal system manifestations in 48 patients with adultJfamilial hypercholesterolaemia and mixed hyper- hypercholesterolaemtia (AFH), 16 withjuvenilefamilial hypercholesterolaemia (7FH), and lipidaemia than controls (figure). The difference 24 with mixed hyperlipidaemia (MH) are compared with controls matched for age, sex, and numberfor each group ofpatients. The number (n) ofpatients and controls in each group with in patients with juvenile familial hyperchole- manifestations is shown above the bars, and the percentage with manifestations on the y axis. sterolaemia and controls was not significant. 46 Klemp, Halland, Majoos, Sten

Table 1 gives the prevalence of the individual of whom 22 (79%) had palpable tendo Achillis manifestations. Tendon xanthomas and tendo xanthomas and six (21%) did not (p<0-001). All Achillis tendinitis were significantly higher in four patients with juvenile familial hyperchole- Ann Rheum Dis: first published as 10.1136/ard.52.1.44 on 1 January 1993. Downloaded from patients with adult familial hypercholestero- sterolaemia with tendo Achillis tendinitis laemia and mixed hyperlipidaemia and oligo- attributed the attacks to injuries. In the adults, arthritis in patients with mixed hyperlipidaemia. an association with injury was less obvious. Two patients with juvenile familial hyperchole- Tendo Achillis tendinitis developed for the first sterolaemia aged 14 and 15 years had palpable time in the late teens in most patients. The tendo Achillis xanthomas, four had had tendo attacks were recurrent in most instances, Achillis tendinitis, all after the age of 14 years, spanned a period of months or years, and in and one had a vague history of oligoarthritis. some were bilateral. In contrast, tendo Achillis Transient tendo Achillis pain and migratory tendinitis was unilateral in the three controls polyarthritis were rare in all three groups. and was not recurrent. The attacks were attri- Recurrent transient tendo Achillis pain was buted to an injury in two of the controls and to recorded in one patient with adult familial wearing boots in the third. hypercholesterolaemia and in none with mixed hyperlipidaemia or juvenile familial hypercholesterolaemia. Most episodes occurred on rising MUSCULOSKELETAL SYSTEM MANIFESTATIONS from bed, were momentary, and were non- AND LIPID LEVELS inflammatory. Five patients, all with adult Table 2 gives the pretreatment cholesterol and familial hypercholesterolaemia, had a history of triglyceride levels in patients with and without polyarthritis/polyarthralgia. Only one of these musculoskeletal system manifestations and the patients described the episodes as migratory. significance of these. The significance of tri- He had had four episodes in three years, each glyceride levels in the adult familial hyperchole- lasting two to 14 days and unaccompanied by sterolaemia and juvenile familial hyperchole- inactivity stiffness or inflammatory changes. sterolaemia groups was not tested because None of these patients had clinical evidence of normal levels were used to establish the groups. rheumatoid arthritis or other arthropathies when examined. Forty one (47%) of the 88 patients had ONSET OF MUSCULOSKELETAL SYSTEM xanthomas. Of these 40 (98%) affected one or MANIFESTATIONS both Achilles tendons. Other sites were the Thirty nine of the 57 (68%) patients with hand extensors in 12 (29%), the finger flexors in musculoskeletal system manifestations asso- one (2%), and the patellar ligament in one (2%) ciated with hyperlipidaemia were able to recall patient. All but one of the latter patients also whether their symptoms antedated or followed had tendo Achillis. None of the controls had the diagnosis of hyperlipidaemia. In 24 (62%) of xanthomas. these patients the musculoskeletal system http://ard.bmj.com/ There was a significant association between manifestations preceded the diagnosis and in 15 tendo Achillis tendinitis and tendo Achillis (38%) they had developed after the diagnosis xanthomas. Twenty eight (32%) of the 88 had been made. The difference was not signi- patients had a history of tendo Achillis tendinitis ficant (p=069).

Table I Comparison of individual musculoskeletal manifestations in three groups of hyperlipidaemic patients with those of controls matched for age, sex and as number. Results given number (%) on October 2, 2021 by guest. Protected copyright. Manifestation AFH* Controls p Value J7FH* Controls p Value MH Controls( p Value (n=48) (n=48) (n= 16) (n = 16) (n=24) (n=24) Tendon xanthomas 28 (58) 0 <0001 2 (13) 0 NS 11 (46) 0 <0001 Achilles tendinitis 17 (35) 3 (6) <0 001 4 (25) 0 NS 7 (29) 0 0 009 Oligoarthritis 10 (21) 6 (13) NSt 1 (6) 0 NS 8 (33) 0 0-004 Migratory polyarthritis 5 (10) 0 NS 0 1 (6) 0 0 Transient Achilles tendon pain 1 (2) 0 NS 0 0 0 0 *(AFH) adult familial hypercholesterolaemia; (JFH) juvenile familial hypercholesterolaemia; and (MH) mixed hyperlipidaemia. t(NS) not significant.

Table 2 Comparison of cholesterol and triglyceride levels in patients with (MSS+) and without (MSS-) selected manifestations in the three groups individually and in the combined groups Cholesterol (mmolll) 7'riglvceride (mmolll) Mean Range p Value Mean Range p Value AFH* MSS+ (n=30) 10 21 665-16 7 003t 1 08 0 11-1%9 MSS- (n=18) 8-92 653-11 7 1-06 0-42-1-85 JFH h MSS+ (n=5) 9.11 6-57-14 14 0 10 1-13 0-17-165 MSS- (n=11) 7-22 6 55-822 0 61 0-360-88 MH* MSS+ (n=17) 9 00 6-76-16-90 0-24 4-64 250-11-03 0 19 MSS- (n=7) 7-96 6-54-894 3-53 2 18-463 All three groups MSS+ (n=52) 9 71 6-57-16 90 0 001t 2 25 0 11-11 03 0-07 MSS- (n=36) 8 21 6-53-1170 1 40 0-364-63 *(AFH) adult familial hypercholesterolaemia; (JFH) juvenile familial hvpcrcholesterolaemia; and (MH) mixed hyperlipidaemia. tSignificant. Musculoskeletal manifestations in hyperlipidaemia 47

LIPID LOWERING TREATMENT appropriate treatment of the underlying Thirty of the 57 patients with musculoskeletal metabolic disorder.

system manifestations associated with hyper- There are difficulties with the classification of Ann Rheum Dis: first published as 10.1136/ard.52.1.44 on 1 January 1993. Downloaded from lipidaemia were able to state whether their the hyperlipidaemias. Our data suggest that symptoms (mainly tendinitis) had either stopped although tendon xanthomas are highly suggestive altogether or had become less frequent and less of familial hyperlipidaemia (Frederickson type severe after receiving lipid lowering treatment. IIA), they are often absent in young patients Nineteen (63%) of these patients felt that they with familial hyperlipidaemia. The diagnosis of had improved, whereas 11 (37%) had not noted familial hyperlipidaemia should therefore not be any difference (p=0 2). dependent on xanthomas in young people. In Xanthalasma and arcus cornealis were signi- addition, a subject with familial hyperlipidaemia ficantly more common in patients with adult may also have hypertriglyceridaemia due to familial hypercholesterolaemia than in the mixed hyperlipidaemia or to diabetes mellitus, controls (p=0-012 and p=0 007 respectively) excessive alcohol consumption, obesity, or the and in patients with mixed hyperlipidaemia use of drugs such as I6 blockers. (p=005) for xanthalasma and arcus cornealis. The pathogenesis of the musculoskeletal system manifestations in hyperlipidaemia is not fully understood. There is evidence suggesting Discussion that the arthropathy is a true inflammatory Epidemiological and other surveys have shown synovitis,' is periarticular,6 or that it is induced that musculoskeletal system disorders are by crystals. Cholesterol clefts have been shown common in the general population.'4 The in xanthomas'5 and positively birefringent purpose ofthis controlled study was to investigate suspected lipid crystals identified in fluid the reported associations between musculo- aspirated from a retrocalcaneal bursa and a skeletal system manifestations and hyper- tendo Achillis nodule in a patient with hyperlipidaemia. cholesterolaemia. 16 Our findings confirm that there is a significant It has also been suggested that tendinitis may association between xanthomas (particularly of be precipitated by unaccustomed exertion.3 the tendo Achillis) and tendo Achillis tendinitis Most of our patients did not associate episodes in patients with adult familial hypercholestero- of tendo Achillis tendinitis with exertion. The laemia. In addition, a significant association was significant association between tendo Achillis shown between xanthomas, tendo Achillis tendinitis and xanthomas in our study suggests tendinitis, and oligoarthritis in patients with that the xanthomas themselves may play a part mixed hyperlipidaemia. We found no asso- in the pathogenesis, possibly by producing an ciation, however, between either migratory inflammatory reaction on a mechanical basis. polyarthritis or transient tendo Achillis pain in In our study the musculoskeletal system any of the groups compared with controls. manifestations of some patients improved after There was no significant difference in the lipid lowering treatment. To establish whether http://ard.bmj.com/ number of patients with juvenile familial hyper- control of the hyperlipidaemia will alleviate the cholesterolaemia with musculoskeletal system musculoskeletal system manifestations requires manifestations compared with controls. The long term prospective studies relating serial juvenile familial hypercholesterolaemia group is lipid profiles to musculoskeletal system manifes- small, however, and firm conclusions from tations. statistical analysis may be inappropriate. It is on October 2, 2021 by guest. Protected copyright. probably more pertinent to note that several of and that We thank Professor H F H Weich, head of the department of the group did have manifestations cardiology for permission to study patients attending the lipid these developed in their late teens, unlike clinic and Professor J J F Taliaard and his staff, department of homozygous familial hypercholesterolaemia in chemical pathology for performing the lipid profiles. which they occurred earlier. This suggests that because of the lower lipid levels in heterozygous familial hypercholesterolaemia a longer period of time is necessary for the development of 1 Khachadurian A K. Migratory polyarthritis in familial hypercholesterolaemia (Type II hyperlipoproteinemia). symptoms. Arthritis Rheum 1%8; 11: 385-93. We showed a significant association between 2 Glueck C J, Levy R I, Fredrickson D S. Acute tendinitis and arthritis. A presenting symptom of familial Type II pretreatment cholesterol levels in the patients hyperlipoproteinemia. JAMA 1%8; 206: 2895-7. with adult familial hypercholesterolaemia and in 3 Goldman J A, Glueck C J, Abrams N R, Steiner P, Herman J H. Musculoskeletal disorders associated with '[ype IV the three groups combined, further suggesting a hyperlipoproteinaemia. Lancet 1972; ii: 449-52. link between cholesterol levels and the risk of 4 Shapiro J R, Fallat R W, Tsang R C, Glueck C J. Achilles tendinitis and tenosynovitis. A diagnostic manifestation of developing musculoskeletal system manifes- familial Type II hyperlipoproteinemia in children. Am .7 tations. Although not significant, there is some _ Dis(Child 1974; 128: 486-90. 5 Buckingham R B, Bole G G, Bassett D R. Polvarthritis indication that increased triglyceride levels may associated with Type IV hyperlipoproteinemia. Arcih Intern also predispose to musculoskeletal system Med 1975; 135: 286-90. 6 Rooney P J, Third J, Madkour M M, Spencer D, Dick W C. manifestations. Transient polyarthritis associated with familial hvperbeta- Our study confirms the findings in other lipoproteinaemia. Q J Med 1978; 187: 249-59. 7 Mathon G, Gagne C, Brun D, Lupien P, Mooriani S. studies that musculoskeletal system mani- Articular manifestations of familial hypercholesterolaemia. festations may antedate the diagnosis of hyper- Ann Rheum Dis 1985; 44: 599-602. 8 Rimon D, Cohen L. Hypercholesterolemic (Type II hyperlipidaemia.2 ' Recognition of these manifesta- lipoproteinemic) arthritis. Case report..7 Rheumatol 1989; tions, particularly in children and in subjects 16: 703-5. 9 Welin L, Larsson B, Svirdsudd K, Tibblin G. Serum lipids, with a strong family history of ischaemic heart lipoproteins and musculoskeletal disorders among 50- and disease, may contribute to early diagnosis and 60-year-old men. Scand.7 Rheumatol 1978; 7: 7-12. 48 Klemp, Halland, Majoos, Steyn

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