Rheumatic manifestations of hyperlipidemia and antihyperlipidemia drug therapy

Rheumatic Manifestations of Hyperlipidemia and Antihyperlipidemia Drug Therapy By David J. Careless and M i c h a e l G. C o h e n Conflicting data exist with respect to the existence and clinical manifestations of a hyperlipidemic arthropathy. Reasonable evidence supports the existence of a migratory poiyarthritis similar to rheumatic fever in patients homozygous for type II hyperlipidemia. Although similar complaints have been described in patients heterozygous for this condition, findings have been inconsistent among various reports. It is possible that high lipid levels are required to induce rheumatic complaints, and these are found predominantly in homozygous patients. Even so, rheumatic syndromes appear to be more attributable to periarthritis because evidence of inflammatory arthritis is largely lacking. In contrast, Achilles tendinitis appears to be associated with heterozygous type !1 hyperlipidemia and presum-

ably is based on lipid deposits within the tendon. Gout is an accepted association of type IV hyperlipidemia. In addition, oligoarticular symptoms have been described with type IV hyperlipidemia. However, no consistent clinical entity has emerged. Drugs used in the treatment of hyperlipidemia are associated with a variety of rheumatic problems, including proximal myopathy and lupus-like syndromes. The most commonly implicated drugs are the hydroxymethylglutaryl-coenzyme A reductase inhibitors and the fibric acid derivatives. Copyright 9 1993 by W.B. Saunders Company

ARLY REPORTS of arthropathy in pa-

taryl-coenzyme A (HMG-CoA) reductase inhibitors. With increased awareness of the risks associated with hyperlipidemia and greater use of lipid-lowering therapy, rheumatic syndromes caused by these drugs probably will be encountered more frequently9 Hyperlipidemias can be classified as either primary or secondary. The secondary types are caused by a variety of diseases including hypothyroidism, diabetes mellitus, and the nephrotic syndrome as well as exogenous agents such as oral contraceptives and alcohol. Hyperlipidemias originally were classified by Fredrickson into six groups, as shown in Table 1. Such disorders place the patient at increased risk of premature atherosclerosis, xanthoma formation in subcutaneous tissues or tendons, and pancreatitis. The value of the Fredrickson classification in categorizing the various disorders of lipoprotein metabolism is less clear in light of the genetic heterogeneity within the individual types in addition to recent work focusing on the role of apoproteins. Nonetheless, it remains the most widely known classification and is the one used in describing the rheumatic associations of hyperlipidemia. In this review, we discuss the spectrum of rheumatic syndromes that may arise in the patient with hyperlipidemia, related either to hyperlipidemia itself or to its therapy.

E tients with hyperlipidemia were assumed tO be related to coincidental rheumatic fever. Since Khachadurian ~ described a series of patients with an apparently distinct hyperlipidem~c arthropathy, controversy has existed w~th regard to the existence of true hyperlipidemic arthropathies. Despite several reports in the literature, their infrequency suggests that the association may be coincidental. Rheumatic syndromes occurring secondary to drugs often are easier to identify. The temporal relationship of symptoms with drug administration and resolution on drug withdrawal supports the association, z This can be confirmed by drug rechallenge if appropriate. Nonetheless, rheumatic syndromes caused by lipid-lowering drugs have been reported relatively infrequently with the notable exception of the hydroxymethylglu9

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i

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From the Rheumatology Department, Princess Alexandra Hospital, Brisbane, Queensland, Australia. David J. Careless, MB, BS: Medical Registrar, Rheumatology Department, Princess Alexandra Hospital; Michael G. Cohen, MB, BS, PhD, FRACP: Consultant Rheumatologist, Pahn Beach, Sydne2,; New South Wales, Australia. Address reprint requests to David J. Careless, MB, BS, Princess Alexandra Hospital, Ipswich Road, IVooloongabba, Brisbane, Queensland 4102, Australia. Copyright 9 1993 by IV..B. Saunders Company 0049-0172/93/2302-000255.00/0

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INDEX WORDS: tendinitis.

Seminars in Arthritis and Rheumatism,

Hyperlipidemia;

arthritis;.

Vo123,No 2 (October), 1993:pp 90-98

RHEUMATICMANIFESTATIONSOF HYPERLIPIDEMIA

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Table 1 : Classification of H y p e r l i p i d e m i a Fredrickson Type

Elevated Lipoprotein

Elevated Lipid

Primary Forms

I

Chylomicrons

Triglycerides

Ila

LDL

Cholesterol

lib

LDL VLDL Chylomicron IDL VLDL VLDL Chylomicrons

Cholesterol Triglycerides Triglycerides Cholesterol Triglycerides _+ cholesterol Cholesterol Triglycerides

III IV V

Lipoprotein lipase deficiency Apoprotein CII deficiency Familial hypercholesterolemia Familial combined hyperlipidemia Polygenic hypercholesterolemia Familial hypercholesterolemia Familial combined hyperlipidemia Familial dysbetalipoproteinemia Familial hypertriglyceridemia Familial hypertriglyceridemia Familial multiple type hyperlipidemia

Abbreviations: LDL,low-densitylipoprotein; VLDL,very low-density lipoprotein; IDL,intermediatedensity lipoproteins.

EPIDEMIOLOGY

Epidemiological support for a distinct hyper: lipidemic arthropathy is largely lacking. Welin et al 3 Studied 1,013 50- and 60-year-old men selected randomly from the general population in a questionnaire-based study with no clinical examination. No significant association between elevated lipid levels and rheumatic complaints was found. With respect to these negative findings, one must remember that the frequency of hereditary type II hyperlipidemia in the surveyed population probably was low in view of the mortality of this condition at earlier ages. Lipid levels in the patients studied probably were not as high as one would expect in homozygotes or heterozygotes with familial hyperlipidemia. Moreover, the questionnaire was limited to symptoms within the preceding 3 months, thereby excluding those who had experienced rheumatic symptoms earlier. Wysenbeck et al 4 found that significant joint pain was reported by 48% of patients with type II hyperlipidemia but only by 26% of the control group. However, the patients were not further interviewed or examined. In an uncontrolled study, Struthers et al5 had a positive response to a screening questionnaire in 57% of patients, but on review only 37% had arthritis. Importantly, only 8% had arthritic complaints other than osteoarthritis, gout, or rheumatoid arthritis. Nonetheless, the latter study may have underestimated the rheumatic complaints because Achilles tendinitis was not reported, pos-

sibly because of the nature of the questionnaire. Even so, the Studies are in concordance in that features of inflammatory arthropathy were uncommon in patients with type II hyperlipidemia. RHEUMATIC SYNDROMES ASSOCIATED WITH HYPERLIPIDEMIA Type II Hyperlipidemia

Clinical Features Homzygotes. In 1968, Khachadurian I reported a possible association between homozygous type II hyperlipidemia a n d a transient migratory polyarthritis similar to acute rheumatic fever. He studied 14 families from which 18 homozygotes were identified. Ten (56%) experienced a rheumatic fever-like illness, and 4 had recurrent episodes. Large joints were involved most frequently, and there was no consistent relationship between the joints affected and the presence of xanthomata. Pain varied from mild to incapacitating, and attacks lasted 2 days to a month. Four of the patients seen during an acute episode were febrile, and examination revealed warmth, tenderness, and diffuse swelling of the affected joints. Fluctuations in plasma cholesterol levels were not related to onset of joint symptoms. Erythrocyte sedimentation rates (ESRs) were elevated during acute attacks and failed to return to normal between attacks. Khachadurian's study differed from subsequent ones in the high incidence of rheumatic complaints. This may be because

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homozygotes were examined rather than heterozygotes as in later studies. Similar clinical presentations also have been documented in isolated case reports of patients who probably were homozygous for type II hyperlipidemia.6-8These reports confirmed findings of elevated ESR values during attacks but did not comment on values between attacks. Heterozygotes. Since Khachadurian's initial description, several series of patients have been reported either supporting or questioning the validity of an association between an arthropathy and type II hyperlipidemia (Table 2). However, all subsequent studies have evaluated patients heterozygous for type II hyperlipidemia. Even among the studies that support an association between type II hyperlipidemia and arthropathy, there is considerable diversity in the rheumatic syndromes reported.

Arthritis/Periarthritis Various presentations suggesting inflammatory arthritis have been reported. Most common is a migratory polyarthritis associated with fever and suggestive of acute rheumatic fever. The prevalence of this syndrome varies from 4% to 3 2 % . 9J~ The mean age at onset in heterozygotes is approximately 18 years, which differs from the more usual childhood onset in homozygotes. Rooney et al 9 described the acute onset of

moderate to severe pain, with maximal symptoms reached within 24 hours and attacks subsiding in less than 2 weeks. Peripheral joints were involved, especially the knees. Significant early morning stiffness and malaise and fever have been reported. Back pain was not encountered. As in homozygotes, recurrent attacks have been described but are not universal, and joints are asymptomatic between attacks. In 3% of patients reviewed by Struthers et al,5 a possible variant of this rheumatic fever-like polyarthropathy affected the small joints of the hands and lasted a few days. Mathon et al ~~ also noted oligoarthritis or monoarthritis in 7% of their study patients, in addition to the polyarticular pattern. The knees and ankles were most commonly affected, and only one patient reported proximal interphalangeal involvement. Recurrences were more common in monoarticular and oligoarticular presentations than in the polyarticular group. This finding contrasts with the finding of frequent recurrences of polyarthritis by Rooney et al. As noted previously, joints were asymptomatic between episodes. It is uncertain whether these rheumatic complaints represent arthritis or periarthritis. Khachadurian I was unable to aspirate synovial fluid in the one case in which this was attempted. Similarly, Rooney et al 9 noted soft

Table 2: Studies Examining the Association Between Hyperlipidemia and Rheumatic C o m p l a i n t s

Reference Khachadurian 1 Wysenbeck et al3

Sthruthers et al4

Rooney et al8 Mathon et aP

Total Patients 18 69

166

41 73

Lipid Profiles Type II homozygotes Familial type II heterozygotes (n = 33) Nonfamilial type II heterozygotes (n = 36) Control group (n = 31) Type II (n = 64) Type IV (n = 85) Type II heterozygotes Type II heterozygotes

Patients with Rheumatic

Problems

Description

10 (56%) 14 (43%)

Migratory polyarthritis Joint pain (feet, ankles)

19 (53%)

Joint pain (feet, ankles)

8 (26%) 2 (3%) 1 (1%) 8 (9%) 13 (32%) 29 (40%)

Joint pain (feet, ankles) Polyarthritis Polyarthritis Gout Migratory polyarthritis Achilles pain (18%) Achilles tendinitis (11%) Monoarthritis oligoarthritis (7%) Polyarthritis (4%)

RHEUMATIC MANIFESTATIONS OF HYPERLIPIDEMIA

tissue swelling with increased skin temperature overlying the affected joints but commented that swelling was not attributable to synovial thickening or effusion. The absence of inflammatory arthritis is further supported by synovial fluid analyses that showed normal viscosity and cell counts in all cases studied acutely. In addition, no patient had increased clearance of 133Xe from the affected joints despite increased uptake of 99Tc over the joint in three of four patients. There is only one report of an elevated synovial fluid cell count. H Few data are available on the laboratory features of this arthropathy. In contrast to the findings in homozygotes, Rooney et al a reported normal ESR readings during acute attacks. Effusiqns containing monosodium urate, calcium p3,rophosphate, or cholesterol crystals have not been reported. This is not to say, however, that pfftients with type II hyperlipidemia cannot develop gout or chondrocalcinosis. Achilles Tendinitis

Of all the possible associations with type II hyperlipidemia, the evidence for Achilles tendinitis is strongest. Mathon et al ~~found that 29% of responders in their survey had a history of Achilles tendon pain or tendinitis. Glueck et a111 and Shapiro et al Iz also noted that tendinitis was a common complaint in patients with type II hyperlipidemia. Attacks were gradual in onset, resolved over a few days, and could be recurrent with asymptomatic intervals. The Achilles tendons were warm, erythematous, and tender to palpation. Symptoms could be so severe that patients were bedridden, but systemic symptoms such as fever were absent. The predeliction of xanthomata for the Achilles tendon suggests a possible causal relationship, although the onset of symptoms often predated their appearance. Other Noninflammatory Arthritides

Struthers et al 5 reported osteoarthritis in 19 of 64 patients with type II hyperlipidemia, with neck, back, hip, knee, and ankle involvement. They considered this a coincidental rather than a causal relationship. Other studies have not commented on the prevalence of osteoarthritis in the populations studied. Struthers et al 5 also reported shoulder complaints in a small number

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of patients. This group had a variety of problems, including adhesive capsulitis, supraspinatus tendinitis, and bicipital tendinitis. DIFFERENTIAL DIAGNOSIS

The differential diagnoses of hyperlipidemic arthropathy include rheumatic fever, crystal arthropathy, palindromic rheumatism, and seronegative spondyloarthropathy. In homozygous patients, rheumatic fever remains an important consideration in view of the migratory nature of the polyarthritis, its predeliction for the younger age group, and the presence of cardiac murmurs in many patients. Nonetheless, it can be excluded on the basis of the lack of other major diagnostic criteria such as chorea, myocarditis, erythema marginatum, and nodules. In addition, serial increases in antistreptolysin O titers (ASOT) have not been observed. Finally, the early development of atherosclerosis, especially in homozygotes, causing aortic valvular sclerosis could explain the murmurs noted, as observed in the postmortem findings in Khachadurian's series. The infrequent documentation of effusions and the absence of crystals exclude a crystal arthropathy. Radiological examination has shown no evidence of chondrocalcinosis. Because of the association with tendinitis and enthesitis, seronegative spondyloarthropathy should be specifically considered in a patient with possible hyperlipidemic arthropathy. This is exemplified by a 27-year-old female patient of ours with type II hyperlipidemia. Since 1987 she has had recurrent episodes of Achilles tendinitis. Subsequently, she developed plantar fasciitis and ankle arthritis before being troubled with episodic arthritis involving the proximal interphalangeal, metatarsophalangeal, right hip, and temporomandibular joints. With an original diagnosis elsewhere of hyperlipidemic arthritis, she is HLA-B27 positive and has responded to treatment with sulphasalazine (unpublished observation). TYPE IV HYPERLIPIDEMIA

With respect to other classes of lipid abnormalities, there is an accepted association between g o u t and hypertriglyceridemia. 13 This may not be causal because such patients often have numerous predisposing factors for hyper-

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CARELESS AND COHEN

lipidemia such as obesity, high purine diets, and alcohol excess, which also contribute to gout. In addition there may be a genetic predisposition to both hypertriglyceridemia and hyperuricemia. 14 There are reports of rheumatic symptoms associated with type IV hyperlipidemia. Goldman et al ~5 and Buckingham et a116 both described cases that could not be classified into a recognizable rheumatic entity. Most patients were middle-aged and had acute or insidious onset of oligoarticular pain involving both large and small joints. The duration of symptoms was variable, with some patients ~periencing painful episodes lasting days to weeks and others having symptoms persisting for months. The patients of Goldman et al Is experienced more severe pain with significant joint tenderness and p~riarticular hyperesthesia. Symptoms suggestive of an inflammatory arthropathy, such as e~irly morning stiffness, were more prominent in the patients of Goldman et al. ~s Synovial fluid analyses were noninflammatory in both groups. Radiological examination of some of the patients of Buckingham et a116showed juxtaarticular osteoporosis and cystic lesions in either the juxtaarticular or metaphyseal regions. A biopsy of one lesion showed fibrous tissue and fat cells but no evidence of cholesterol deposits. Gout was excluded on the basis of historical and clinical features as well as synovial fluid analysis. OTHER HYPERLIPIDEMIAS

There are no reports of articular manifestations associated with type I hyperlipidemia. The type III form is autosomal recessive and manifest by increased cholesterol and triglyceride levels. A specific type of palm crease xanthoma is related to this condition, but associated arthropathies have not been reported. 17 SECONDARY HYPERLIPIDEMIAS

Rheumatic syndromes associated with secondary hyperlipidemias have not been examined specifically. Nonetheless, it is unlikely that any clear associations would be identifiable because of the heterogeneity of the underlying conditions. Moreover, many of these conditions are associated with rheumatic complaints (eg, diabetes mellitus and diabetic cheiroarthropathy).

PATHOGENESIS

Because the association between hyperlipidemia and arthropathy has not been firmly established, any discussion of a possible pathogenic mechanism must be hypothetical. In a comparison of synovial fluid lipid profiles between patients with type IV hyperlipidemia and those with other rheumatic problems such as gout or rheumatoid arthritis, Goldman et al ~s found no significant differences. The role of cholesterol crystals in the pathogenesis of inflammation is unclear. Isolation of cholesterol crystals from inflamed joints is unusual, being observed most often in joint fluids from patients with rheumatoid arthritis. Zuckner et a118postulated a number of possible explanations for their presence, including local synthesis, hemorrhage into the joint, necrosis of synovial tissue, intraarticular steroids use, slow absorption from the joint cavity, and increased diffusion from the blood. This group also performed experiments with rabbits, showing that intradermal and subcutaneous injection of cholesterol crystals could produce a local inflammatory response. Knee joints injected with a similar preparation did not show clinical inflammation. However, histopathological examination of the synovium showed a mild inflammatory reaction with giant cells. Thus, cholesterol crystals may act as proinflammatory agents in a fashion similar to monosodium urate and calcium pyrophosphate crystals. Cholesterol crystals may need an appropriate coating to elicit an inflammatory response, as seen with monosodium urate. 19However, their absence in the rare effusions associated with hyperlipidemia and the relative lack of inflammation in that arthropathy suggest they are not a major pathogenic factor. Furthermore, the infrequency of definite inflammatory features in these patients militates against a direct causal relationship. Nonetheless, high concentrations may be required to initiate an inflammatory response and may only be found in homozygotes. The pathogenesis of tendinitis with type II hyperlipidemia has not been addressed clearly in the literature. Tendinitis is more frequent than arthritis in heterozygotes, occurring in up to 25% of cases. 17 Xanthomata are not always present during the initial attacks but develop with time. Possible causes include microscopic

RHEUMATIC MANIFESTATIONS OF HYPERLIPIDEMIA

deposits of crystalline cholesterol with a subsequent inflammatory process or local ischemia in a relatively avascular tissue. Another possibility is that xanthomata cause local pressure in relation to footwear. MANAGEMENT

Most acute cases of arthropathy in type II hyperlipidemia settle spontaneously. Some patients have been treated with nonsteroidal antiinflammatory drugs, although evidence of shortening of the duration of the acute episodes is lacking. 9 Of the 10 patients of Rooney et al, 9 all were on lipid-lowering diets and half were on cholestyramine or colestipol therapy. Despite this treatment, 6 had recurrent episodes of arthritis during the 4-year follow-up period; unfortunately, the lipid status during arthritis flares was not reported. Cari-oll and Bayliss7 report one patient treated with diet and colestipol, resulting in decreased plasm a cholesterol level. Before lipid-lowering treatment, the patient reported recurring episodes (two to three per year) of large joint polyarthritis. Over the next 18 months, there were only two episodes of lower limb pain that were different from the patient's previous episodes. This suggested some improvement of the arthropathy with correction of hyperlipidemia. In one series of patients with type IV hyperlipidemia there was a correlation between improvement in plasma triglyceride levels and articular symptoms in 30% of patients. ~6 RHEUMATIC SYNDROMES ASSOCIATED WITH LIPID DRUG THERAPY

The most commonly used preparations in the treatment of hyperlipidemia include the bile acid-binding resins, nicotinic acid, fibric acid derivatives, probucol, and HMG-CoA reductase inhibitors. 2~ In terms of musculoskeletal side effects, the most frequently implicated drugs are the fibric acid derivatives and HMGCoA reductase inhibitors. 21,22 MYOPATHIES Clofibrate (a fibrie acid derivative) myopathy may manifest simply as asymptomatic increases in creatine phosphokinase (CPK) and aldolase 9 levels or may, on occasion, be so severe as to result in renal failure secondary to rhabdomyoly-

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sis. It may occur within a few days of beginning therapy or be delayed for up to 2 years, with the incidence increasing in the presence of renal impairment. Myalgic symptoms are prominent, and muscle cramping has also been reported. Weakness and muscle tenderness occur in the majority of patients, usually affecting the proximal muscles to the greatest degree. Some cases may occur with pain alone, without significant weakness; however, elevation of CPK levels is universal. Results of electromyographic studies and muscle biopsies vary from normal to consistent with a myopathic process, although inflammatory changes have not been recorded. 23,24 Gemfibrozil is a newer fibric acid derivative that does not appear to have the same propensity to cause muscle disorders. Fusella and Strosberg 25 describe a patient with polymyositis who had been stable for 9 years on methylprednisolone therapy. Two months after beginning gemfibrozil therapy she developed the acute onset of rash and increasing weakness associated with fever, leukocytosis, and elevated CPK levels. She responded to the cessation of gemfibrozil and an increase in steroid dosage. No muscle biopsy or drug rechallenge was performed. Myopathy is arecognized complication of therapy with the HMG-CoA reductase inhibitors, lovastatin, and simvastatin. Tobert26 reports that it occurs in 0.5% of patients taking lovastatin alone. The myopathy may appear as pain and predominantly proximal muscle weakness associated with an increase in CPK level. Less commonly, rhabdomyolysis and renal failure occur. The manufacturers have received reports of polymyalgia rheumatica associated with lovastatin therapy, but full clinical details have not been published. Whether this is simply a variant of the usual presentation of myopathy or a separate syndrome is undetermined. 27,2s Nicotinic acid, either alone or in combination with other drugs, has also been implicated in causing myopathy, although the incidence appears to be less than with cloflbrate or the HMG-CoA reductase inhibitors. Litin and Anderson 29 report muscle symptoms in three patients on nicotinic acid therapy. Nicotinic acid was the sole agent in two patients, whereas in the other it was used in combination with

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gemfibrozil. All patients complained of leg cramping and aching and had mild to moderate elevations of CPK levels. Symptoms resolved within a few days of nicotinic acid cessation. The frequency of myopathy in patients taking both lovastatin and gemfibrozil is approximately 5% but increases to 30% if, immunosuppressive therapy (most commonly cyclosporin A) is administered concurrently. In most cases the myopathy is more severe, with much higher CPK levels, than with monotherapy. A significant proportion have rhabdomyolysis and renal failure, especially cardiac transplant recipients) ~ In some cases muscle biopsies show atrophy, necrosis, and degeneration, but there are no reports of inflammatory changes. 33,34Resolution o~ the myopathy occurs a few days to weeks after drug withdrawal. i There have been reports of myopathy occurring when nicotinic acid and lovastatin were used incombination. Reaven and Witztum 35 have described a patient receiving lovastatin who developed rhabdomyolysis some months after nicotinic acid therapy began. One other report 3~ describes a cardiac transplant patient who received nicotinic acid for 3 months, lovastatin for 9 months, and cyclosporin before the onset of muscle pain and weakness. Acute renal failure due to rhabdomyolysis developed, and hemodialysis was required. Both lovastatin and nicotinic acid were discontinued, and the dose of cyclosporin A was reduced. Resolution of symptoms and recovery of renal function occurred over the next month. The mechanism of drug-induced myopathy is unknown. Some investigators suggest the fibric acid derivatives may interfere with muscle membrane cholesterol synthesis or amino acid or glucose metabolism. 36 Similarly, for the HMG-CoA reductase inhibitors the mechanisms underlying the myopathic side effects have not been elucidated. These drugs inhibit mevalonic acid production, an important component in the synthesis of muscle membrane cholesterol and in mitochondrial metabolism. Thus, inhibition of mevalonic acid production may severely impair muscle function. 37 To investigate this possibility, Maher et al 3s measured plasma mevalonate levels after lovastatin administration in three patients with previous iovastatin-related myopathy and in

CARELESS AND COHEN

three controls. They found no significant difference in the extent of the decrease in meval0nate concentrations between the two groups. Therefore, it is unlikely that the myopathy was related to the reduced mevalonate concentrations. The reason for the increased incidence of myopathy with combination therapy may relate to an additive or synergistic effect on muscle. Alternatively, interference with the metabolism or excretion of the drugs themselves could result in elevated plasma levels of one or both drugs with consequent increased likelihood of toxicity. DRUG-INDUCED LUPUS SYNDROME

There have been reports of a lupus-like syndrome occurring with lovastatin usage. 27,2sIn the only cases fully described, Ahmad 39 reports two patients who developed polyarthritis, positive antinuclear antibody tests, leukopenia, and elevated ESR after using lovastatin. One patient had detectable antihistone antibodies, a common but nonspecific finding in drug-induced lupus. 2,4~Lovastatin therapy was discontinued in both patients, and a short course of prednisone was prescribed ( < 7 days). This resulted in complete resolution of symptoms and disappearance of autoantibodies when tested 6 weeks later. A single patient with clofibrate-induced lupus has been reported. Howard and Brown 41 describe a patient who had been taking clofibrate for 2 years and developed weight loss, anorexia, malaise, arthralgias, and fevers. Further investigations showed an elevated ESR, leukopenia, and positive antinuclear antibody. Symptoms resolved within 2 weeks of discontinuing clofibrate therapy. Laboratory abnormalities had normalized when tests were repeated 6 weeks later, including disappearance of antinuclear antibody. SUMMARY

There has been a lack of consensus in the medical literature about the existence of a distinct hyperlipidemic arthropathy and the clinical spectrum if such exists. Nonetheless, the single series by Khachadurian and subsequent anecdotal reports favor the existence of a migratory polyarthropathy resembling rheumatic fever in patients with homozygous type II hyperlip-

RHEUMATIC MANIFESTATIONS OF HYPERLIPIDEMIA

97

idemia. The syndrome has its onset in childhood and is relapsing in nature. In view of the rarity of homozygous type II hyperlipidemia, treatment has not been examined formally although management of the hyperlipidemia may be beneficial. A similar arthropathy has been described in patients heterozygous for type II hyperlipidemia. However, considerable variability in clinical presentation has been described in reports supporting the association. The prevalence of such an arthropathy, if it exists, is likely to be in the order of 5% of patients. In view of the more consistent findings in homozygous patients, high levels of certain lipids may be required to induce rheumatic symptoms. The pathogenesis of the rheumatic symptoms is uncertain because little evidence exists for an inflamhaatory arthritis per se. Rather, most data point toward periarthritis as the major problem. Achilles tendinitis appears more definitely associated with heterozygous type II hyperlipidemia. :Although macroscopic xanthomata are not always observed, tendon deposits probably are of pathogenic significance. The association between gout and type IV hyperlipidemia is well known although the basis

of the association is not entirely delineated. An oligoarthropathy with or without symptoms suggestive of inflammation has been described in association with type IV hyperlipidemia. In addition, radiographic changes including cystic lesions have been noted. However, the cysts do not contain lipid deposits and the relationship with symptoms is unclear. No controlled studies have ascertained whether the symptoms described with this form of hyperlipidemia occur more often than in an otherwise normal population. Rheumatic complications resulting from hypolipidemic drug therapy are more clearly defined. A proximal myopathy is the most common pattern and occurs most often in patients taking HMG-CoA reductase inhibitors or fibric acid derivatives. The risk of this complication increases with combination therapy or with the addition of cyclosporin A in the case of HMGCoA reductase inhibitors. As with many drugs, drug-induced lupus is a rare complication. Nonetheless, recognition remains important because of the reversibility of the syndrome upon withdrawal of the causative drug.

REFERENCES 1. Khachadurian AK: Migratory polyarthritis in familial hypercholesterolaemia (type II hyperlipoproteinemia). Arthritis Rheum 11:385-393, 1968 2. Cohen MG, Prowse MV: Drug-induced rheumatic syndromes: Diagnosis, clinical features and management. Med Toxicol Adv Drug Exp 4:199-218, 1989 3. Welin L, Larsson B, Svardsudd K, et al: Serum lipids, lipoproteins and musculoskeletal disorders among 50- and 60-year-old men. Scand J Rheumatol 7:7-12, 1978 4. Wysenbeck AJ, Shani E, Beigel Y: Musculoskeletal manifestations in patients with hypercholesterolaemia. J Rheumatol 16:643-645, 1989 5. Struthers GR, Scott DL, Bacon PA, et al: Musculoskeletal disorders in patients with hyperlipidaemia. Ann Rheum Dis 42:519-523, 1983 6. Rimon D, Cohen L: Hypercholesterolaemic (type II hyperlipoproteinaemic) arthritis. J Rheumatol 16:703-705, 1989 7. Carroll G J, Bayliss CE: Treatment of the arthropathy of familial hypercholesterolaemia. Ann Rheum Dis 42:206209, 1983 8. Bluestone R: tlyperlipoproteinaemia and arthritis (two cases). Proc R Soc Med 64:669-670, 1971 9. Rooney PJ, Third J, Monir Madkour M, et al: Transient polyarthritis associated with familial hyperbetalipoproteinaemia. Q J Med 187:249-259, 1978 10. Mathon G, Gagne C, Brun D, et al: Articular manifes-

rations of familial hypercholesterolaemia. Ann Rheum Dis 44:599-602, 1985 11. Glueck CJ, Levy RI, Fredrickson DS: Acute tendinitis and arthritis--A presenting symptom of familial type II hyperlipoproteinaemia. JAMA 206:2895-2899, 1968 12. Shapiro JR, Fallat RW, Tsang RC, et ah Achilles tendinitis and tenosynovitis--A diagnostic manifestation of familial type II hyperlipoproteinaemia in children. Am J Dis Child 128:486-490, 1974 13. Rooney PJ, Ballantyne D, Buchanan WW: Disorders of the locomotor system associated with abnormalities of lipid metabolism and the lipoidoses. Clin Rheum Dis 1:163-193, 1975 14. Yu T, Dorph D J, Smith H: Hyperlipidaemia in primary gout. Semin Arthritis Rheum 7:233-244, 1978 15. Goldman JA, Glueck CJ, Abrams NR, et al: Musculoskeletal disorders associated with type IV hyperlipoproteinaemia. Lancet 2:449-452, 1972 16. Buckingham RB, Bole GG, Bassett DR: Polyarthritis associated with type 1V hyperlipoproteinaemia. Arch Intern Med 135:286-290, 1975 17. Fishel B, Rosenbach TO, Yaron M, et al: Ityperlipidaemias and rheumatic manifestations. Clin Rheumatol 5:75-79, 1986 18. Zuckner J, Uddin J, Gantner GE, et ah Cholesterol crystals in synovial fluid. Ann Intern Med 60:436-446, 1964 19. Terkeltaub RA, Ginsberg MH: The inflammatory

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reaction to crystals. Rheum Dis Clin North Am 14:353-364, 1988 20. Steiner A, Weisser B, Vetter W: A comparative review of the adverse effects of treatments for hyperlipidaemia. Drug Safety 6:118-130, 1991 21. Le Quintrec J-S, Le Quintrec J-L: Drug-induced myopathies. Ballieres Clin Rheumatol 5:1, 1991 22. Zuckner J: Drug-induced myopathies. Semin Arthritis Rheum 19:259-268, 1990 23. Langer T, Levy RI: Acute muscular syndrome associated with administration of clofibrate. N Engl J Med 279:856-858, 1968 24. Rush P, Baron M, Kapusta M: Clofibrate myopathy: A case report and a review of the literature. Semin Arthritis Rheum 15:226-229, 1986 25. Fusella J, Strosberg JM: Polymyositis exacerbated by gemfibrozil. J Rheumatol 17:572-573, 1990 26. Tobert JA: Letter of correspondence. N Engl J Med 318:48, 1988 27. Tobert JA, Shear CL, Chremos AN, et al: Clinical experience with Iovastatin. Am J Cardiol 65:23F-26F, 1990 28. Mantell GE, Burke T, Staggers J: Extended clinical safety profile of lovastatin. Am J Cardio166:11B-15B, 1990 29. Litin SC, Anderson CF: Nicotinic acid-associated m~'opathy: A report of three cases. Am J Med 86:481-483, 1989 30. Norman DJ, lllingworth DR, Munson J, et al: Myolysis and acute renal failure in a heart-transplant recipient receiving Iovastatin. N Engl J Med 318:46-47, 1988 31. East C, Alivizatos PA, Grundy SM, et al: RhabdomyC

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olysis in patients receiving lovastatin after cardiac transplantation. N Engl J Med 318:47-48, 1988 32. Corpier CL, Jones PH, Suki WN, et al: Rhabdomyolysis and renal injury with lovastatin use--Report of two cases in cardiac transplant recipients. JAMA 260:239-241, 1988 33. Ross Pierce L, Wysowski DK, Gross TP: Myopathy and rhabdomyolysis associated with lovastatin gemfibrozil combination therapy. JAMA 264:71-75, 1990 34. Goldman JA, Fishman AB, Lee JE, et al: The role of cholesterol-lowering agents in drug-induced rhabdomyolysis and polymyositis. Arthritis Rheum 32:358-359, 1989 35. Reaven P, Witztum JL: Lovastatin, nicotinic acid and rhabdomyolysis. Ann Intern Med 109:597-598, 1988 36. Mastalgia FL: Adverse effects of drugs on muscle. Drugs 24:304-321, 1982 37. Walravens PA, Greene C, Frerman FE: Lovastatin, isoprenes and myopathy. Lancet 2:1097-1098, 1989 38. Maher VMG, Pappu A, lllingworth DR, et al: Plasma mevalonate response in Iovastatin-related myopathy. Lancet 2:1098, 1989 39. Ahmad S: Lovastatin-induced lupus erythematosus. Arch Intern Med 151:1667-1668, 1991 40. Cohen MG, Pollard KM, Webb J: Antibodies to histones in systemic lupus erythematosus: Prevalence, specificity and relationship to clinical and laboratory features. Ann Rheum Dis 51:61-66, 1992 41. Howard EJ, Brown SM: Clofibrate-induced antinuclear factor and lupus-like syndrome. JAMA 226:13581359, 1973