Lipid-Associated Rheumatologic Syndromes




Rheumatologic manifestations of hyperlipidemia and lipid-associated arthritis are rarely seen in the rheumatologist’s office. On the other hand, a rheumatologist may be the clinician who identifies and initiates proper therapy for disorders related to hyperlipidemia when the musculoskeletal manifestations of these syndromes are recognized. In this article both the joint and tendon manifestations are reviewed, including the lesser known lipid liquid crystal form of arthritis. The relationship between gout and hyperuricemia is briefly discussed, as are the autoimmune manifestations of lipid-lowering therapy.


Key points








  • Tendon xanthomas are associated with Type II and III hyperlipidemia and their presence is a marker for an increase the risk of cardiovascular disease.



  • Arthritis associated with hyperlipidemia may affect one or multiple joints and is likely a periarthritis in most cases.



  • Lipid liquid crystal arthritis is self-limited inflammatory arthritis characterized by the presence of positively birefringent spherules in the synovial fluid.



  • There is an association between hyperlipidemia and gout that is likely both environmental and genetic.



  • Statins have been implicated in the development of autoimmune disease including a recently described necrotizing myopathy.






Introduction


Lipid-associated musculoskeletal syndromes are uncommon problems seen in the rheumatologist’s office. The rheumatologist, however, may be the first clinician to recognize the manifestations of a lipid-associated syndrome and initiate proper investigation and therapy. Khachadurian was one of the first to report that patients with hyperlipidemia experienced musculoskeletal symptoms. The single-author article from the American University in Beirut reported that 10 of 18 patients homozygous for familial type II hyperlipidemia had attacks of acute migratory polyarthritis lasting up to a month that resembled acute rheumatic fever, as well as tendon xanthomata. No other explanation for the arthritis was uncovered, and the implication was that the hyperlipidemia was the cause of the attacks. Since then a variety of reports covering this topic and expanding on the musculoskeletal manifestations of hyperlipidemia has been published. This article reviews the current literature regarding lipid-associated syndromes involving joints and tendons, and also reviews the data regarding the relationship of hyperlipidemia with hyperuricemia and gout. Finally, drug-induced rheumatologic illness related to lipid-lowering therapy is briefly discussed.




Introduction


Lipid-associated musculoskeletal syndromes are uncommon problems seen in the rheumatologist’s office. The rheumatologist, however, may be the first clinician to recognize the manifestations of a lipid-associated syndrome and initiate proper investigation and therapy. Khachadurian was one of the first to report that patients with hyperlipidemia experienced musculoskeletal symptoms. The single-author article from the American University in Beirut reported that 10 of 18 patients homozygous for familial type II hyperlipidemia had attacks of acute migratory polyarthritis lasting up to a month that resembled acute rheumatic fever, as well as tendon xanthomata. No other explanation for the arthritis was uncovered, and the implication was that the hyperlipidemia was the cause of the attacks. Since then a variety of reports covering this topic and expanding on the musculoskeletal manifestations of hyperlipidemia has been published. This article reviews the current literature regarding lipid-associated syndromes involving joints and tendons, and also reviews the data regarding the relationship of hyperlipidemia with hyperuricemia and gout. Finally, drug-induced rheumatologic illness related to lipid-lowering therapy is briefly discussed.




Lipoproteins and the current classification of dyslipidemia


The 5 major types of hyperlipidemia are classified by their relevant forms of lipoprotein dysmetabolism under the Fredrickson classification system ( Table 1 ). A proper understanding of this system requires a brief review of the 5 major lipoproteins and their basic functions.



Table 1

Fredrickson/World Health Organization classification of dyslipidemias
































Type Elevated Lipoprotein(s) Lipids Elevated
I Chylomicrons Triglycerides
IIa LDL Cholesterol
IIb LDL, VLDL Cholesterol > triglycerides
III IDL (VLDL remnants), chylomicrons Cholesterol and triglycerides
IV VLDL Triglycerides
V VLDL, chylomicrons Triglycerides > cholesterol

Abbreviations: IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; VLDL, very low-density lipoprotein.

Data from Fredrickson DS. An international classification of hyperlipidemias and hyperlipoproteinemias. Ann Intern Med 1971;75(3):471–2; and Durrington P. Dyslipidaemia. Lancet 2003;362(9385):717–31.


Lipoproteins are assemblies of lipids (triglycerides and/or cholesterol, in the case of the lipoproteins discussed in this article) and protein (referred to as apolipoproteins or apoproteins), which serve to transport lipids in the body. Lipid metabolism can be broadly characterized as being under the control of both endogenous and exogenous pathways. The lipoprotein associated with exogenous (dietary) lipid metabolism is the chylomicron, which is mainly a carrier of triglycerides but which also carries, to a significantly lesser extent, cholesterol esters. Chylomicrons are formed in enterocytes and are transported through the lymphatic system to the circulation, where they are broken down by lipoprotein lipase into free fatty acids (from triglycerides) and apoproteins. Ultimately, the remaining chylomicron remnants are taken up by hepatocytes and their contents reprocessed (eg, remaining triglycerides can be packaged for reexport into the circulation as part of very low-density lipoproteins [VLDLs]).


Endogenous pathways of lipid metabolism refer to the processing of hepatically derived lipids, and begin with export of VLDLs from the liver. As with chylomicrons, VLDLs carry triglycerides and, to a lesser extent, cholesterol, and are broken down in the periphery by lipoprotein lipase to yield, among other elements, a combination of free fatty acids and apoproteins. The result is the formation of smaller, denser VLDL “remnants” (also referred to as intermediate-density lipoproteins [IDLs]), which in turn can be broken down further by hepatic lipase to yield IDL remnants known as low-density lipoproteins (LDLs). As the VLDL is broken down, it becomes denser and more enriched in cholesterol, as evidenced by LDL’s main role as a carrier of cholesterol rather than triglycerides.


High-density lipoprotein (HDL), like LDL, is chiefly a carrier of cholesterol. Its main role is to absorb excess cholesterol from intracellular pools and to transport this cholesterol, via a combination of direct and indirect pathways, back to the liver or to steroidogenic tissues such as the adrenals, ovaries, and testes. This transport can be done directly via interaction with scavenger cholesterol receptors on target tissues, or indirectly via initial transfer of cholesterol esters to LDL, which in turn delivers these esters to the tissues.


The roles of the 5 major lipoproteins (in order of decreasing size and increasing density) can be summarized as follows:




  • Chylomicrons: large lipoproteins that carry dietary, or exogenous, lipids (triglycerides > cholesterol)



  • VLDLs: carriers of hepatically derived, or endogenous, lipids (triglycerides > cholesterol)



  • IDLs (also referred to as VLDL remnants): carriers of endogenous cholesterol and triglycerides



  • LDLs: carriers of endogenous cholesterol



  • HDLs: absorb excess cholesterol from intracellular pools and return this cholesterol to the liver and steroidogenic tissues (adrenals, ovaries, and testes)





Hyperlipidemia and tendinopathy


Of the major classes of hyperlipidemia, types II and III have been shown to be associated with xanthomatous disease, and type II has been associated with tendinopathy. Type II hyperlipidemia is characterized by elevation of LDL levels (see Table 1 ) and has 2 known subtypes (types IIa and IIb). It can be inherited as a familial disease or present as a polygenic or sporadic disorder. Patients homozygous for familial type II hyperlipidemia have mutations in both LDL receptor (LDLR) alleles, and develop tendon xanthomata that can be either symptomatic or asymptomatic. These xanthomata are collections of lipid-laden macrophages that typically develop over the Achilles tendons (although other tendon areas, including the triceps tendons, may also be involved) and that, in homozygotes, typically develop in childhood. In addition, type II homozygotes may develop fever and a migratory polyarthritis that mimics rheumatic fever, which was first reported by Khachadurian and is discussed in more depth in the next section. Of note, there was no clear relationship between the observed joint pains and the locations of xanthomata.


Tendon xanthomata are also found in patients who have type II heterozygous hyperlipidemia ( Fig. 1 ). Xanthomata present later in life than in homozygotes (who typically die of cardiovascular disease before the age of 30 years), are present at a comparatively lower frequency, and are not present in all patients. As with their homozygous counterparts, these xanthomata can be asymptomatic. The Achilles tendon is the most common location of xanthomata in patients with type II hyperlipidemia, and Mathon and colleagues reported that 18% of 73 patients with familial heterozygous type II hyperlipidemia had Achilles pain and 11% had evidence of Achilles tendinitis. In a controlled cross-sectional study, Beeharry and colleagues reported that 46.6% of 133 patients with familial heterozygous type II hyperlipidemia had had 1 or more episodes of Achilles pain, compared with 6.9% of 87 unaffected controls. The patients were also significantly much more likely to report the pain as severe or very severe, with pain lasting an average of 4 days, and more likely than the controls to seek medical attention for the Achilles symptoms. One of the early studies of symptomatic Achilles tendon involvement reported that tendinitis could be unilateral or bilateral, that patients could have up to 12 attacks per year, and that one patient had 4 to 5 attacks per year for 40 years. The presence of tendon xanthomata is an independent risk factor for cardiovascular disease and indicates the need for more aggressive lipid-lowering therapy. In a meta-analysis of xanthoma formation, heterozygous type II hyperlipidemia, and cardiovascular risk, Oosterveer and colleagues found that the presence of xanthomata conferred a 3.2-fold higher risk for cardiovascular disease. Increasing age, male gender, and levels of LDL cholesterol and triglycerides increased the risk of developing xanthomata. The xanthoma has a composition similar to that of atheroma, and treatment-associated regression of xanthomata with either statins or fibrates may be a marker of atheroma regression. Achilles tendon xanthomata are easily detected by ultrasonography or magnetic resonance imaging (MRI) before they may be detectable clinically. Ultrasonography, in turn, is the easiest and most cost-effective way of detecting xanthomata, and can also be used to quantitatively measure treatment-associated xanthoma regression.




Fig. 1


Achilles tendon xanthoma in a patient with type II heterozygous hyperlipidemia.

( From Durrington P. Dyslipidaemia. Lancet 2003;362(9385):719; with permission.)


Type III hyperlipidemia (familial dysbetalipoproteinemia) is an autosomal recessive disorder involving 2 apoprotein E2 alleles that results in elevated levels of IDL (VLDL remnants) and chylomicrons and, in turn, elevated cholesterol and triglyceride levels. Tuberoeruptive xanthomata (which typically involve the extensor surfaces) and plantar crease xanthomata (xanthomata palmare striatum) are typical of this disorder. These xanthomata are asymptomatic and do not involve joint or tendon areas. Of note, reports have shown that close to half of these patients have asymptomatic hyperuricemia, with actual gout attacks being rare.


Beyond familial forms of hyperlipidemia, secondary forms (such as hyperlipidemia secondary to diabetes or thyroid disease) can also present with xanthomata. Rheumatic symptoms (such as joint pains) associated with several of the secondary hyperlipidemias are common, but in light of a lack of studies examining the causes of these symptoms as well as the clinical heterogeneity and genetic complexity of the underlying diseases, clear associations have not been found.


Two final entities that deserve note are cerebrotendinous xanthomatosis and sitosterolemia, both of which are rare autosomal recessive disorders of lipid metabolism associated with tendon xanthomata but not actual tendinitis or arthritis. Cerebrotendinous xanthomatosis involves a mutation in the sterol 27-hydroxylase gene, which leads to accumulation of dihydrocholesterol (cholestanol). It is associated with asymptomatic xanthomata of the Achilles tendons that appear in the second to fourth decades of life, as well as a variety of other symptoms including cataracts, diarrhea, vascular disease, cerebellar ataxia, and dementia.


Sitosterolemia involves excessive intestinal absorption, and subsequent increased plasma levels, of plant sterols. Patients develop asymptomatic tendon xanthomata as well as accelerated atherosclerosis.




Hyperlipidemia-associated arthritis


The 1968 report of Khachadurian has been the basis for the association of hyperlipidemia with arthritis. Of 18 young homozygous patients with familial type II hyperlipidemia, 10 were reported to develop self-limited attacks of migratory polyarthritis that could be severe enough to cause the sufferer to be bedridden. In the 10 affected patients, Khachadurian ruled out acute rheumatic fever and hyperuricemia in all cases as a cause of the arthritis. Sedimentation rates and C-reactive protein could be elevated and the patient could be febrile as well. The sedimentation rate often remained elevated between attacks of arthritis. The joints were described as being swollen, but the one attempted arthrocentesis from a swollen knee was unsuccessful in that no fluid was obtained. A photo of a patient’s hands included in the report shows marked fullness around the metacarpophalangeal joints, and proximal interphalangeal (PIP) joints in particular are described as being xanthomatous. All of the patients included in this report had xanthomata. The lack of obtainable synovial fluid and the appearance of the hands raise the question of a periarthritis rather than a true arthritis.


A much more detailed report of the arthritis of hyperlipidemia was published in 1978 by Rooney and colleagues. These investigators followed 41 patients with familial hyperbetalipoproteinemia for up to 4 years, noting the symptoms and joints involved, and reporting on fluid obtained during arthrocentesis and even doing xenon clearance from joints assumed to be inflamed. Again a transient migratory polyarthritis was noted, which affected both large and small joints in up to 10 of these patients, lasting 3 to 12 days. The pain was moderate to severe and in no case was the arthritis attributable to acute rheumatic fever of gout. Synovial fluid was obtained from 6 swollen joints; in all cases the fluid had 200 or fewer white blood cells (WBCs) per cm 3 and was reported to have normal viscosity. Bacteriologic and crystal analyses were negative in all patients. Xenon clearance for affected joints was also normal, suggesting to the investigators that the arthritis was in all cases actually a periarthritis. In a case report of a male patient with swelling of PIP joints and familial hypercholesterolemia, MRI revealed periarticular fat deposition, which by appearance may have been capsular in location but certainly not intra-articular. Fine-needle aspiration of the periarticular lipid accumulation at the PIP joints in a young girl with familial hypercholesterolemia demonstrated the presence of abundant foam cells (ie, macrophages laden with lipids and found in atherosclerotic plaques as well as xanthomata of skin and tendons). Foam cells are metabolically active and may produce cytokines and other proinflammatory molecules, or possibly metabolize the internalized lipid to cause it to become phlogistic. These activities may contribute to periarticular inflammation seen in affected patients. A patient with a similar periarticular deposition of lipid is shown in Fig. 2 .




Fig. 2


( A ) Dorsal view of the hand showing marked periarticular fullness around he PIP joints in a patient with Type II hyperlipidemia. ( B ) Palmar view of the same hand showing palmar xanthomata ( arrows ) in addition to the periarticular fullness.

( From Sharma A, Dogra S, Mahajan R, et al. An unusual cause of joint swelling. Lancet 2010;375:1109; with permission.)

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Oct 1, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Lipid-Associated Rheumatologic Syndromes

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