Rheumatology Advance Access originally published online on October 13, 2006
Rheumatology 2006 45(12):1577-1578; doi:10.1093/rheumatology/kel344
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Atorvastatine for chronic synovitis due to massive intra-articular cholesterol monohydrate deposition in long-standing rheumatoid arthritis
Department of Rheumatology, Medical Centre Leeuwarden, POB 888, 8901 BR Leeuwarden, The Netherlands
Correspondence to: T. L. Th. A. Jansen, Department of Rheumatology, Medical Centre Leeuwarden, POB 888, 8901 BR Leeuwarden, The Netherlands. E-mail: T.Jansen{at}znb.nl
SIR, Crystal-induced arthritis is quite common in rheumatology, particularly negatively birefringent needles due to monosodium urate and positively birefringent rhomboids due to calcium pyrophosphate. Negatively birefringent plates with notched corners are due to cholesterol monohydrate but only rarely occur or are under-recognized; it is a challenge for clinicians to correctly diagnose these [1, 2]. Which therapy is to be considered once cholesterol plates have been diagnosed remains unclear from literature.
A 51-yr-old female with unremarkable lipid profile presented with exacerbation of rheumatoid arthritis (RA) and a particularly painful synovitis of knee and shoulder. RA had been diagnosed 15 yrs earlier. Several disease-modifying antirheumatic drugs had previously been prescribed as monotherapy and as combination therapy (dual, but not triple): oral methotrexate (MTX with folic acid supplementation), sulphasalazine (SSZ) and hydroxychloroquine (HCQ), all without significant efficacy. Tolerance problems with MTX made her discontinue the MTX and continue SSZ monotherapy. Despite high disease activity, 28 joint count (DAS28) 5.1, she complied to SSZ for several years. Puncture of the right shoulder and left knee revealed a voluminous white colloidal fluid [1]. Micro-organisms were excluded. Polarization microscopy revealed cholesterol monohydrate plates. Treatment options aiming primarily at reducing total bulk of intra-articular cholesterol, and secondly at reducing DAS28, were considered; see Table 1. Failure on both end points was seen during 8 weeks of follow-up using weekly parenteral MTX 10 mg (without tolerance problems). Following intra-articular injection of 40 mg methylprednisolone acetate, a large voluminous increase of synovial fluid was produced, again loaded with cholesterol plates. It was only when atorvastatine 20 mg daily was started that the cholesterol bulk completely resolved; see Table 1. Possibly MTX in part, but particularly atorvastatine, should be held responsible for the resolution of the large bulk of intra-articular cholesterol.
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Data from literature on treatment options of cholesterol crystal synovitis are lacking. Cases with cholesterol crystal deposition have only sporadically been reported in the literature [2]. If deposition occurs in rheumatoid diseases, then it occurs most frequently in structures with synovial lining and without concomitant hyperlipidaemia. General interest of immunologists/rheumatologists in statins has increased over the last years. Trial of Atorvastatin in RA (TARA) has drawn attention to the pivotal role statins may play in chronic rheumatoid inflammation [3]. [Interestingly, statins have next to anticholesterol, also immunomodulatory and anti-inflammatory properties.] They appear to act as direct repressors of class II major histocompatibility complex (MHC)-mediated T-cell activation while not affecting constitutive expression of class II MHC in dendritic cells and B-lymphocytes [4]. Statins selectively block ß2 integrin and lymphocyte-function-associated antigen I (LFA-1) by binding to a novel allosteric site within LFA-1 [5]. Another beneficial effect of statins may be the switch from Th1 to Th2 cytokines, as demonstrated for atorvastatine in a murine model [6]. Statins reduce CD40 expression in atheroma-associated cells in atherosclerotic lesions in situ in treated patients [7]. Fluvastatin has recently been shown to induce apoptosis in vitro in RA synoviocytes through a mitochondrial and caspase-3-dependent pathway and by inhibition of the geranylgeranyl pathway [8]. One may speculate that some of these previously proven mechanisms of action may be of relevance in the presented case.
Cholesterol crystalloids may appear as negatively birefringent, large, flat rectangular plates with notched corners, ranging from 8 to 100 µm, consisting of monohydrate cholesterol. These are thermodynamically stable and not easily cleared. This case lends support to the hypothesis that locoregional monohydrate cholesterol production or one of the aforementioned mechanisms (suppression of class II MHC or Th1–Th2 switch) play a pivotal role in the aetiopathogenesis of cholesterol synovitis, as cholesterol synovitis can be inhibited by atorvastatine in humans.
The authors have declared no conflicts of interest.
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