Systemic lupus erythematosus and gouty arthritis: an uncommon association
S. Bajaj,
B. J. Fessler and
G. S. Alarcón
Division of Clinical Immunology and Rheumatology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
Correspondence to: G. S. Alarcón, 830 Faculty Office Tower, 510 20th Street South, Birmingham, Alabama 352943408, USA. E-mail: graciela.alarcon{at}ccc.uab.edu
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Abstract
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Objective. To examine the frequency of gouty arthritis in patients with systemic lupus erythematosus (SLE) and elucidate the clinical factors that predispose to this occurrence.
Methods. A chart review of in-patients (19892001) and out-patients (19992001) with ICD9 billing codes for gouty arthritis/tophaceous gout and SLE was performed. Twenty-six patients were identified. Patients meeting American College of Rheumatism criteria for SLE and crystal-proven gout or a self-limited inflammatory arthritis felt to be crystal-induced (i.e. definite gout) were included.
Results. Ten patients were identified. Their mean age was 46.5 yr; 80% were African-American and 70% were women. Nine of the ten had lupus nephritis and four had undergone renal transplantation. An acute worsening of renal function unrelated to lupus activity preceded almost all gout flares. Lupus activity at the time of the first gout attack as measured by the Systemic Lupus Activity Measure (SLAM) was low. Eight patients were on prednisone (mean dose 8 mg/day) for their SLE at the time the attack of gout occurred.
Conclusions. Gouty arthritis is uncommon in SLE; it occurs primarily in patients with long-standing SLE and nephritis. Worsening renal function usually preceded gout attacks, but SLE disease activity was minimal. Crystal-induced arthritis should be included in the differential diagnosis of a lupus patient presenting with acute inflammatory arthritis because the long-term treatment of the two conditions differs substantially.
KEY WORDS: Gout, Systemic lupus erythematosus, Arthritis, Lupus nephritis, Renal insufficiency.
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Introduction
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Although some patients with systemic lupus erythematosus (SLE) may have hyperuricaemia owing to renal insufficiency, they seldom develop gout. It is possible that the unique milieu present in SLE or the therapy for SLE (i.e. corticosteroids and non-steroidal anti-inflammatory drugs) is protective against gout or simply that clinicians misdiagnose gout, assuming that the arthritis is due to lupus. We recently had the opportunity to diagnose gout in a young African-American woman with a history of lupus and chronic renal insufficiency. The attack followed a bout of gastroenteritis with mild dehydration and worsening azotaemia. Her case prompted us to examine the frequency of gouty arthritis in SLE patients and to explain the factors which may predispose to its development.
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Patients and methods
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Approval from the University of Alabama at Birmingham's (UAB) Human Subjects Institutional Review Board was obtained. Twenty-six patients with gouty arthritis/tophaceous gout and SLE were initially identified using ICD9 billing codes (274.0, 274.82 and 710.0, respectively). These patients were either admitted to the UAB (19892001) or were seen in the out-patient clinic (19992001). Ten patients who met four or more American College of Rheumatism (ACR) criteria for SLE [1, 2] and had either crystal-proven gout (physician or laboratory technician documenting the presence of monosodium urate crystals in synovial fluid) or a self-limited inflammatory arthritis felt to be crystal-induced were included. In total there were 1453 patients with SLE admitted to the hospital during the above time course; eight of the patients in the study were from the in-patient and two were from the out-patient setting. SLE disease activity at the time of the first gout attack was assessed from the medical records using the Systemic Lupus Activity Measure (SLAM) [3, 4]. Duration of SLE and gout was calculated from the time of initial onset of these two disorders.
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Results
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Acute gouty arthritis was noted in 0.55% of all SLE admissions over 12 yr (19892001). Table 1 illustrates basic demographic data and duration of both diseases. The mean age of these patients was 46.5 yr; most patients were in their 40s and 50s with the exception of our index case (age 22). Eighty per cent were African-Americans and 70% were women. In 9/10 patients, a diagnosis of lupus was present for many years (mean 19.6 yr, range 936) prior to the diagnosis of gout. Only one patient was diagnosed with lupus after the diagnosis of gout was established. Gout was confirmed by arthrocentesis in 7/10 patients; in the remaining three the clinical presentation was felt to be consistent with crystal-induced arthritis, as they had hyperuricaemia and a history of recurrent podagra with prompt resolution of symptoms on colchicine.
Table 2 depicts additional clinical manifestations [lupus nephritis (nine patients), renal transplant (four patients)], serological data and medications. One transplant recipient was taking cyclosporin for immunosuppression. All 10 patients had hyperuricaemia with a mean uric acid level during attack of 0.7 mmol/l. An acute worsening of renal function (rise in serum creatinine) preceded almost all gout flares (9/10) including our index case. In 8/9 patients in whom lupus was diagnosed prior to gout, the mean time between first (baseline) and second (during acute gout attack) creatinine determination was 4 months (range 18 months). In all cases, the azotaemia was felt to be unrelated to SLE activity (i.e. pre-renal azotaemia, allergic interstitial nephritis). Lupus activity was minimal in all patients at the time of their first gout attack (SLAM score 2.4). Complement levels were assayed in 8/10 patients during the attack and were found to be normal in all eight patients. More than half of the patients (6/10) were on diuretic therapy at the time of the first attack. The majority of the patients were either on a tapering schedule of prednisone (n = 8) or were on no corticosteroids at all (n = 2). The mean daily prednisone dose was 8 mg (range 020).
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Discussion
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Lupus patients frequently have renal disease and hypertension and are commonly on diuretics. Diuretics, along with underlying renal insufficiency, can substantially decrease clearance of uric acid causing hyperuricaemia, thereby predisposing to the development of gout; however gout is uncommon in SLE. Moidel and Good [5] first reported a case of coexistent gout and SLE in 1981. Using Medline, we identified 24 cases of coexistent gout and SLE reported in the literature over the last 22 yr [520]. In addition, there are two case reports of patients with SLE and urate deposition in skin and subcutaneous tissue without any evidence of arthritis [21, 22]. Our series adds 10 new cases to the literature.
From our review, several important issues emerge: (i) the coexistence of SLE and gout is indeed uncommon, (ii) patients typically have a history of lupus nephritis and experience worsening azotaemia prior to a gout attack, and (iii) at the time of the gout attack lupus is quiescent.
Renal manifestations are common in lupus; most patients with coexistent gout and lupus reported in the literature have a history of lupus nephritis and that was the case in 90% of our patients. Acute worsening of renal function unrelated to lupus activity preceded the first gout attack in 9/10 patients. We do not know if that is true for historical cases as creatinine levels prior to and during the first gout attack have not been provided. Patients with chronic renal insufficiency are known to have a less intense inflammatory response to monosodium urate (MSU) crystals than normal subjects [23] and gout attacks are less severe and less frequent in such individuals. Recently, monocytes from uraemic patients were shown to produce significantly lower amounts of interleukin 1ß (IL-1ß), IL-6 and tumour necrosis factor after stimulation with urate crystals [24].
One transplant recipient was on cyclosporin, which is known to cause hyperuricaemia by interfering with urinary uric acid excretion. Patients on cyclosporin frequently have polyarticular attacks and a rapidly progressive course with development of tophi. Cyclosporin may have predisposed this patient to the development of gout.
As stated earlier, lupus disease activity at the time of gout attack is usually minimal, and that was the case in our patients (low SLAM scores, low maintenance prednisone dose and normal serum complement levels). Lupus patients typically had hypocomplementaemia at diagnosis and during lupus flares, but normal levels have been noted by most other authors at the time of the attack. MSU crystals are potent activators of the complement cascade, and the complement system is believed to play a key role in the pathogenesis of inflammation associated with gout [25, 26]. If MSU crystals require near normal levels of complement proteins to induce inflammation then the presence of decreased complement levels in patients with active SLE may pose a barrier to urate-induced inflammation. Additionally, the inflammatory response in acute gouty arthritis is in large part a result of the interaction between polymorphonuclear (PMN) cells and MSU crystals. This interaction results in ingestion of MSU by PMN cells, and release of cytokines resulting in an intense inflammatory response. Granulocytes in SLE patients have been demonstrated to have impaired phagocytosis, which may be one of the reasons why patients with active SLE are unable to mount an adequate inflammatory response to MSU crystals [2730].
Another potential explanation for the negative association between gout and lupus may be a change in structure of the MSU crystal in lupus patients because of a protein coat (apo B lipoprotein) that makes the crystal less inflammatory. MSU crystals incubated with serum become less stimulatory for the leucocyte. This is mainly due to the binding of apo B lipoprotein to the MSU crystal [26]. Patients with SLE are frequently on corticosteroids. Glucocorticosteroid-associated lipid abnormalities include hypertriglyceridaemia, hypercholesterolaemia and a raised low-density lipoprotein (LDL) cholesterol level. The major apolipoprotein of LDL is apo B. A high serum LDL level translates into a high serum apo B level, which has been shown to inhibit cellular responses to the MSU crystals by binding to the crystal surface, thereby physically inhibiting particlecell interaction and subsequent phagocytosis of MSU and membrane activation.
Finally, it is important to remember that the mainstays of SLE treatment are corticosteroids, which are potent anti-inflammatory agents. Corticosteroids block increased vascular permeability associated with inflammation; they also suppress chemotaxis and phagocytosis by neutrophils. Treatment with corticosteroids, along with the other mechanisms for decreased MSU-mediated inflammation in lupus as outlined above, may explain why some lupus patients have been noted to have urate deposition in their skin and subcutaneous tissue but lack a history of acute arthritis.
Management of gout can be challenging in patients with SLE and renal insufficiency; levels of both colchicine and allopurinol have to be prescribed according to the patient's renal function. Corticosteroids can be used to manage acute gout flares. Non-steroidal anti-inflammatory drugs are not recommended. Urate oxidase is being evaluated in some clinical trials for the treatment of gout, and if approved it may be useful in this clinical scenario.
In summary, our review confirms that gouty arthritis is uncommon in SLE patients. It is typically observed in patients with long-standing SLE. Patients with a history of lupus nephritis and those on diuretics are at higher risk for developing gout. An acute worsening of renal function preceded the gout flare in more than two-thirds of our patients. SLE activity at the time of gout attack was minimal. Based on the difference in age and gender of the affected populations in these two diseases, it may be reasonable to expect a negative association for the concurrent occurrence of gout and SLE; the actual reasons for the uncommon association may be multifactorial. As crystal-induced arthritis can mimic an articular lupus flare, it is extremely important to distinguish the two conditions because the long-term treatment differs. Lupus patients presenting with monoarticular arthritis should always have arthrocentesis performed and synovial fluid should be examined for crystals in addition to being cultured and stained to rule out infection. This should be performed irrespective of the patient's age and even in young pre-menopausal women, as supported by our index case and others in the literature [13].
The authors have declared no conflicts of interest.
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Submitted 7 April 2003;
Accepted 3 September 2003