Pavillon 2BService de rhumatologie du Professeur Vignon, Centre Hospitalier Lyon Sud and
1 Unité d'anatomopathologie, Laboratoire M. Meyrieux, Lyon, France
Correspondence to:
S. Richard, Centre Hospitalier Lyon Sud, Chemin du Grand Revoyet, 69495 Pierre Benite, France.
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Abstract |
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Methods. Seventy-four liver biopsies were obtained in 57 rheumatoid arthritis patients before initiation of MTX (group 1, 38 cases), in cases of a persistently high level of transaminases during 1 yr of treatment (group 2, 10 cases) and after a MTX total dose of 2 g (group 3, 26 cases). Eleven biopsies of groups 1 and 3 originated from the same patient in 11 cases. Specimens were examined blindly by two anatomopathologists. The three groups were compared with an ANOVA. Sequential biopsies performed in 11 patients were compared with the Wilcoxon paired test.
Results. The Roenigk score and the SSS were significantly correlated (P<0.0001). Only a mild fibrosis was found in 33.8% (25/74) of the biopsies with the Roenigk score. Liver fibrosis, graded as mild (48.6%), moderate (41.8%) or severe (4%), was demonstrated in 94.6% (70/74) of the biopsies with the SSS. The Roenigk score and the SSS of the three patient groups were not statistically significantly different. The scores did not progress in the 11 patients who had serial biopsies.
Conclusion. SSS is much more sensitive than the Roenigk score for the evaluation of hepatic fibrosis. However, SSS did not show progression of hepatic fibrosis in patients with rheumatoid arthritis treated with MTX.
KEY WORDS: Semi-quantitative scoring system of hepatic fibrosis, Methotrexate, Rheumatoid arthritis, Hepatic fibrosis
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Introduction |
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In RA patients, MTX monitoring relies on ACR (American College of Rheumatology) recommendations [5] for liver biopsy, using Roenigk histological grading [6], and serum transaminases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)]. However, liver enzymes are not always correlated with histological data [7] and the Roenigk score was found to be insensitive for detection of small changes in the degree of fibrosis [8]. In France, a new semi-quantitative histological scoring system (SSS) is used by hepatologists to assess specifically hepatic fibrosis in alcoholic and viral hepatitis [9]. It analyses four sites of fibrosis: centrolobular vein (CLV), portal tract (PT), perisinusoidal space (PS), and width and number of septa (WS and NS) when present.
Both the Roenigk score and the SSS have been used for the evaluation of liver biopsies of patients with rheumatoid arthritis.
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Patients and methods |
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Before entering the study, patients had received 2.2±1.3 other disease-modifying anti-rheumatic drugs (DMARDs). Their daily dose of non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids (milligrams prednisone equivalent) was recorded. Patients starting MTX after liver biopsy initially received a 7.5 mg oral weekly dose. They were asked not to drink any alcohol.
At the time of liver biopsy, patients were evaluated clinically and biologically. Recorded clinical variables, morning stiffness and Lee and Ritchie indexes, were determined by the same physician. Laboratory assessment included: erythrocyte sedimentation rate (ESR) (Westergren method), C-reactive protein, complete blood count, rheumatoid factor (Latex nephelometric method), levels of AST (upper range 45 IU/l), ALT (upper range: 65 IU/l) and albumin (range: 3946 mg/l) (Table 1).
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LB were performed by a gastroenterologist using a thin bore Menghini-type needle by a transthoracic approach. No side effects occurred and good quality samples were regularly obtained. Samples (>10 mm long) were fixed in Bouin's solution and embedded in paraffin-wax. Four micrometre-thick sections were stained in picrosirius red solution.
Liver biopsy assessment
Two semi-quantitative scoring systems were performed blindly on the specimens by two liver pathologists. When their Roenigk scores differed, the pathologists conferred and then gave the mean of both measures. The inter-observer reproducibility for the SSS is not stated here because it has been determined in chronic viral hepatitis by the same liver pathologists [9]. The inter-observer correlation was 0.756 (Kendall's t B) for the SSS and ranged from 0.735 to 0.884 for the different items (CLV, PS, PT, WS, NS).
The Roenigk scale.
The Roenigk scale is divided into five grades measuring fibrosis and other histological lesions [6]. Grade I represents normal findings or mild fatty changes; grade II includes severe spotty hepatocellular necrosis; grade IIIA is a mild portal fibrosis, with or without fibrotic septa extending into the lobule; grade IIIB represents piecemeal necrosis or moderate-to-severe septal fibrosis with portal-to-portal, or portal triad-to-central vein bridging; grade IV is true cirrhosis with loss of normal architecture, fibrosis and nodular regeneration.
The semi-quantitative scoring system.
Chevalier et al.'s SSS [9] was designed for the staging and follow-up of hepatic fibrosis in patients with chronic liver diseases. It is specifically focused on hepatic fibrosis which is graded in four main sites: CLV (graded 02), PT (graded 03), PS or Disse's space (graded 02), together with WS and NS when present (WS: graded 15 and NS: graded 03). SSS is given by CLV+PS+PT+2(WSxNS), ranging from 0 to 35 (Fig. 1). For each item, the selected value corresponds to the most representative lesion of the biopsy sample. SSS is normal from 0 to 1, reflects mild fibrosis between 2 and 4, moderate fibrosis between 5 and 10, pre-cirrhosis from 11 to 15, and cirrhosis when >15.
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Results |
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AST, ALT and daily dose of prednisone were not correlated with any of the two scores.
Comparison of the three groups of patients
Patient characteristics.
The 38 patients of group 1 (pre-treatment group) were significantly (P<0.05) older and had more active RA than patients of the other groups (Table 1). They differed significantly (P<0.05) from other groups by a longer duration of morning stiffness, a higher Lee and Ritchie index, a higher ESR and a higher CRP level.
AST and ALT were higher in the third group than in the first one (P=0.0002 and P=0.001, respectively), but their mean values remained within the normal range. Albuminaemia was significantly (P=0.03) lower in group 1 than in group 3.
The number of previous DMARDs and NSAIDs, cortisone intake, and the rheumatoid factor level were similar in the three groups.
Histological scores
The Roenigk mean score was 1.8±0.9, 2.3±0.8 and 1.6±0.9 in groups 1, 2 and 3, respectively. No statistically significant difference between the three groups was found. A mild fibrosis (grade IIIA) was observed in 39.5% (15/38), 40% (4/10) and 23.1% (6/26) of patients in groups 1, 2 and 3, respectively (Fig. 2).
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The Roenigk score and the SSS did not vary significantly in the 11 patients with paired biopsies. In this latter group, the Roenigk mean score was 1±0 and 1.12±0.64, and mean SSS was 5.1±3.2 and 4.5±2.6 before and after MTX, respectively.
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Discussion |
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SSS was found to be much more sensitive than the Roenigk score for the assessment of hepatic fibrosis in RA patients (2 =64, P<0.005). The Roenigk score demonstrated a mild fibrosis in 33.8% of the specimens. By contrast, fibrosis was demonstrated by SSS in 94.5% of the same specimens and was graded as mild, moderate and even severe. The frequency of fibrosis was lower with the Roenigk score than with the SSS for two reasons. The Roenigk score is a composite five grade score measuring fatty infiltration, inflammation, necrosis, cirrhosis and only portal fibrosis while the SSS quantifies fibrosis at different localizations and ranges largely from 0 to 35. The relative sensitivity to change of the two scores has not been evaluated since they did not differ in the three groups of patients. Nevertheless, SSS might be recommended for the evaluation of hepatic fibrosis in RA patients treated with MTX.
Hepatic histological alterations were frequently observed in patients who were biopsied before MTX initiation. The findings were similar to previously reported observations [10, 11]. Such lesions are generally attributed to RA itself and also to the intake of NSAIDs, analgesics, corticosteroids and DMARDs, which may induce fatty change, inflammation, necrosis or fibrosis [12]. The alterations were only graded IIIA with the Roenigk score. Hepatic fibrosis was routinely detected by SSS in such specimens but was rarely graded as severe, in agreement with the study of Ruderman et al. [11].
Hepatic fibrosis is the main concern of long-term treatment with MTX. The main target of MTX is the space of Disse [2]. Fibrogenesis in PS is frequently attributed to other drugs such as vitamin A, azathioprine or mercaptopurine [13]. Fibrosis is considered as a slower process that may be initiated by recurrent flares of necrosis, or may occur independently, in relation to another stimulant [7]. Neither the Roenigk score nor the SSS demonstrated any progression of hepatic fibrosis in patients having received 2 g of MTX, or showing abnormal levels of transaminases. Such stability has been reported and attributed to a tapering of NSAIDs, steroids and alcohol that often accompanies MTX therapy [12]. However, such a reduction in other drug intake was not observed in this small group. The currently used sensitive method for fibrosis confirms the apparent lack of hepatotoxicity of long-term administration of MTX in RA patients, the estimated risk of cirrhosis being 0.1% after 5 yr of treatment [1]. However, we had only 11 follow-up biopsies and we have not performed liver biopsies after cumulative doses larger than 2 g.
According to the ACR recommendations [5], a pre-treatment liver biopsy should be considered for patients with a risk factor for liver disease (excessive alcohol consumption, chronic viral hepatitis B or C, abnormal baseline AST values). Post-treatment liver biopsies must be performed only when a patient develops persistent biological abnormalities: increase in AST levels or decrease in albumin, below the normal range, in at least six assays over a 12-month period with monthly monitoring. Liver enzymes or albuminaemia were unrelated to the Roenigk score or the SSS in the present study, confirming the current opinion that there is no reliable marker of MTX hepatotoxicity [8]. Liver biopsy has a potential morbidity and mortality [5] and its cost-effectiveness in MTX-treated RA patients is debatable [15]. Other methods for detection of MTX hepatotoxicity would be helpful but remain to be evaluated [8, 16].
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References |
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