Kenneth H. Fye

Methotrexate and histologic hepatic abnormalities: A meta-analysis

STUDY OBJECTIVE To determine the risk of liver toxicity from the long-term administration of methotrexate in patients with rheumatoid arthritis or psoriatic arthritis. DESIGN A meta-analysis of 15 studies examining the relationship between long-term, low-dose methotrexate administration and biopsy evidence of liver fibrosis. PATIENTS A total of 636 patients from 15 studies. RESULTS The incidence of progression of liver disease (defined as worsening of at least one grade on the histologic classification of Roenigk) among 636 patients was 27.9% (95% confidence intervals 24.3 to 31.6). The rate of progression of liver disease in the 15 studies was associated with the cumulative dose of methotrexate (p = 0.01). Patients on average had a 6.7% (95% confidence intervals 2.1 to 11.4) chance of progressing at least one histologic grade on liver biopsy for each gram of methotrexate taken. The overall incidence of advanced pathologic changes on liver biopsy (grades IIIB or IV) among 636 patients was 5.0% (95% confidence intervals 3.5 to 7.0). The development of advanced histologic changes was not associated with the cumulative dose of methotrexate (p = 0.08). Patients who according to their history were heavy drinkers (at least 100 g of alcohol per week) were more likely to have advanced changes on liver biopsy (17.8% versus 4.5%, p = 0.0003) and to show histologic progression (73.3% versus 25.9%, p = 0.0002). Patients with psoriasis were more likely than patients with rheumatoid arthritis to have advanced changes (7.7% versus 2.7%, p = 0.003) and histologic progression (33.1% versus 24.3%, p = 0.02). CONCLUSIONS The risk of liver toxicity in patients undergoing long-term, low-dose methotrexate therapy is substantial, and that risk increases with the total cumulative dose and with heavy consumption of alcohol. Heavy users of alcohol should not receive long-term methotrexate therapy. For most patients who are not heavy users of alcohol, liver biopsies should be done periodically to monitor for the occurrence of liver toxicity.

Immune complexes in hepatitis B antigen-associated periarteritis nodosa: Detection by antibody-dependent cell-mediated cytotoxicity and the raji cell assay

A subpopulation of peripheral blood lymphocytes with the ability to lyse target cells coated with specific antibody (antibody-dependent cell-mediated cytotoxicity, ADCC) was serially studied in a patient with hepatitis B antigen-associated periarteritis nodosa. The effector lymphocytes possess FC and complement receptors but do not require complement for functional activity. We found that the patients ADCC was decreased during periods of disease activity and was almost normal during remission. The patients serum could block ADCC in normal lymphocytes, and the blocking ability correlated with the concentration of immune complexes as determined by the Raji cell assay (a radioimmunoassay using complement receptors on human cultured lymphoblastoid cells). The concentration of immune complexes and the ADCC blocking ability of ther serum both correlated with disease activity. Serum from five other patients with active vasculitis was found to contain significant amounts of immune complexes and was able to block normal ADCC. It appears that the ADCC assay can be used to detect the presence of circulating immune complexes and to monitor disease activity in periarteritis nodosa.

Clinical diagnosis of segmental arterial mediolysis: Differentiation from vasculitis and other mimics

Segmental arterial mediolysis (SAM) is a rare vasculopathy of unknown etiology characterized by disruption of the arterial medial layer, with resultant susceptibility to vessel dissection, hemorrhage, and ischemia. Since the first case of SAM described by Slavin and Gonzalez-Vitale in 1976 (1), approximately 50 cases have been reported in the literature (2). Although the abdominal visceral arteries are most frequently affected in SAM (3), any vessel may be involved, including the retroperitoneal (4), intracranial (2, 5, 6) and coronary arteries (7–9). The histopathologic changes begin with vacuolar degeneration of smooth muscle cells in the arterial media, followed by fibrin deposition at the medial-adventitial junction (7). This in turn predisposes to dissecting aneurysms (3, 10). The angiographic appearance of SAM is variable, ranging from arterial dilation to aneurysm formation (single or multiple) to stenoses or occlusion, frequently with dissection (3, 11). Correspondingly, symptoms arise both from stenoses and occlusions (e.g., postprandial pain from intestinal ischemia) and from dissections and aneurysms (e.g., sudden and catastrophic intraperitoneal bleeding). In contrast to true vasculitis, inflammatory cells in SAM are present inconsistently and, when present, are thought to be secondary rather than primary to the pathogenesis of the disease (1). The differential diagnosis of SAM includes atherosclerosis, fibromuscular dysplasia, infection (e.g., mycotic aneurysm and endocarditis), connective tissue diseases (e.g., Bechet’s disease and polyarteritis nodosa), neurofibromatosis, and inherited defects in vessel wall structural proteins (e.g., type IV Ehlers Danlos and Marfan’s syndrome) (Table 1). Herein, we describe two cases of SAM seen at our instituation over the past 20 years and review the salient clinical presentation and treatment of SAM. We report characteristics that may be helpful in distinguishing cases of SAM from other entities in the differential diagnosis. Table 1 Clinical and laboratory features distinguishing Segmental Arterial Mediolysis (SAM) from its mimics*. Case 1 The patient was a 25-year-old female who was admitted to the hospital with an eleven-month history of intermittent episodes of anorexia, abdominal pain, and diarrhea. Symptoms had persisted despite discontinuation of oral contraception and initiation of low-dose aspirin therapy. Her past medical history was unremarkable. Family history was unremarkable except for benign hypermobility syndrome in the patient’s mother. On physical examination, the patient was normotensive and had normal height and arm span. She had no carotid, subclavian, abdominal, or femoral bruits. Skin, chest, abdominal, and neurologic examinations were normal. Joint exam was remarkable only for hyperextensibility of the knees, reducible flexion contractures of the fingers, and hammertoe deformities of the feet. Complete blood count revealed anemia with hemoglobin of 11 g/dl. Serum creatinine, liver enzymes, amylase, and lipase were normal, and urine pregnancy test was negative. Antinuclear antibody assay (ANA) was positive to a low titer of (1:80). The erythrocyte sedimentation rate was 20 mm/hr. The remainder of the serologic, metabolic, immunologic, and hematologic evaluations were within normal limits, including negative hepatitis serologies, negative double-stranded DNA, anti-Smith, and anti-ribonucleoprotein (RNP) antibodies, and normal complement C3 and C4 levels. Computed tomography (CT) of the abdomen showed thickening of the colonic wall with mucosal enhancement and fat stranding surrounding the splenic flexure. Colonoscopy revealed ischemic colitis of the splenic flexure. Biopsies of the ischemic areas were not obtained due to risk of possible perforation. Biopsies of the non-ischemic areas were normal, as was magnetic resonance angiography (MRA) of the abdomen. Conventional mesenteric angiography revealed focal stenoses of the right and left hepatic arteries, occlusion of the left colic artery near the splenic flexure with collateral vessel formation, and hyperemia of multiple branches of the splenic artery (Figure 1). Figure 1 Angiographic and histologic features of segmental arterial mediolysis in Case 1. (a) Focal stenoses of the right and left hepatic arteries (arrows). (b) Hyperemic blush in the left colonic flexure, suggesting formation of small collateral vessels from ... Because of persistent ischemic colitis, the patient underwent a partial colectomy of the splenic flexure. Vascular pathology of the colonic arteries showed patchy, isolated destruction of the arterial media involving both the internal and external elastic laminae (Figure 1). In a few sections the media was absent, with direct juxtaposition of the intima and the adventitia. In areas of medial destruction, there was intimal proliferation with marked luminal narrowing. All of the lesions were of a similar age. There was no evidence of inflammation, and giant cells, neutrophils, and cholesterol deposits were absent. After two years of followup, the patient remains asymptomatic.

Stem cell transplant for myelodysplastic syndrome–associated histiocytoid sweet's syndrome in a patient with arthritis and myalgias

Introduction Sweet’s syndrome is an acute febrile neutrophilic dermatosis first described by Robert Sweet in 1964 (1). It can occur as an idiopathic entity but can also be drug induced or associated with a number of malignancies (2). Eightyfive percent of associated malignancies are hematologic, most commonly acute myelogenous leukemia (AML) (3). The diagnosis is based upon the presence of the single major criterion and 2 of 4 minor criteria. The major criterion is histologic demonstration of a neutrophilic dermatosis without evidence of vasculitis (2). The minor criteria include 1) a fever 38°C, 2) association with malignancy or connective tissue disease, 3) an excellent response to corticosteroid or potassium iodide therapy, and 4) an elevated erythrocyte sedimentation rate or leukocytosis. Sweet’s syndrome is also seen in patients with myelodysplastic syndromes (MDS). MDS is a group of stem cell disorders caused by disturbances in progenitor cell growth and maturation that are characterized by progressive and refractory cytopenias (4). The disorders frequently progress to AML. The decreased survival in these patients is generally due to infections related to the severe cytopenias. When Sweet’s syndrome is present, it portends a poor prognosis in patients with MDS (4). The association of MDS and Sweet’s syndrome with cryofibrinogenemia has been reported once previously (5). We report a case of MDS-associated Sweet’s syndrome with concomitant cryofibrinogenemia in a 57-year-old man. He proved refractory to traditional therapies (including corticosteroids, cytotoxic agents, and plasmaphoresis) and was treated with stem cell transplantation.

Rheumatoid arthritis: Targeted interventions can minimize joint destruction

PREVIEW Rheumatoid arthritis can cause joint erosion and deformity, pain, stiffness, and decreased function and range of motion. Early diagnosis is crucial to prevent permanent joint damage. In this article, Drs Williams and Fye discuss articular and extra articular manifestations of rheumatoid arthritis as well as the evolving treatment approaches to this complex disease.