Autoimmune disease is a risk factor for the development of non-Hodgkin's lymphoma.

OBJECTIVE: To investigate the relationship of prior autoimmune disease to the development of non-Hodgkin's lymphoma (NHL). METHODS: Patients with NHL (n = 278) seen from 1993 to 2002 were compared with a group of patients with other hematological disorders (controls, n = 317) seen at the same time. All patients were questioned about prior autoimmune disease. Comparisons between NHL patients and controls were based on analysis of a 2 2 table of counts using Fisher's exact test. Analysis of the effect of autoimmune disease on NHL status, controlling for other risk factors, was performed using logistic regression. RESULTS: Thirty-six (13%) NHL patients had a prior autoimmune disease compared to 5% of controls (p = 0.001). Sixty-nine percent of NHL patients with a prior autoimmune disease were female compared to 43% without a prior autoimmune disease, and this was similar in control patients, 69% and 48%, respectively. Twenty percent of all women with NHL had a history of autoimmune disease compared to 7% of women in the control group (p = 0.001). Nineteen of the NHL patients with autoimmune disease (56%) received immunosuppressive treatment compared to 5 (38%) in the controls. CONCLUSION: Autoimmune disease may account in part for the increase in NHL, especially in women.

Inflammatory diseases in older adults: polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is a common inflammatory disease in adults over age 50, and particularly in women. Teasing apart the diagnosis of PMR from other inflammatory and degenerative diseases is mandatory because there are effective treatments for this reversible condition. Onset of PMR is usually acute, with pain typically beginning in the neck and upper arms, though it can begin in the pelvic girdle. Low grade fever may occur; swelling of the joints is not typical, although swelling of the knees may be present on occasion. There are no specific laboratory or radiographic findings although some consider an elevated sedimentation rate (> 50 mmg/hr) to be essential to diagnosis. Differential diagnoses can be myriad. Treatment, typically with prednisone (occasionally methylprednisolone), requires individualized regimens, particularly during tapering.

Inflammatory disease in older adults. Cranial arteritis.

Cranial arteritis (CA), also called giant cell arteritis or temporal arteritis, is a vasculitis primarily affecting adults over age 50. It is a large vessel vasculitis, and giant cells classically can be identified on histopathologic examination of temporal arteries, but are not essential for diagnosis. Patients typically present with severe headaches, fatigue, polymyalgia-like symptoms, or ischemic complaints such as jaw claudication. Visual loss is the major feared irreversible outcome and can occur in up to 50% of those with untreated disease. Glucocorticoids, typically high dose prednisone (> or = 60 mg/d) is the first-line treatment and successfully controls the inflammatory disease in the vast majority of patients. Most patients can be tapered off steroids within 6 months to 2 years.

Effect of halofuginone on the development of tight skin (TSK) syndrome.

The end point of pathogenic events in scleroderma is fibrosis of the skin and internal organs. Fibrosis in scleroderma results from the over synthesis and deposition of collagen in the connective tissue. The morbidity and mortality of the scleroderm is very high and presently there is no specific treatment. Halofuginone is a drug with great potential for the treatment of scleroderma since it inhibits the synthesis of collagen type I by fibroblasts. We have studied the in vivo effect of halofuginone in tight skin (TSK) mice that spontaneously develop a scleroderma-like disease due to a genetic defect. Our results demonstrate that halofuginone prevented the occurrence of skin sclerosis when administered to newborn mice and reduced cutaneous hyperplasia when administered in adult TSK mice. These effects correlated with a decreased number of cells synthesizing collagen gene transcripts and a reduction in the level of autoantibodies specific for human target antigens. These results indicate that halofuginone may have use as a therapeutic in the treatment of fibrotic disease.

Halofuginone inhibition of COL1A2 promoter activity via a c-Jun-dependent mechanism.

OBJECTIVE: The naturally occurring compound halofuginone has been shown to antagonize collagen synthesis by fibroblasts both in vitro and in vivo. We previously demonstrated that this inhibitory property was related to the ability of halofuginone to disrupt transforming growth factor beta signal transduction. The present study further analyzed the ability of halofuginone to affect transcription factors that can regulate type I collagen gene expression by examining its effect on c-Jun, the negative regulator of collagen gene transcription. METHODS: The phosphorylation state of c-Jun in the presence of halofuginone was examined via direct Western blotting, and the transcriptional activity of the activator protein 1 (AP-1) binding element via electrophoretic mobility shift assay and luciferase reporter assay. We determined whether the effect of halofuginone on collagen synthesis was dependent on the presence of c-Jun by ectopic expression of a wild-type or dominant-negative c-Jun construct in the presence of halofuginone and assaying alpha2(I) collagen promoter strength via luciferase reporter assay. The effect of halofuginone on alpha2(I) collagen message levels in fibroblasts when wild-type or dominant-negative c-Jun was overexpressed was determined. We also determined whether halofuginone had an effect on the phosphorylation state of c-Jun in the skin of TSK/+ mice via immunohistochemistry. RESULTS: Treatment of fibroblasts with 10(-8)M halofuginone enhanced basal and mitogen-mediated phosphorylation of c-Jun in culture. This elevated phosphorylation of c-Jun correlated with enhanced DNA binding and transcriptional activation of an AP-1 complex consisting of c-Jun and Fos but lacking the c-Jun antagonist JunB. Overexpression of c-Jun enhanced in a dose-dependent manner the ability of halofuginone to inhibit the activity of a luciferase reporter construct under control of the -3200-bp to +54-bp COL1A2 promoter, whereas the expression of a dominant-negative c-Jun construct abolished this effect. Northern blotting showed that overexpression of c-Jun enhanced the ability of halofuginone to reduce collagen alpha2(I) messenger RNA levels in fibroblasts, whereas expression of the dominant-negative c-Jun abolished this effect. Topical administration of a halofuginone-containing cream for 20 days to TSK mice, which spontaneously develop dermal fibrosis, greatly increased the phosphorylated form of c-Jun in the skin; this was followed by a decrease in skin thickness and type I collagen messenger RNA expression. CONCLUSION: Our findings illustrate the powerful down-regulatory property of c-Jun toward type I collagen and establish that halofuginone exerts its effect on collagen synthesis in a c-Jun-dependent manner.

Ticlopidine-induced lupus: a report of 4 cases.

Drug-induced lupus has been associated with various medications. Ticlopidine hydrochloride is a platelet aggregation inhibitor that has been associated with thrombotic thrombocytopenic purpura, which is believed to be immune mediated. We describe 4 patients with drug-induced lupus following the institution of ticlopidine therapy. The 4 patients, who had systemic lupus erythematosus following ticlopidine use, were examined between 1997 and 1999. The clinical features of these patients, namely, older age of onset, presence of pleurisy and arthritis, and paucity of central nervous system, renal, or skin involvement, are consistent with drug-induced lupus. All had detectable antihistone antibodies. All 4 patients had clinical and serological improvement following ticlopidine withdrawal, allowing cessation or reduction of corticosteroid therapy. We suspect that ticlopidine can cause drug-induced lupus, and that this exposure should be considered particularly in the examination of elderly patients with systemic lupus erythematosus.

Halofuginone, an inhibitor of type-I collagen synthesis and skin sclerosis, blocks transforming-growth-factor-beta-mediated Smad3 activation in fibroblasts.

Halofuginone is a drug that has been shown to have an antifibrotic property in vitro and in vivo. Whereas halofuginone shows promise as a therapeutic agent for a variety of diseases including scleroderma, liver cirrhosis, cystic fibrosis, and certain types of cancer, the mechanism of action remains unknown. Using the tight skin mouse (TSK) model for scleroderma, we evaluated the ability of halofuginone to inhibit spontaneous development of dermal fibrosis. We found that administration of a low dose of halofuginone both in adult and newborn animals for 60 d prevented the development of cutaneous hyperplasia (dermal fibrosis). In vitro halofuginone was found to reduce the amount of collagen synthesized by fibroblasts. This effect was due to a reduction in the promoter activity of the type-I collagen genes as treatment of fibroblast cultures with 10(-8) M halofuginone reduced the level of alpha2(I) collagen message detectible by northern blot and greatly reduced the activity of a reporter construct under control of the -3200 to +54 bp alpha2(I) collagen promoter. In addition, analysis of transforming growth factor beta signaling pathways in fibroblasts revealed that halofuginone inhibited transforming-growth-factor-beta-induced upregulation of collagen protein and activity of the alpha2(I) collagen promoter. Further we found that halofuginone blocked the phosphorylation and subsequent activation of Smad3 after transforming growth factor beta stimulation. Apparently the inhibitory property was specific to Smad3 as there was no inhibitory effect on the activation of Smad2 after stimulation with transforming growth factor beta. Our results demonstrate that halofuginone is a specific inhibitor of type-I collagen synthesis and may elicit its effect via interference with the transforming growth factor beta signaling pathway.