Inflammatory bowel disease related osteonecrosis: report of a large series with a review of the literature.

BACKGROUND: Osteonecrosis is a major complication of inflammatory bowel disease usually associated with steroid use. There are few large series available detailing the specifics of affected patients. AIM: To identify any specific characteristics of osteonecrosis in this cohort. A major focus was placed on steroid dose, the average time between diagnosis of IBD and appearance of osteonecrosis and the frequency of multiple joint involvement. METHODS: Our study identified 23 patients in the practices of five gastroenterologists at the Mount Sinai Medical Center. We retrospectively reviewed their clinical history, as well as imaging studies. We classified osteonecrosis according to the Association Research Circulation Osseous (ARCO) staging system. RESULTS: Although our prednisone dosing data could not be used as an accurate predictor of onset or joint distribution, there was a tendency for correlation between the average daily dosing and the ARCO score. The ARCO scoring system was consistent for patients with bilateral hip involvement. The distribution of affected joints in IBD is similar to other conditions associated with osteonecrosis, with hips being the most frequently involved joints. Data showed bilateral involvement in most hips, but usually unilateral disease in the shoulders and knees. Treatment options include core decompression for early stages, whereas joint replacement surgery is required for stages 3 and 4. CONCLUSION: IBD predisposes patients to corticosteroid induced osteonecrosis. An exact threshold dose has not been determined. The data suggests that either long term therapy or short term high dose treatment increases the risk of osteonecrosis. Even if symptoms are limited to one joint, multiple joints are often involved and comprehensive testing with MRI is indicated in all cases.

How to do without steroids in inflammatory bowel disease.

This review covers the use of steroids in the treatment of both ulcerative colitis and Crohn's disease. It looks at controlled trials and uncontrolled trials as to the benefits of this agent in both inducing and maintaining remission. The review also stresses the high incidence of toxicity with prolonged use of steroids and the fact that controlled trials have clearly shown that steroids do not maintain remission in either disorder. Alternatives to initiating steroids in mild to moderately active ulcerative colitis and Crohn's disease are presented. The use of steroids in fistulizing versus nonfistulizing Crohn's is also covered. Finally, there is a review of data and discussion of the role of antibiotics, immunosuppressives, and combination therapy for both ulcerative colitis and Crohn's disease. The expectation is that the reader will consider alternatives to initiating and maintaining steroids for prolonged periods of time in the treatment of inflammatory bowel disease.

Intravenous cyclosporine in refractory pyoderma gangrenosum complicating inflammatory bowel disease.

BACKGROUND: Pyoderma gangrenosum complicates inflammatory bowel disease in 2-3% of patients and often fails to respond to antibiotics, steroids, surgical debridement or even colectomy. METHODS: We performed a retrospective chart analysis of 11 consecutive steroid-refractory pyoderma patients (5 ulcerative colitis, 6 Crohn's disease) referred to our practice and then treated with intravenous cyclosporine. Pyoderma gangrenosum was present on the extremities in 10 patients, the face in 2, and stomas in 21. At initiation of intravenous cyclosporine, bowel activity was moderate in 3 patients, mild in 4, and inactive in 4. All patients received intravenous cyclosporine at a dose of 4 mg/kg/d for 7-22 days. They were discharged on oral cyclosporine at a dose of 4-7 mg/kg/d. RESULTS: All 11 patients had closure of their pyoderma with a mean time to response of 4.5 days and a mean time to closure of 1.4 months. All seven patients with bowel activity went into remission. Nine patients were able to discontinue steroids, and nine were maintained on 6-mercaptopurine or azathioprine. One patient who could not tolerate 6-mercaptopurine had a recurrence of pyoderma. No patient experienced significant toxicity. CONCLUSION: Intravenous cyclosporine is the treatment of choice for pyoderma gangrenosum refractory to steroids and 6-mercaptopurine should be used as maintenance therapy.

Review article: the efficacy of infliximab in Crohn's disease--healing of fistulae.

In the management of fistulae, the current therapeutic approach is the use of a combination of antibiotics and/or a combination of immunomodulatory agents. However, clinicians treating patients with fistulae, particularly those with fistulizing Crohn's disease, have little data from controlled clinical trials of these pharmacologic agents or regimens to substantiate their use in treating this complication. Therapy with the anti-tumour necrosis factor-alpha antibody, infliximab, has shown promise in treating patients with Crohn's disease and those with the disease complicated by fistulae. A recent clinical trial was designed specifically to evaluate infliximab in the treatment of fistulizing Crohn's disease. Study results demonstrated infliximab to be the first therapeutic agent to show statistical efficacy in fistulae closure in a placebo-controlled trial. Therapy with the chimeric monoclonal antibody was characterized by a rapid onset of closure and a lasting benefit of action. Two patient cases from the clinical trial are presented to exemplify the dramatic effectiveness of this novel therapeutic approach in modulating the immune response of patients with this debilitating complication of Crohn's disease.

Fistula response to methotrexate in Crohn's disease: a case series.

BACKGROUND: Controlled trials have demonstrated the efficacy of methotrexate in the induction and maintenance of remission in luminal Crohn's disease; however, its effect on fistulizing disease is unknown. AIM: To describe the response to methotrexate therapy in a series of patients with fistulizing Crohn's disease. METHODS: A retrospective chart review was conducted of all patients with Crohn's disease receiving methotrexate in one practice. The response of patients with fistulizing and luminal disease was assessed using clinical and laboratory criteria. Fistula response was categorized as either complete or partial closure. RESULTS: Thirty-seven courses of methotrexate therapy were given to 33 patients with luminal and/or fistulizing Crohn's disease. In 16 patients with fistulas, four (25%) had complete closure, five (31%) had partial closure and all had failed or were intolerant to 6-mercaptopurine therapy. Overall, response to methotrexate was seen in 23 of 37 (62%) treatment courses in patients with luminal and/or fistulizing Crohn's disease. Two of the 33 patients (6%) had a significant adverse event. CONCLUSIONS: In this case series, 56% of patients with Crohn's fistulas on methotrexate showed a complete or partial response to therapy. Further studies are needed to confirm the role of methotrexate alone, and in combination with other therapies, for the treatment of fistulizing Crohn's disease.

Repifermin (keratinocyte growth factor-2) for the treatment of active ulcerative colitis: a randomized, double-blind, placebo-controlled, dose-escalation trial.

BACKGROUND: Repifermin (keratinocyte growth factor-2) has been shown to reduce inflammation in animal models of colitis. AIM: To evaluate repifermin for the treatment of active ulcerative colitis. METHODS: Eighty-eight patients with active ulcerative colitis were enrolled in a 6-week, double-blind trial. Patients were randomized to receive treatment for five consecutive days with intravenous repifermin at a dose of 1, 5, 10, 25 or 50 microg/kg, or placebo. The primary objective of the study was to evaluate the safety of repifermin. The primary efficacy outcome was clinical remission at week 4, defined as a score of zero on the endoscopic appearance and stool blood components of the Mayo score and a score of zero or unity on the stool frequency and physician's global assessment components. RESULTS: At week 4, the rates of clinical remission in the 1, 5, 10, 25 and 50 microg/kg repifermin groups were 19%, 9%, 0%, 0% and 0%, respectively, and 11% for the placebo group (P = 0.32 for repifermin vs. placebo). The frequencies of commonly occurring adverse events and severe adverse events were similar in both groups. CONCLUSIONS: Intravenous repifermin at a dose of 1-50 microg/kg was very well tolerated, but there was no evidence that repifermin was effective for the treatment of active ulcerative colitis at these doses. An additional study to determine the efficacy of repifermin at doses of > 50 microg/kg or for a longer treatment duration may be warranted, as the maximally tolerated dose was not reached in the present study.

Expression of metalloproteinases and tissue inhibitors of metalloproteinases in giant cell tumor of bone: an immunohistochemical study with clinical correlation.

The clinical behavior of giant cell tumors (GCTs) is unpredictable. To gain insight into this tumor's biological behavior, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were studied. These substances play essential roles in wound healing and neoplastic invasion and metastasis. Paraffin-embedded tissue was collected from 18 cases of histologically benign GCT, with 17 treated by curettage and 1 by resection. Eight cases showed no recurrence after a minimum of 2.5 years, and 10 had local recurrence. One showed metastasis. Antibodies to MMP-9, MMP-2, TIMP-1, and TIMP-2 were applied by immunohistochemical methods. In all cases, MMP-9 was strongly expressed in giant cells predominantly in a diffuse pattern and was strong but focal in stromal cells. MMP-2 decorated stromal cells and giant cells heterogeneously. TIMP-1 was variably expressed in giant cells of the nonrecurrent cases and was strongly present in a diffuse or patchy distribution in the stromal cells in 6 of 8 cases. However, in 9 of 10 recurrent cases, TIMP-1 was expressed weakly by both giant and stromal cells. TIMP-2 was variably expressed in the giant cells of the nonrecurrent cases, but 6 of 8 nonrecurrent cases showed strong stromal cell positivity for TIMP-2. Weak staining for TIMP-2 was observed in 7 of 10 recurrent cases in the stromal cells and 9 of 10 recurrent cases in the giant cells. These results indicate that expression of MMPs and TIMPs differs in giant cells and stromal cells in the same tumor. More significantly, in contrast to the nonrecurrent giant cell tumors, there is an imbalance in the MMPs and TIMPs in the recurrent tumors with a net excess of MMPs. This unopposed expression of MMPs in GCTs may play a role in breakdown of extracellular matrix and tissue invasion. Finally, these markers may prove useful in predicting behavior in these tumors.

Toxic megacolon.

Toxic megacolon, its incidence, differential diagnosis, and presenting signs and symptoms are reviewed in this article. The typical histologic and radiographic features are described with a review of the potential triggering factors. An outline of requirements for adequate monitoring of the patient with toxic megacolon is provided. The general management and specific medical management are discussed in detail, and the medical outcome with both medical and surgical intervention is reviewed.

Neutropenia is not required for clinical remission during azathioprine therapy in inflammatory bowel disease.

Inflammatory bowel disease is an idiopathic chronic inflammatory process of the gastrointestinal tract. The aetiology remains unknown but probably involves a combination of genetic susceptibility, environmental triggers and abnormal immune regulation. Immunomodulators are effective in treating inflammatory bowel disease. Azathioprine and 6-mercaptopurine (6MP) are the most frequently used immunomodulator agents. These agents are probably underused by many clinicians because of concerns about myelosuppression, pancreatitis, allergic reactions and hepatotoxicity, which can occur in a fraction of patients taking these drugs. Therefore, clinicians have sought ways to optimize therapeutic response and limit toxic side effects. Neutropenia, although uncommon, can occur in patients taking azathioprine or 6MP. The question of neutropenia effecting clinical response has been raised as a possible indicator of therapeutic response. In the study from Campbell and Ghosh [7] in this issue of the European Journal of Gastroenterology and Hepatology, no difference in relapse rates was noted between neutropenic and non-neutropenic patients. In fact, severe life-threatening neutropenia was seen in four patients.

The modern medical management of acute, severe ulcerative colitis.

The management of patients with acute, severe ulcerative colitis requires careful in-hospital assessment of the patient and the coordinated treatment of a team of experienced gastroenterologists and surgeons. Complete understanding of the potential complications and their management, especially toxic megacolon, is essential. We review the current medical arsenal and advocate a standardized approach to management that includes continuous, high dose intravenous hydrocortisone, more aggressive use of topical steroids as well as feeding the patients and continuing (but not initiating) oral 5-aminosalicylic acid (5-ASA) agents. For those patients whose disease proves refractory to intravenous steroids, intravenous cyclosporin (with an acute response rate of 82%) is an essential component in the medical management of these patients. Antibiotics should be used only when specifically indicated. Total parenteral nutrition has not been shown to be helpful in the acute setting. Air contrast barium enema and colonoscopy have been used to predict response but may be dangerous diagnostic modalities in these acutely ill patients and are no better than good clinical judgement. We review and advocate long-term management of acute response using 6-mercaptopurine or azathioprine. The surgical experience and the postoperative complications of the ileal pouch anal anastomosis, which include acute pouchitis in 50-60%, chronic pouchitis in 5-10% and recent reports of dysplasia among patients with chronic pouchitis, must be considered before colectomy is advised. Over 80% of patients with acute severe colitis can be spared colectomy using our current arsenal of medical therapies.

Giant-cell tumor of bone with pulmonary metastases.

We reviewed the cases of seven patients with histologically benign primary giant-cell tumor of bone and histologically proved metastases to the lung. All seven had a Stage-3, aggressive, benign lesion with interruption of the cortex and soft-tissue extension. The main histological features of the primary lesion were identical to those of the pulmonary metastases. In only one of the seven patients were the metastases detected simultaneously with the primary lesion. All seven patients were treated by surgical resection of the lung nodules and chemotherapy. Of the seven patients, four were alive and free of disease after an average follow-up of nine years; two were receiving chemotherapy; and one, who had had immunosuppression for an allograft transplant, died less than one year after the discovery of the pulmonary lesions. Based on this small series, we concluded that patients with a Stage-3 giant-cell tumor of bone may be at risk for pulmonary spread of the disease. This lesion, with its benign histological picture even in lung lesions, has a favorable prognosis when treated with pulmonary resection of the nodules. However, the role for chemotherapy after pulmonary surgery is still unclear.

The meaning of radiolucencies in parosteal osteosarcoma.

Parosteal osteosarcoma with either intralesional radiolucencies or extralesional clefts within the tumor was identified in eighteen patients. In each patient, both high-quality radiographs and whole macrosections of the lesions were available for correlative study of the radiolucencies. The intralesional radiolucencies were characterized as either deep or peripheral. Study of the macrosections showed that most of the peripheral lucent areas were comprised of low-grade malignant cartilaginous or fibrous tissue that was mixed with fat and bone trabeculae. The majority (67 per cent) of the high-grade dedifferentiated areas of tumor, however, corresponded to the deep radiolucencies. We think that the presence of a deep radiolucent area on a computed tomographic scan or other preoperative radiographic staging studies must create suspicion that a high-grade (grade-II) dedifferentiated region exists within an otherwise low-grade parosteal osteosarcoma.

Benign fibrous histiocytoma of bone.

The cases of seven patients who had a lytic lesion that was histologically similar to a metaphyseal fibrous defect (non-ossifying fibroma) of bone were studied. The patients all were adults and had pain without a fracture. These features were considered distinctive for the lesion, which has the same histological appearance as benign fibrous histiocytoma of soft tissue. The lesion is a benign tumor with fibroblastic and histiocytic differentiation. This picture may be seen in foci in other lesions of bone (aneurysmal bone cyst, fibrous dysplasia, and giant-cell tumor). Ten cases of giant-cell tumor of bone that had a large component of the same foci were also reviewed. It should be emphasized that these areas are secondary reactive tissue rather than the true neoplastic tissue of benign fibrous histiocytoma.

Dedifferentiated chondrosarcoma.

The cases of forty-six patients who had dedifferentiated chondrosarcoma were reviewed. Two groups were identified: one in which a low-grade malignant chondrosarcoma was the precursor lesion and one in which a moderate to high-grade malignant chondrosarcoma was the precursor lesion. The radiographic features of these lesions ranged from that of a cartilaginous lesion that appeared to be benign to that of a destructive osteolytic tumor in which the cartilaginous component was overshadowed by the dedifferentiated component. Only three of the forty-six patients survived for more than two years. Resection alone, even when it was wide or radical, was not successful in controlling this lethal sarcoma.

A history of immunosuppressive drugs in the treatment of inflammatory bowel disease: origins at the Mount Sinai Hospital.

If the cause of Crohn's disease and ulcerative colitis turns out to be some immunopathologic mechanism, many of the steps leading to such an understanding of their pathogenesis can be attributed to concepts that originated at The Mount Sinai Hospital. Perhaps immodestly, we can claim a role in the acceleration and the acceptance of these concepts; however, many contributions were made by others, including Moschkowitz, Klemperer, Otani, Crohn, Ginzburg, Oppenheimer, Marshak, and Janowitz. This does not mean that clinicians and researchers from other institutions did not contribute to this understanding. As happens so often in medical history, elucidation of many disease processes are serendipitous. The concept of autoimmune diseases was introduced when we were house officers at Mount Sinai. The early days of transplant surgery soon followed along with the introduction by Hitchings and Elion of azathioprine to inhibit rejection. The concept of immunosuppression slowly evolved into possible treatment of any disease thought to be caused by autoimmunity, including those diseases of the bowel, seen so frequently at The Mount Sinai Hospital: ileitis, granulomatous colitis, ileocolitis, and ulcerative colitis. Although most of the world called granulomatous disease of the bowel Crohn's disease, it was only after the deaths of Drs. Crohn, Ginzburg, and Oppenheimer that we accepted this single eponym. However, we will always pay tribute to all three Mount Sinai physicians who wrote the original paper that described the disease.

Bronchiolitis obliterans in a patient with ulcerative colitis receiving mesalamine.

An 18-year-old woman with ulcerative colitis (UC) developed diffuse pulmonary infiltrates and hypoxemia three months after reinstitution of oral mesalamine. Lung biopsy revealed bronchiolitis obliterans with interstitial pneumonitis. Clinical and radiographic abnormalities improved upon discontinuation of mesalamine and treatment with corticosteroids. This patient presented the problem of differential diagnosis of pulmonary disease associated with inflammatory bowel disease (IBD), including lesions believed to result from lung involvement secondary to IBD, as well as adverse reactions to medications. We present and analyze evidence associating mesalamine with pulmonary toxicity in this patient, but emphasize that the distinction between adverse drug reaction and extraintestinal manifestations of IBD is difficult.

Sarcoma in association with bone infarcts. Report of five cases.

Sarcoma associated with bone infarct is rare, and only 41 well-documented cases have been published. We describe five additional patients, three women and two men, aged 39 to 57 years. The tumors involved the femur (three patients), tibia (one patient), and humerus (one patient). In three patients, the infarcts were idiopathic. Radiologic evidence of malignancy was found in all patients, and bone infarcts were suspected in four. Four of the patients had malignant fibrous histiocytoma and one an osteosarcoma. Histologically, bone infarcts were seen in all patients, but in three they were mostly replaced by tumor. Portions of intact infarcts were seen adjacent to the tumor, indicating that they had preceded the development of the sarcoma. No hypercellular or atypical reparative tissue was found in the infarcted bones or in three additional uncomplicated infarcts studied from the same patients. The pathogenesis of sarcoma arising in bone infarct is unknown. The prognosis is poor; four of our five patients died within 2 years.

Tumors of the ankle and foot.

Although tumor and tumor-like conditions of the foot and ankle are unusual, certain bone and soft tissue lesions are more common than others. Conventional radiographs remain essential in all such cases and are especially specific for intraosseous tumors. MR imaging is more sensitive to the presence and extent of both bone and soft tissue lesions.

Disease-associated fractures: detection and management in the elderly.

Pathologic fractures in the elderly result from a variety of conditions, including malignancies and Paget's disease. Comprehensive laboratory and radiological evaluation is essential to analyze both the underlying etiology and the extent of the disease. Surgical intervention is critical in stabilizing these fractures so that pain is relieved and function is improved.

A specific protein found in human senescent fibroblasts.

The limited potential for proliferation of human fibroblasts in culture represents cell level senescence. Aging is a programmed process under genetic control, and at certain stage of the life-span of animal cells, some genes start to express. Studying the biomarkers of senescent cells is important to understanding the basic mechanism of aging which may be relevant to the normal cell growth control and tumor biology. A protein with 72,000 Dalton molecular weight was detected by the hybridoma method in our laboratory. The protein shows specificity to senescent or presenescent cells of several cell lines, including WI-38, K.D., U2OS, etc.