OBJECTIVE:To review current literature on the gastrointestinal tract (GIT) manifestations of systemic sclerosis (SSc) and to report on 5 patients with severe gastrointestinal SSc. MATERIALS AND METHODS:The clinical course and histopathology of 5 patients are described. A review of the medical literature registered in MedLine and PreMedLine databases from 1996 through mid-2004 was performed using the keywords systemic sclerosis and scleroderma and combining them with text words such as gastric, gastrointestinal, anorectal, colonic, and hepatic. RESULTS:All 5 patients had severe GIT involvement: 4 with diffuse cutaneous SSc (dcSSc) and 1 with limited cutaneous SSc (lcSSc). Autopsy results of 2 patients who died from severe malnutrition and aspiration pneumonia are presented. Literature review includes involvement from oral cavity to anus with varying degrees of severity. Most GIT manifestations result from dysmotility secondary to infiltration of the gastrointestinal wall with fibrous tissue and can cause life-threatening malabsorption and malnutrition. Diagnostic tests, pathology, and treatments of GIT SSc are reviewed. CONCLUSIONS:GIT involvement in SSc can be severely debilitating and even life-threatening. Although morbidity is inevitable, appropriate supportive treatment can prolong survival. RELEVANCE:GI complications of SSc cause significant morbidity and mortality.

OBJECTIVE:To determine if minocycline therapy improved skin thickness in early, diffuse systemic sclerosis (SSc) by > or =30%, a level of improvement unlikely to occur in the natural history of the disease as determined by recent controlled trials.METHODS:Subjects with diffuse SSc of < or =5 years' duration were treated with oral minocycline for 1 year. The primary outcome measure was the modified Rodnan skin thickness score (MRSS).RESULTS:Of 36 subjects initially enrolled, 31 returned for at least 1 followup visit and were included in the analysis (modified intent-to-treat analysis). The group consisted of 23 women and 8 men, with a mean age of 51.7 years (range 26-82 years) and a mean disease duration of 23.5 months (range 6-60 months). The mean MRSS at entry was 22.7 (range 12-43), and at the final visit it was 18.6 (range 2-48). There was no statistically significant difference in the change in skin scores between the minocycline-treated subjects and subjects previously reported in the D-penicillamine (D-Pen) trial. In addition, when adjusted for disease duration, a comparison of MRSS in the minocycline trial subjects (including all subjects active at each time point) and the previously reported D-Pen trial subjects showed no difference and no treatment effect. Fourteen subjects did not complete all 12 months of treatment; 10 of them withdrew due to disease progression. Disease duration was significantly shorter for the noncompleters than for the completers (P < 0.03).CONCLUSION:The degree of change in the MRSS was similar to that expected in the natural course of this disease. Based on these data, minocycline is not an effective therapy for SSc.

Background: Relaxin is a pregnancy-related hormone that has tissue remodeling and antifibrotic effects. Systemic sclerosis (scleroderma) is characterized by fibrosis of the skin, vasculature, and internal organs. Objective: To assess the efficacy, safety, and dose-response effect of recombinant human relaxin in patients with scleroderma.Design: Multicenter, parallel-group, randomized, double-blind, placebo-controlled trial.Setting: Academic referral centers.Patients: 68 patients who had had stable, diffuse scleroderma (moderate to severe) for less than 5 years.Intervention: Recombinant human relaxin. 25 or 100 mu g/kg of body weight per day, or placebo administered by continuous subcutaneous infusion over 24 weeks.Measurements: Modified Rodnan skin score was the primary efficacy measure. Secondary measurements were pulmonary function, the Health Assessment Questionnaire, and other measures of scleroderma that reflected fibrosis.Results: Patients who received 25 mu g/kg of recombinant human relaxin per day had significantly lower skin scores than those who received placebo (mean change, -3.6 at 4 weeks [P = 0.021], -7.5 at 12 weeks [P < 0.001], and -8.7 at 24 weeks [P = 0.040]). Similar trends were noted in other outcome measures, including forced vital capacity, measures of oral aperture and hand extension, functional status, and global assessment. Patients who received 100 mu g/kg of relaxin per day did not differ from those who received placebo. Drug-related adverse events included menometrorrhagia, reversible anemia, and complications of the subcutaneous drug administration system (site irritation and local infection).Conclusions: Twenty-four weeks of recombinant human relaxin. 25 mu g/kg per day, is associated with reduced skin thickening, improved mobility, and improved function in patients with moderate to severe diffuse scleroderma.

OBJECTIVE To evaluate the efficacy and tolerability of an oral preparation of iloprost, a prostacyclin analog, in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (scleroderma). METHODS A multicenter, randomized, parallel-group, placebo-controlled double-blind study was performed at university and community-based medical centers. Patients were randomly assigned to receive either 50 microg of iloprost orally twice daily or an identical gelatin-coated capsule containing placebo for 6 weeks. Outcome measures included average total daily duration of RP attacks, average number of RP attacks, and RP condition scored via a standardized daily diary. RESULTS Three hundred eight patients with scleroderma (272 women, 36 men, mean age 49 years [range 18-80]) were enrolled. One hundred fifty seven were assigned to receive iloprost and 151 to receive placebo. One hundred forty-three patients in the iloprost group (91.1%) and 144 in the placebo group (95.4%) completed the 6-week treatment phase. Fifteen of these treated patients (8 iloprost, 7 placebo) failed to complete all of the followup visits. The mean reduction in the average duration of attacks from baseline to week 5-6 was 24.32 minutes in the iloprost group and 34.34 minutes in the placebo group (P = 0.569). Likewise, the mean reduction from baseline to week 5-6 in the daily frequency of attacks was 1.02 in the iloprost group and 0.83 in the placebo group (P = 0.459). The Raynaud's condition score, a patient-completed assessment of the severity of RP attacks, was reduced by 1.32 in the iloprost group and 1.00 in the placebo group (P = 0.323). The lack of significant difference between treatment groups did not change when a variety of factors, including use of other vasodilators, duration of disease, classification of scleroderma (limited versus diffuse), or number of baseline digital ulcers were taken into account. Premature withdrawal from the study due to adverse events occurred in 10 patients (6.4%) in the iloprost group and 3 (2.0%) in the placebo group (P = 0.058). CONCLUSION Oral iloprost at a dosage of 50 microg twice daily is no better than placebo for management of RP secondary to scleroderma, either during 6 weeks of treatment or during 6 weeks of posttreatment followup.

OBJECTIVE:Quantification of serum nucleotide pyrophosphohydrolase (NTPPHase) activity in healthy subjects and in patients with various rheumatic diseases or with quad/hemiplegia, hemodialysis, or renal transplant.METHODS:Colorimetric assay of enzyme activity in serum.RESULTS:Serum NTPPHase activity in 85 healthy subjects was independent of age or sex and was highly reproducible in each individual. The biologic and methodologic coefficients of variation were nearly identical. Elevated enzyme levels were found in sera from patients with osteoarthritis/spondylosis, calcium pyrophosphate dihydrate (CPPD) crystal deposition, scleroderma, fibromyalgia, or hemodialysis. Renal transplant patients receiving cyclosporine had the highest enzyme activity of any group, whereas transplant patients not taking this drug had normal levels. Histograms of values in all groups showed a normal distribution.CONCLUSION:Serum NTPPHase activity levels were significantly elevated in patients with degenerative arthritis whether or not CPPD crystals were present, in patients with either scleroderma or fibromyalgia, and in patients receiving hemodialysis therapy or taking cyclosporine.

Concurrent joint infection with Mycobacterium tuberculosis (TB) and demonstration of intraarticular monosodium urate (MSU) crystals has not previously been reported. We describe a patient with chronic tophaceous gout from whose joints both TB and MSU crystals were isolated. We propose a mechanism to explain this condition.

Background: Relaxin is a pregnancy-related hormone that has tissue remodeling and antifibrotic effects. Systemic sclerosis (scleroderma) is characterized by fibrosis of the skin, vasculature, and internal organs. Objective: To assess the efficacy, safety, and dose–response effect of recombinant human relaxin in patients with scleroderma. Design: Multicenter, parallel-group, randomized, double-blind, placebo-controlled trial. Setting: Academic referral centers. Patients: 68 patients who had had stable, diffuse scleroderma (moderate to severe) for less than 5 years. Intervention: Recombinant human relaxin, 25 or 100 µg/kg of body weight per day, or placebo administered by continuous subcutaneous infusion over 24 weeks. Measurements: Modified Rodnan skin score was the primary efficacy measure. Secondary measurements were pulmonary function, the Health Assessment Questionnaire, and other measures of scleroderma that reflected fibrosis. Results: Patients who received 25 µg/kg of recombinant human relaxin per day had significantly lower skin scores than those who received placebo (mean change, −3.6 at 4 weeks [P = 0.021], −7.5 at 12 weeks [P < 0.001], and −8.7 at 24 weeks [P = 0.040]). Similar trends were noted in other outcome measures, including forced vital capacity, measures of oral aperture and hand extension, functional status, and global assessment. Patients who received 100 µg/kg of relaxin per day did not differ from those who received placebo. Drug-related adverse events included menometrorrhagia, reversible anemia, and complications of the subcutaneous drug administration system (site irritation and local infection). Conclusions: Twenty-four weeks of recombinant human relaxin, 25 µg/kg per day, is associated with reduced skin thickening, improved mobility, and improved function in patients with moderate to severe diffuse scleroderma.

An 85-year-old woman with rheumatoid arthritis that was treated with azathioprine presented with a posterior thoracic soft-tissue mass. A computed tomographic scan demonstrated a large mass in the chest wall that extended into the pleural space and several pulmonary nodules that were consistent with metastatic disease. A fine-needle biopsy was performed, and a morphologic diagnosis of sarcoma was made. As the patient was relatively asymptomatic and the lesion was inaccessible to a surgical procedure, no therapy was recommended. Therapy with azathioprine was discontinued. One year later, the mass had resolved. To our knowledge, this is the first reported case of a soft-tissue sarcoma complicating azathioprine treatment of rheumatoid arthritis.

Objective. To determine the prevalence of sexual abuse in women diagnosed as having fibromyalgia (FM) compared with controls.Methods. A self-administered questionnaire designed to obtain information regarding demographics, health care utilization, and history of sexual and physical abuse was completed by 40 women with FM and by 42 women who had no evidence of connective tissue disease or other major medical condition.Results. Women with FM reported more physical symptoms and were significantly different on multiple indices of health compared with controls. Twenty-six FM subjects (65%) reported sexual abuse, in comparison with 22 controls (52%). The prevalence and type of abuse were not significantly different between groups. Sexually abused FM subjects reported significantly more symptoms than did non-sexually abused FM women, but did not differ in the number of symptoms for which they sought medical treatment,Conclusion. Sexual abuse does not appear to be a specific factor in the etiology of FM, but is correlated with the number and severity of associated symptoms.

We describe a patient with viral induced aplastic anemia who developed severe bone pain after treatment with multiple courses of antithymocyte globulin, cyclosporine A, recombinant human granulocyte macrophage colony stimulating factor and deferoxamine. Radiographs and bone biopsy revealed extensive new trabecular bone formation in long bone diaphyses and adjacent periosteal reaction. The effects of hematopoietic growth factors, cyclosporine A and deferoxamine on bone metabolism are reviewed.

The recent development of other nonsteroidal anti-inflammatory agents (NSAIDs) has challenged the role of aspirin in the initial treatment of rheumatoid arthritis. The ready availability of aspirin as "an over-the-counter" preparation has contributed to its low esteem among both patients and physicians as a truly potent anti-inflammatory agent. But whether these newer, more expensive NSAIDs are more efficacious in the treatment of rheumatoid arthritis than aspirin remains to be proven. Most clinical trials of the newer agents have compared their efficacy against fixed doses of aspirin which were almost always too small to produce optimal anti-inflammatory serum salicylate levels. In our experience, individually tailored doses of aspirin remains the most predictable and consistently effective NSAID available for the initial treatment of rheumatoid arthritis. We also want to make it clear that we almost never rely on aspirin or other NSAIDs to control seropositive rheumatoid arthritis. Their chief advantage is rapidity of action. We do rely on the use of remittive agents to control rheumatoid joint inflammation, in conjunction with aspirin or other NSAID.

To the Editor.—Pharmaceutical firms have expended enormous resources to develop and promote the use of nonsteroidal anti-inflammatory drugs (NSAIDs), chiefly for treatment of various rheumatic diseases. Some of these agents have become widely used as substitutes for aspirin. Controlled clinical trials of these agents, almost always against fixed daily doses of plain aspirin, have usually shown "equivalent" anti-inflammatory effects with less toxicity. Unfortunately, these fixed daily doses almost certainly produced serum salicylate levels that were subtherapeutic, ie, less than 20 mg/dL(1.45 mmol/L). This is especially true in trials involving patients with serious chronic inflammatory conditions such as rheumatoid arthritis. In our experience, none of the NSAIDs have been as reliable as the use of aspirin in doses individually prescribed to produce stable serum salicylate levels of 20 to 30 mg/dL (1.45 to 2.15 mmol/L). Aspirin remains our first choice in the treatment of diseases such as rheumatoid arthritis,

Cyclophosphamide, azathioprine, and hydroxychloroquine sulfate were prescribed for 31 patients (26 women and five men) with rheumatoid arthritis refractory to conventional therapy. Maintenance drug dosages (mean +/- SD) were as follows: cyclophosphamide, 30 +/- 24 mg/day; azathioprine, 74 +/- 44 mg/day; and hydroxychloroquine sulfate, 210 +/- 92 mg/day. Disease suppression began in 30 patients within three to 24 months (mean, nine months). Results after 43 months (range, 12 to 102 months) were as follows: 16, complete remission; seven, near remission; seven, partial disease suppression; one, no response. None remained in prolonged remission without some form of therapy. Treatment was discontinued in three patients because of pulmonary infection (two) or thrombocytopenia (one). Four patients had five malignant neoplasms (surgical cures) before therapy (two breast, one colon, one melanoma, one endometrial); four patients developed a malignant neoplasm during combined drug therapy (one colon, one endometrial, one lung, one erythroleukemia); and three died. The absolute risk of malignancy from combined drug therapy is still unclear. We concluded that combined use of remittive agents may have promise in treatment of severe rheumatoid arthritis; cyclophosphamide should be replaced with a nonalkylating agent; and the place of combined drug therapy remains uncertain in the absence of controlled trials.

A 47-year-old woman with rheumatoid arthritis (RA) had been treated with greater than 7 g of gold sodium thiomalate over a 5 year period when aplastic anemia developed. Treatment with corticosteroids, plasmapheresis and infusion of N-acetylcysteine (NAC) resulted in complete hematologic remission. Infusion of NAC increased daily urinary excretion of gold and use of an ambulatory infusion pump with a Hickman catheter allowed protracted outpatient infusion for more than 4 months' duration. It is now 20 months since the onset of aplastic anemia and she remains in complete hematologic remission.