Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS.

OBJECTIVE: To assess the safety, tolerability, and efficacy of interferon beta-1a (IFNbeta-1a) combined with methotrexate (MTX), i.v. methylprednisolone (IVMP), or both in patients with relapsing-remitting multiple sclerosis (RRMS) with continued disease activity on IFNbeta-1a monotherapy. METHODS: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0-5.5, and > or = 1 relapse or gadolinium-enhancing MRI lesion in the prior year on IFNbeta-1a monotherapy. Participants continued weekly IFNbeta-1a 30 microg i.m. and were randomized in a 2 x 2 factorial design to adjunctive weekly placebo or MTX 20 mg p.o., with or without bimonthly IVMP 1,000 mg/day for 3 days. The primary endpoint was new or enlarged T2 lesion number at month 12 vs baseline. The study was industry-supported, collaboratively designed, and governed by an investigator Steering Committee with independent Advisory and Data Safety Monitoring committees. Study operations, MRI analyses, and aggregated data were managed by an academic coordinating center. RESULTS: The 313 participants had clinical and MRI characteristics typical of RRMS. Combinations of IFNbeta-1a with MTX or IVMP were generally safe and well tolerated. Although trends suggesting modest benefit were seen for some outcomes for IVMP, the results did not demonstrate significant benefit for either adjunctive therapy. The data suggested IVMP reduced anti-IFNbeta neutralizing antibody titers. CONCLUSIONS: This trial did not demonstrate benefit of adding low-dose oral methotrexate or every other month IV methylprednisolone to interferon beta-1a in relapsing-remitting multiple sclerosis.

Avonex Combination Trial in relapsing--remitting MS: rationale, design and baseline data.

OBJECTIVE: To review the rationale, design and baseline data of the Avonex Combination Trial (ACT), an investigator-run study of intramuscular interferon beta-1a (IM IFNbeta-1a) combined with methotrexate (MTX) and/or IV methylprednisolone (IVMP) in relapsing-remitting multiple sclerosis (RRMS) patients with continued disease activity on IM IFNbeta-1a monotherapy. METHODS: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0-5.5, and >or=1 relapse or gadolinium-enhancing MRI lesion in the prior year while on IM IFNbeta-1a monotherapy. Subjects continued IFNbeta-1a 30 mcg IM weekly and were randomized in a 2 x 2 factorial design to adjunctive weekly placebo or MTX 20 mg PO, with or without IVMP 1,000 mg/day for three days every other month. ACT was industry-supported, and collaboratively designed and governed by an Investigator Steering Committee with independent Advisory and Data Safety Monitoring Committees. Study operations, MRI analysis and aggregated data were managed by the Cleveland Clinic MS Academic Coordinating Center. RESULTS: In total 313 subjects were enrolled with clinical and MRI characteristics typical of RRMS. Most subjects (86.9%) qualified with a clinical relapse, with or without an enhancing MRI lesion, in the preceding year. At baseline, 21.4% had enhancing lesions, and 5.1% had anti-IFNbeta neutralizing antibodies. ACT's management and operational structures functioned well. CONCLUSION: This study provides an innovative model for academic-industry collaborative MS research and will enhance understanding of the utility of combination therapy for RRMS patients with continued disease activity on an established first-line treatment.

Trends in rheumatic disease: update on new diagnostic and treatment strategies.

Advances in our understanding of the pathophysiology of rheumatic and immunologic diseases have led to improved therapies, such as tumor necrosis factor inhibitors and bisphosphonates. These drugs can not only alleviate symptoms but also alter the course of the disease. However, they also have significant potential side effects, which mandate, more than ever, correct diagnosis and vigilant monitoring for toxicity.

Alveolar hemorrhage in systemic lupus erythematosus: presentation and management.

AIM: To describe our experience with alveolar hemorrhage (AH) in systemic lupus erythematosus (SLE). METHODS: Review of medical records and pertinent medical literature using MEDLINE and reference lists from retrieved publications. PATIENTS: Seven patients with SLE admitted with episodes of AH (n = 11). RESULTS: Six patients were female, and one was male. Mean age at the time of AH was 31.1 years. Mean duration of SLE was 4.5 years. AH occurred within 3 weeks of SLE onset in two patients. Recurrent AH was observed in four patients. Six patients were already receiving treatment for SLE at the time of AH. All patients presented with dyspnea and new pulmonary infiltrates. Hemoptysis occurred in only 54%. All patients had BAL within 48 h of presentation. Temperature > or =39 degrees C (102.2 degrees F) accompanied 82% of episodes. Glomerulonephritis was the most common nonpulmonary SLE manifestation (74%). Treatment with empiric IV antibiotics was initiated in 10 episodes. Initial treatment included high-dose corticosteroids (prednisone, 1 to 3 mg/kg/d [n = 2]; or IV methylprednisolone, 1 g/d [n = 9], with or without oral cyclophosphamide, 2 to 3 mg/kg/d [n = 7]). Plasmapheresis (three to four sessions) was added in five episodes for persistent AH. All patients survived. CONCLUSIONS: AH may mimic pneumonia. Hemoptysis may not be evident. Infection must be aggressively excluded, especially since many patients with AH are already receiving immunosuppressive therapy. AH frequently recurs despite ongoing immunosuppression. Although high mortality rates have been reported with AH in SLE, we observed 100% survival.

Systemic lupus erythematosus-associated alveolar hemorrhage: presentation, treatment, and outcome.

Alveolar hemorrhage (AH) is a rare, dramatic, and life-threatening manifestation of systemic lupus erythematosus (SLE), which may occur early or late in disease evolution. Presentation is highly variable, and hemoptysis may be absent. The most reliable clinical signs include a drop in hemoglobin accompanied by new pulmonary infiltrates. Extrapulmonary disease, especially nephritis, is common; however, milder SLE symptoms may be minimal and "masked" in patients receiving immunosuppression for other symptoms of SLE. Predictors of patients at risk for this complication are unclear at this time. An aggressive diagnostic approach to exclude infection is indicated. Use of broad-spectrum antibiotics, coincident with immunosuppressive treatment of the AH, while awaiting initial culture results, is prudent. Treatment regimens lack standardization because of the absence of controlled clinical trials and the rarity of this complication. Timely intensification of immunosuppression is required and effective. The capacity of AH to occur and recur, despite ongoing immunosuppressive therapy, is noted, but long-term AH-free episodes among survivors are attainable.

Perioperative management of selected problems in patients with rheumatic diseases.

Patients undergoing surgery are subject to multiple perioperative problems. This article reviews several issues that occur in surgical patients with rheumatic diseases, including management of medications, diagnosis of fat embolism syndrome, prophylaxis against endocarditis, postoperative fever, and perioperative myocardial infarction.

COX 2-selective NSAIDs: biology, promises, and concerns.

Celecoxib (Celebrex) is the first of a new family of nonsteroidal anti-inflammatory drugs (NSAIDs) that selectively inhibit cyclooxygenase 2 (COX 2) while sparing COX 1. Clinical trials indicate that it is approximately as effective in relieving the pain of osteoarthritis and the pain and inflammation of rheumatoid arthritis as nonselective NSAIDs, but causes less gastrointestinal ulceration and bleeding. This paper reviews the pharmacology and possible clinical role of celecoxib and other COX 2-selective NSAIDs.

General tolerability and use of nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are generally well tolerated medications but are associated with several adverse effects that may occur as a result of the physiologic effects of inhibition of cyclooxygenase (COX) or for idiosyncratic reasons. Selective COX-1-sparing NSAIDs may be associated with fewer COX-related complications, such as primary gastric injury and bleeding. Adverse effects in other organ systems including liver, skin, and bone may not be diminished with the use of selective COX inhibitors. Prevention of colonic polyps and adenocarcinoma of the colon seems to be mediated by inhibition of the COX-2 isoenzyme.

Infections and systemic vasculitis.

Bacterial infections can clinically mimic a primary vasculitic syndrome and can directly cause a vasculitis that may respond to prompt recognition and treatment of the infection. Increasing direct and indirect evidence is establishing links between certain infections and vasculopathies, including aortitis, atherosclerosis, and Wegener's granulomatosis. The literature on the hepatitis viruses, particularly hepatitis C, and various vasculitic syndromes continues to grow. The spectrum of clinical syndromes, including "essential" cryoglobulinemia (elicited by the hepatitis viruses) and HIV, continues to broaden. Clinical trials have begun to demonstrate the therapeutic value of antiviral therapy in patients with these conditions.

Septic arthritis.

Septic arthritis is a medical emergency that can lead to significant morbidity and mortality. Prompt recognition and treatment are critical to ensuring a good prognosis. Thus, this article reviews the clinical presentation, microbiology, diagnostic workup, and outcome of nonprosthetic joint infections.

Individualizing the treatment of gout.

Treatment for gouty arthritis should be individualized to address the patient's other medical problems and the likelihood that gout will become chronic. We present a typical case and review the options, explaining their utility for this and other patients.

Intravenous gamma-globulin therapy.

Initially used as replacement therapy in patients with hypogammaglob-ulinemia, intravenous gamma-globulin (IVIg) preparations are increasingly being used as treatment for various autoimmune disorders. Although expensive, IVIg has become first-line or adjunctive therapy in the treatment of disorders as diverse as autoimmune or post-transfusion thrombocytopenia, autoimmune hemolytic anemia, Kawasaki's disease, inflammatory myositis, myasthenia gravis, pediatric acquired immune deficiency syndrome, bone marrow transplantation, and inflammatory de-myelinating polyneuropathy. IVIg remains the first line of therapy in patients with humoral immunodeficiency syndromes. Clinical studies support the selective use of this therapy in the above disorders; it has also been tried as therapy in many other diseases, with varied results. IVIg therapy has received Food and Drug Administration approval for use as maintenance treatment of patients with primary humoral immunodeficiencies and as therapy for acute or chronic autoimmune thrombocytopenic purpura.