Safety and efficacy of hydroxychloroquine as maintenance therapy for rheumatoid arthritis after combination therapy with methotrexate and hydroxychloroquine.

OBJECTIVE: To evaluate the ability of hydroxychloroquine sulfate (HCQ) to extend the response to combination therapy with HCQ and methotrexate (MTX) and the safety of longterm HCQ maintenance therapy in patients with active rheumatoid arthritis (RA). METHODS: Two-part study consisting of an open label segment evaluating combination HCQ/MTX therapy followed by a double blind segment evaluating maintenance therapy for a total of 60 weeks. First, all patients were treated with HCQ 400 mg/day and MTX 7.5 to 15 mg/week for 24 weeks. Then, responders were randomized into 3 groups: (1) HCQ with MTX as needed for disease flare (n = 40), (2) HCQ 400 mg/day (n = 41), or (3) placebo with MTX as needed for disease flare (n = 40), each for 36 weeks. RESULTS: Clinical disease and laboratory variables improved significantly during initial combination therapy with HCQ and MTX. After MTX withdrawal, HCQ-containing maintenance regimens delayed the onset of disease flare (p = 0.023). There were no unexpected adverse events at any time or between-group differences in the distribution of adverse events during the double blind segment. CONCLUSION: Combination of HCQ and MTX appeared to be effective and well tolerated for 24 weeks. After withdrawal of MTX, HCQ extended the response seen with combination therapy and was well tolerated for 36 weeks. Initial therapy with HCQ and MTX, followed by maintenance HCQ, may be a useful alternative for the treatment of RA.

Polymyalgia rheumatica with a low erythrocyte sedimentation rate: comparison of 10 cases with 10 cases with high erythrocyte sedimentation rate.

Polymyalgia rheumatica (PMR) is an inflammatory disorder characterized by severe proximal myalgias associated with an elevated erythrocyte sedimentation rate (ESR). In this report 10 otherwise typical PMR patients with an ESR <35 mm/hr, and 10 PMR patients with an ESR > 35 mm/hr were examined and prospectively followed. We report the initial laboratory response to steroids in both groups as well as follow-up (average32.6 months in the low ESR group). The average follow-up for this study is the longest reported for low ESR PMR. The most significant difference noted was a longer duration before diagnosis and therapy for the low ESR group. Both groups showed similar clinical and laboratory response to therapy and similar post-treatment disease duration.The absence of an elevated ESR does not exclude the diagnosis of PMR. Clinical response to steroids and a drop in the ESR after therapy are proposed as useful to confirm the diagnosis.

Tenidap in patients with rheumatoid arthritis. A 4-week, placebo-controlled study.

The present double-blind, placebo-controlled study was conducted to compare the safety and efficacy of tenidap in patients with rheumatoid arthritis (RA). Patients with flare of active RA following NSAID withdrawal were randomized to receive either placebo (n = 67) or tenidap (n = 131; 40-200 mg/day). The mean changes from baseline in efficacy and biochemical variables were compared between treatment groups at endpoint (4 weeks). The improvements in four of the five primary efficacy variables were significantly greater in the tenidap group compared with the placebo group (p < 0.01). Tenidap was also associated with an 18% reduction in erythrocyte sedimentation rate (ESR) and a marked, 51%, reduction in serum C-reactive protein (CRP) level, both of which were significantly greater than the changes in the placebo group (p < 0.05). The percentage of patients who discontinued because of side effects was the same in both groups (3%). In conclusion, tenidap 40-200 mg/day was effective and well tolerated in the treatment of patients with RA for 4 weeks.

Methotrexate in rheumatoid arthritis. A five-year prospective multicenter study.

OBJECTIVE: To evaluate the efficacy and tolerability of oral methotrexate (MTX) in rheumatoid arthritis (RA) in a long-term prospective trial. METHODS: One hundred twenty-three patients with RA who completed a 9-month multicenter randomized trial comparing MTX and auranofin enrolled in this 5-year prospective study of MTX. RESULTS: Significant (P = 0.0001) improvement compared with baseline was noted in all clinical disease variables, functional status, and the Westergren erythrocyte sedimentation rate (ESR). "Marked improvement" occurred in 87 (71%) and 85 (69%) of the patients, respectively, in the joint pain/tenderness index and the joint swelling index at the last evaluable visit. Forty-four patients (36%) withdrew during the study. Eight (7%) withdrew due to lack of efficacy, and 8 (7%) due to adverse experiences, including 1 patient with cirrhosis. At 5 years, 64% of patients were still taking MTX and completed the study. CONCLUSION: This large prospective study of long-term MTX treatment demonstrates sustained clinical response and improvement in the Westergren ESR and functional assessment scores, with an acceptable toxicity profile.

Lack of a renal-protective effect of misoprostol in rheumatoid arthritis patients receiving cyclosporin A. Results of a randomized, placebo-controlled trial.

OBJECTIVE: To assess whether the synthetic prostaglandin misoprostol is renal protective in rheumatoid arthritis (RA) patients who are beginning cyclosporin A (CSA) therapy. METHODS: In this randomized, placebo-controlled, multicenter trial, 50 patients with active RA were randomized to receive either misoprostol (800 micrograms/day) or placebo for 16 weeks. After 2 weeks of pretreatment with misoprostol or placebo, all patients concomitantly received CSA at an initial and maximum dosage of 5 mg/kg/day for 12 weeks. RESULTS: A significant increase in the serum creatinine level was observed in both treatment groups, with no difference noted between groups. There was a high withdrawal rate in both groups, primarily due to adverse events. CONCLUSION: A renal-protective effect was not demonstrated for misoprostol compared with placebo in RA patients who are beginning CSA therapy.

Aspirin alters methotrexate disposition in rheumatoid arthritis patients.

Intravenous methotrexate (MTX) (10 mg), either alone or with oral aspirin (ASA) (3,900 mg/day), was administered to 15 patients with rheumatoid arthritis. Systemic and renal clearance of MTX were lower, and the unbound fraction of MTX was higher when patients were also receiving ASA than when taking MTX alone. No acute hematologic, renal, or hepatic toxicity was observed with either treatment. The findings of this study therefore indicate that concomitant aspirin therapy acutely alters the clearance of low-dose MTX in patients with rheumatoid arthritis.

Prolactin, immunoregulation, and autoimmune diseases.

Cells of the immune system synthesize prolactin and express mRNA and receptors for that hormone. Interleukin 1, interleukin 6, gamma interferon, tumor necrosis factor, platelet activator factor, and substance P participate in the release of prolactin. This hormone is involved in the pathogenesis of adjuvant arthritis and restores immunocompetence in experimental models. In vitro studies suggest that lymphocytes are an important target tissue for circulating prolactin. Prolactin antibodies inhibit lymphocyte proliferation. Prolactin is comitogenic with concanavalin A and induces interleukin 2 receptors on the surface of lymphocytes. Prolactin stimulates ornithine decarboxylase and activates protein kinase C, which are pivotal enzymes in the differentiation, proliferation, and function of lymphocytes. Cyclosporine A interferes with prolactin binding to its receptors on lymphocytes. Hyperprolactinemia has been found in patients with systemic lupus erythematosus. Fibromyalgia, rheumatoid arthritis, and low back pain patients present a hyperprolactinemic response to thyrotropin-releasing hormone. Experimental autoimmune uveitis, as well as patients with uveitis whether or not associated with spondyloarthropathies, and patients with psoriatic arthritis may respond to bromocriptine treatment. Suppression of circulating prolactin by bromocriptine appears to improve the immunosuppressive effect of cyclosporine A with significantly less toxicity. Prolactin may also be a new marker of rejection in heart-transplant patients. This body of evidence may have an impact in the study of rheumatic disorders, especially connective tissue diseases. A role for prolactin in autoimmune diseases remains to be demonstrated.

Methotrexate in rheumatoid arthritis: effects on disease activity in a multicenter prospective study.

One hundred and twenty-three patients with rheumatoid arthritis (RA) who successfully completed a randomized trial comparing oral methotrexate (MTX) to auranofin enrolled in a longterm prospective study of oral MTX. Of the 91 patients who completed 24 months of therapy, a significant (p = 0.0001) improvement was noted compared to baseline in all clinical disease variables and the Westergren erythrocyte sedimentation rate (ESR). Marked improvement occurred in 94 (76%) and 98 (80%) of the patients in the joint pain/tenderness index and joint swelling index at the last evaluable visit (mean 26 months). Of the 77 patients with an elevated ESR at baseline, 29 (38%) patients normalized it (less than 20 mm/h) while receiving therapy (p less than 0.01). A significant reduction in prednisone dose was also seen. Adverse events occurred frequently but were generally mild in severity. Twenty-seven patients (22%) withdrew during the study. Four (3%) withdrew due to lack of efficacy, and 6 (5%) because of adverse experiences. The overall probability of continuing therapy in the study for 48 months was projected at 72%. This large prospective study supports the observation of earlier smaller studies that MTX is an effective drug in the treatment of RA.

Eosinophilia-myalgia syndrome in association with L-tryptophan ingestion.

The association between the recently described eosinophilia-myalgia syndrome and L-tryptophan is now well established. We describe a patient with eosinophilia-myalgia syndrome who developed incapacitating myalgias and peripheral eosinophilia responsive only to high dose corticosteroids. When massive upper gastrointestinal hemorrhage developed while receiving corticosteroid therapy, surgery was complicated by striking abdominal wall rigidness. A discussion of this case and of eosinophilia-myalgia syndrome is presented.

HIV associated arthropathy: HIV antigen demonstration in the synovial membrane.

Light and electron microscopic studies were performed on the synovial membranes of 5 patients with HIV associated arthropathy. An immunoperoxidase technique with the use of monoclonal antibodies against CD4, CD8, B and DR lymphocytes, and HIV p24 antigen was also used. Mild to moderate nonspecific proliferative changes and increased vascularity of the subsynovial space were seen. Electron dense deposits and viral-like particles were not observed. Immunohistochemical staining revealed HIV p24 positive staining in cells of the synovial lining layer and in the mononuclear cells of the subsynovial space. CD4, CD8, with predominance of CD8, and B and DR cells were also present. The presence of HIV p24 antigen may be indicative of a role, yet to be defined, in the pathogenesis of HIV associated rheumatic disorders.

Low-dose methotrexate compared with auranofin in adult rheumatoid arthritis. A thirty-six-week, double-blind trial.

Weekly treatment with low-dose oral methotrexate (MTX) was compared with daily auranofin (AUR) treatment in a 36-week double-blind, randomized, multicenter study of 281 patients with active, adult-onset rheumatoid arthritis. Both treatment groups showed significant improvement by the usual measures of clinical efficacy. The response with MTX occurred earlier and was consistently greater than that with AUR. An intent-to-treat analysis showed significantly greater improvement (P less than 0.01) with MTX for painful and swollen joint counts and physician and patient global assessments of disease activity. Adverse reactions were reported more frequently in the AUR group, and more AUR-treated patients were withdrawn from the study because of toxicity. MTX was thus more effective and better tolerated than AUR in this study.

Ketoprofen versus indomethacin in patients with rheumatoid arthritis: a multicenter double blind comparative study.

Oral ketoprofen (200-300 mg/day) and indomethacin (100-150 mg/day) were compared in a 12-week double blind study involving 140 patients with rheumatoid arthritis. The treatments were generally equally effective in most assessments, producing highly significant (p less than 0.01) improvements from baseline values within one week. Only isolated statistically significant differences (p less than 0.05) were detected between the 2 treatments: ketoprofen had a more pronounced effect than indomethacin in functional class (Weeks 1 and 12), swollen joint score (Week 1), and patients' global assessments (Week 12); indomethacin was significantly superior in improving grip strength at Week 4. The clinical significance of these statistically established differences may be questioned. The incidence of side effects, primarily gastrointestinal and neurologic, was also comparable in the 2 treatments.

Human adjuvant disease following augmentation mammoplasty.

Two patients are described in whom a progressive systemic sclerosis-like illness developed several years after silicone augmentation mammoplasty. Both had removal of breast implants, followed by marked-to-complete recovery from clinical abnormalities. This entity is increasingly recognized and has become known as human adjuvant disease.

Psoriatic arthritis and acquired immunodeficiency syndrome.

We describe 2 patients who developed psoriatic arthritis during the course of acquired immunodeficiency syndrome. Both patients developed skin and articular involvement characteristic of psoriatic arthritis; these manifestations were refractory to conventional therapy. Our findings suggest that psoriatic arthritis should be added to the expanding spectrum of musculoskeletal manifestations of the acquired immunodeficiency syndrome.

Rheumatic manifestations of human immunodeficiency virus infection.

PURPOSE: The prevalence and characteristics of the rheumatic and extra-rheumatic manifestations of human immunodeficiency virus (HIV) infection were determined in a prospective manner. PATIENTS AND METHODS: One hundred one patients with HIV infection were consecutively interviewed and examined. The prevalence of autoantibodies and their association with rheumatologic symptoms were also determined. RESULTS: The musculoskeletal system was involved in 72 patients. Thirty-five patients had arthralgias, 10 had Reiter's syndrome, two had psoriatic arthritis, two had myositis, and one had vasculitis. Also found were two previously unreported syndromes. The first, occurring in 10 patients, consisted of severe intermittent pain involving less than four joints, without evidence of synovitis, of short duration (two to 24 hours), and requiring therapy (ranging from nonsteroidal antiinflammatory drugs to narcotics). The second, occurring in 12 patients, consisted of arthritis (oligoarticular in six patients, monoarticular in three patients, and polyarticular in three patients) involving the lower extremities and lasting from one week to six months. The synovial fluid of five patients (three with arthritis, one with Reiter's syndrome, and one with psoriatic arthritis) was sterile and inflammatory. CONCLUSION: Musculoskeletal complications are common in advanced stages of HIV infection. Persons in a high-risk group for HIV infection who manifest oligoarthritis with or without any other extra-articular manifestation suggestive of Reiter's syndrome or other form of spondyloarthropathy should be tested for HIV.