Richard I. Rynes

Fish-Oil Fatty Acid Supplementation in Active Rheumatoid Arthritis: A Double-Blinded, Controlled, Crossover Study

STUDY OBJECTIVE to determine the efficacy of fish-oil dietary supplements in active rheumatoid arthritis and their effect on neutrophil leukotriene levels. DESIGN nonrandomized, double-blinded, placebo-controlled, crossover trial with 14-week treatment periods and 4-week washout periods. SETTING academic medical center, referral-based rheumatology clinic. PATIENTS forty volunteers with active, definite, or classical rheumatoid arthritis. Five patients dropped out, and two were removed for noncompliance. INTERVENTIONS treatment with nonsteroidal anti-inflammatory drugs, slow-acting antirheumatic drugs, and prednisone was continued. Twenty-one patients began with a daily dosage of 2.7 g of eicosapaentanic acid and 1.8 g of docosahexenoic acid given in 15 MAX-EPA capsules (R.P. Scherer, Clearwater, Florida), and 19 began with identical-appearing placebos. The background diet was unchanged. MEASUREMENTS AND MAIN RESULTS the following results favored fish oil placebo after 14 weeks: mean time to onset of fatigue improved by 156 minutes (95% confidence interval, 1.2 to 311.0 minutes), and number of tender joints decreased by 3.5 (95% Cl, -6.0 to -1.0). Other clinical measures favored fish oil as well but did reach statistical significance. Neutrophil leukotriene B4 production was correlated with the decrease in number of tender joints (Spearman rank correlation r=0.53; p less than 0.05). There were no statistically significant differences in hemoglobin level, sedimentation rate, or presence of rheumatoid factor or in patient-reported adverse effects. An effect from the fish oil persisted beyond the 4-week washout period. CONCLUSIONS fish-oil ingestion results in subjective alleviation of active rheumatoid arthritis and reduction in neutrophil leukotriene B4 production. Further studies are needed to elucidate mechanisms of action and optimal dose and duration of fish-oil supplementation.

Severe flare of rheumatoid arthritis after discontinuation of long-term methotrexate therapy. Double-blind study.

To determine if long-term methotrexate-induced improvement of rheumatoid arthritis is sustained after the drug is discontinued, 10 unselected patients with responses to weekly oral methotrexate given for at least 36 months (mean 40.1) were randomly assigned to receive methotrexate or identical-appearing placebo tablets for two months. After one month, all five patients receiving placebo had to have the study terminated due to a flare of their disease manifested by statistically significant deterioration in multiple clinical parameters. It is concluded that patients receiving long-term methotrexate must continue the drug to maintain clinical benefits.

Acquired immunodeficiency syndrome-associated arthritis

A subacute, oligoarthritic syndrome developed in four patients with human immunodeficiency virus (HIV) infection. Three had true acquired immunodeficiency syndrome (AIDS) and all had lymphocyte abnormalities. The arthritis was characterized by extreme pain and disability in three patients and moderate pain in one. Knees and ankles were affected. Symptoms developed over a one- to six-week interval; response to treatment was rapid, especially to intra-articular corticosteroids. Despite the clinical severity of the arthritis, synovial fluids were non-inflammatory and biopsy specimens revealed only mild chronic synovitis. A definite etiology could not be established. None of the patients had recognized infections predisposing to reactive arthritis, and the three patients who underwent tissue typing were HLA-B27-negative. A viral infection, including HIV, is a possible cause. In distinction to these four patients, arthritides with clearly established etiologies developed during this same time period in four other HIV-infected patients.

Ophthalmologic safety of long-term hydroxychloroquine sulfate treatment

The fear of retinal toxicity has been a major factor limiting the use of chloroquine and hydroxychloroquine. Patients reported to develop retinal toxicity with visual loss usually took daily dosages higher than those currently in use. Toxicity with low dosages (for example, 250 mg per day chloroquine or 400 mg per day hydroxychloroquine) usually reveals pigment abnormalities; associated loss of vision is rare. When 99 patients treated with hydroxychloroquine for more than one year were studied prospectively, four patients showed evidence of retinal toxicity; none developed visual loss, and all abnormalities were completely reversible after drug discontinuation. All persons receiving antimalarials should be evaluated by an ophthalmologist at baseline and every six months thereafter. Funduscopic examinations and visual field testing with a red object must be included. Although this protocol may detect abnormalities that are not drug related, no loss of vision has developed in patients so monitored.

Non-organic non-psychotic psychopathology (NONPP) in patients with systemic lupus erythematosus

C ENTRAL NERVOUS SYSTEM (CNS) abnormalities occur frequently in patients with systemic lupus erythematosus (SLE)‘-” with a reported incidence ranging from 25%3 and 37%5 to 75%8 in retrospective clinical reviews. These abnormalities include psychiatric and neurologic dysfunction. Organic brain syndromes, overt psychoses, seizures, peripheral and cranial neuropathies, stroke, cerebellar signs and vascular headaches are among the more prominent findings in CNS-SLE.3-5,” Less severe psychiatric abnormalities which cannot be readily explained on the basis of a structural lesion may also occur. These findings, which we have termed non-organic, nonpsychotic psychopathology (NONPP), are often not mentioned or dismissed with the vague term “functional.” This may in part be attributed to the difficulty in assessing such psychopathology in a chronic disease state.‘* Standardized psychiatric testing has not previously been employed to evaluate psychopathology in SLE. Correlation of NONPP with other disease manifestations such as organic CNS disease, clinical activity or serologic abnormalities has rarely been attempted.‘9’3 The present study assesses these milder psychiatric findings in patients with SLE and attempts to place them in perspective. To accom-

Genetic deficiency of the second component of complement (C2) associated with systemic lupus erythematosus: Relation of the complement abnormality and disease manifestations☆

Abstract Systemic lupus erythematosus (SLE) was documented in a patient with genetic deficiency of the second complement component (C2). A review of disease manifestations in this patient and in others with SLE and genetic C2 deficiency previously reported on suggest that many findings such as fever, skin lesions, central nervous system involvement, the presence of autoantibodies and leukopenia occur in patients with SLE independent of whether or not they have C2 deficiency. However, renal disease appears mild in patients with genetic C2 deficiency despite the presence of immunoglobulins and complement components demonstrated in glomeruli by immunofluorescent microscopy. Electron microscopic study of glomeruli from the patient we describe showed electron-dense deposits consistent with the immunofluorescent findings. Tubuloreticular inclusion bodies identical to those previously seen in patients with SLE were also observed. Analysis of serum complement components and tissue deposition of complement components suggests activation of both the classic and alternative complement pathways in patients with C2 deficiency. The clinical, pathologic and complement findings in this group of patients support the hypothesis that although SLE is similar in patients with and without C2 deficiency, renal disease remains mild when this classic pathway component is not present. Histocompatibility antigen analysis of the family of the propositus confirmed the association of C2 deficiency with an A10, B18 haplotype, and with a haplotype not previously associated with C2 deficiency, AW32, BW40. One sibling with this latter haplotype has normal C2 levels, presumably as a result of recombination.

Hydroxychloroquine treatment of rheumatoid arthritis

A variety of placebo-controlled and open studies have demonstrated the effectiveness of hydroxychloroquine in the treatment of rheumatoid arthritis. The excellent responses to recurrent treatment in a sample patient illustrate the value of hydroxychloroquine. Because low daily doses of hydroxychloroquine are associated with greater ophthalmologic safety, it would be advantageous to use the smallest effective daily dose, but there are no published controlled efficacy studies using daily doses of less than 400 mg. Hydroxychloroquine may best be employed to treat patients with new onset of disease or those in whom disease is not rapidly progressive. Great potential exists for the use of hydroxychloroquine in combination therapy, but optimal utilization of combination regimens will require performances of additional controlled studies.

Identification of the α-γ subunit of the eighth component of complement (C8) in a patient with systemic lupus erythematosus and absent C8 activity: Patient and family studies☆

Abstract The serum of a patient with systemic lupus erythematosus (SLE) and no known history of Neisseria infections lacked the activity of the eighth component of complement (C8). Antisera specific for human C8 identified in the serum of the patient and four relatives, whose C8 activity was well below normal, cross-reacting material which differed from normal C8 in electrophoretic mobility and molecular size. Electrophoresis of this C8-related material eluted from a F(ab′)2 anti-C8 immunoadsorbent column revealed the presence of the α-γ subunit of C8. That this material was intact α-γ subunit was shown by successful reconstitution of C8 hemolytic activity in the probands serum by purified β subunit. We conclude that the C8-related antigen in the serum of the proband and four apparently heterozygous relatives is the α-γ subunit of C8. The presence or absence of the α-γ subunit in C8-deficient individuals does not appear to influence the type of disease to which they are predisposed since we were unable to find similar C8 antigen in another C8-deficient patient with SLE. Similarly, susceptibility to Neisseria infections has been reported in individuals with and without functionless C8 antigen. Histocompatibility (HLA) studies showed that C8 deficiency in this family is not inherited in association with HLA antigens and the patient does not have the DR antigens commonly associated with SLE.

Enhancement of Granulocyte Oxidative Metabolism in Sera from Patients with C2 Deficiency and Systemic Lupus Erythematosus

Serum or plasma from 3 patients with C2 deficiency (C2D) and systemic lupus erythematosus (SLE) significantly enhanced chemiluminescence and superoxide anion production by polymorphonuclear leukocytes (PMN) after stimulation with phorbol myristate acetate or latex beads. PMN from patients and normal individuals were supranormally activated when resuspended in plasma from these patients. No such effect was seen with plasma from a patient with C2D but with no evidence of SLE, from patients with SLE but not C2D, from patients with C1q or C8 deficiency, from C4-deficient guinea pigs, or NZB-NZW mice. Because oxygen-derived free radicals may cause joint or tissue damage, C2D patients who have or develop this activity in their plasma may be more prone to SLE or other collagen-vascular diseases.