Rheumatology Rounds at the Hospital for Special Surgery. Aspects of systemic lupus erythematosus: consideration of viral and genetic factors, and remarks on therapy.

The presentation of SLE in one member of a twin pair has provided the background for discussion of genetic and environmental variables involved in the pathogenesis of the syndrome. There are promising leads (developing in parallel with studies in man and in NZB mice) suggesting that SLE results from the interaction of genetic factors with an etiologic stimulus provided by type-C RNA viruses. The principles of management of SLE have been reviewed briefly.

Interleukin-1-production by monocytes from patients with systemic lupus erythematosus.

Production of interleukin-1 (IL-1) by glass-adherent monocytes from 18 patients with systemic lupus erythematosus (SLE) was measured. Patients were divided into three groups according to disease activity. A deficient production of IL-1 was found in monocytes of SLE patients both without stimulation and after stimulation with 5 micrograms of lipopolysaccharide. The decreased production correlated with the degree of disease. Addition of phorbol myristate acetate to monocytes caused only partial normalization of the decreased IL-1 production. The IL-1 deficiency in SLE is postulated to be a part of complex abnormalities of cell-mediated immunity in this disease.

Benoxaprofen administered once a day: determination of optimum dosage schedule.

Six centers participated in a double-blind crossover study in patients with rheumatoid arthritis (RA) and osteoarthritis to evaluate the most advantageous timing of the daily dose of benoxaprofen. The study results revealed no significant difference between the morning and evening dose administered at a daily dose of 600 mg; however, more patients with RA preferred the evening dose.

The efficacy and safety of auranofin compared to placebo in rheumatoid arthritis.

This double-blind multicenter study compares the effect of adding auranofin (AF) 3 mg bid or placebo to patients already taking nonsteroidal antiinflammatory drugs for rheumatoid arthritis. The 242 patients who completed 3 months of therapy demonstrated that the group receiving AF responded better than those receiving placebo. Of the 144 patients who completed 6 months coded medication, the efficacy in the AF group was superior to the placebo group in several parameters including a reduction in the number of painful or swollen joints, grip strength, dropout rate, and global efficacy as judged by the evaluating physician. A significant lowering of the Westergren erythrocyte sedimentation rate and immunoglobulin levels was noted in the AF treated patients. This study includes data summarizing the difference between both groups with respect to on-therapy conditions and toxicity.

The human vasculitis syndromes.

The vasculitides consist of a spectrum of clinical syndromes having in common necrotizing inflammation of the vascular system. Typical classification systems are based on both size of vessel involved and clinical gestalt. The author favors a pragmatic classification. Symptoms are manifestations of systemic inflammation and of organ ischemia secondary to inflammatory vascular occlusion. Multicenter studies suggest that the most common vasculitides do not satisfy criteria for one of the specific nosological entities and would be classified as "other" vasculitides. For those syndromes fitting a classical description (e.g., Wegener's, polyarteritis nodosa, Henoch-Schoenlein purpura), therapy is straight-forward. For those defying classification, therapy must be empirically directed at the manifestations causing symptoms.

Churg-Strauss syndrome and polyarteritis nodosa.

In the past year, the major contributions to our understanding of Churg-Strauss syndrome and polyarteritis nodosa were the development of classification criteria by which to separate these from other vasculitides. The absence of granulomas in most biopsies from patients with Churg-Strauss syndrome was noted. Other reports suggested that allergic disease may be only one of the hypereosinophilic conditions that predispose to this form of vasculitis. Eosinophilia and vasculitis occurring in a patient after dietary supplementation with L-tryptophan were reported, and the prominent cardiac involvement in Churg-Strauss syndrome was reemphasized. Impressive responses of that disease to cyclophosphamide were documented in one patient. In the American College of Rheumatology Vasculitis Classification Study, polyarteritis nodosa was one of the hardest vasculitides to distinguish. Several reports reiterated the serious risk of major pulmonary hemorrhage from microscopic polyarteritis of the lung, which probably represents a forme fruste of Wegener's granulomatosis. Although no new studies of therapy in polyarteritis were reported, a review of infections in such patients indicated that exposure to more than 15 mg/d of prednisone correlated with infectious complications, and that intra-abdominal infections were particularly problematic.

Significance of persisting serologic abnormalities in SLE.

The significance of abnormal serum anti-DNA and complement levels persisting in SLE patients on treatment has been explored. Instances when serologic abnormalities returned to normal were followed by a significantly longer mean duration of remission. When anti-DNA persisted at abnormal levels, a more severe exacerbation was likely to follow, although this result was not the case for persisting hypocomplementemia. These data did not result from two variants of SLE, one mild and one severe, because druation of remission correlated directly with dosage of steroid. Randomly discovered abnormalities in anti-DNA and complement levels were of limited predictive value, because they frequently persisted for over 1 year before exacerbations occurred. Hypocomplementemia resolved spontaneously without recognizable exacerbation in nearly half the observed instances.

Studies of murine complement. Correlation of hypocomplementemia with other disease parameters in individual NZB/W mice and demonstration of anti-complementary material.

We have utilized a new assay for murine complement components to explore the relationship of complement titers to other parameters of disease activity in individual NZB/W female mice. Titers had fallen significantly by 6 months of age, concomitantly with the appearance of antiDNA in serum and of C3 and immunoglobulin in renal glomeruli. The period of hypocomplementemia antedating proteinuria was extremely variable. Heat stable anti-complementary material was found in serum from older NZB/W mice.

Simultaneous use of multiple serologic tests in assessing clinical activity in systemic lupus erythematosus.

Ten technics for quantifying and qualifying anti-DNA antibodies were correlated with manifestations of disease activity in sera from 27 patients with systemic lupus erythematosus (SLE) using both a simple and a stepwise regression. In the stepwise analysis, a panel consisting of four of these tests provided maximal correlation (r = 0.68) with clinical status. Low IgM anti-DNA was a significant correlate of nephritis in stepwise discriminant function analysis. Multivariate analysis can offer distinct advantages over simple correlation in understanding the role of serological abnormalities in disease expression in SLE.

The radiographic diagnosis of sacroiliitis. A comparison of different views with computed tomograms of the sacroiliac joint.

Conventional radiography is the standard method of objectively identifying sacroiliitis. Single views of the sacroiliac joints can be unequivocally interpreted in 70-80% of patients with low back pain. A series of views usually correctly resolves the ambiguity in the remaining 20-30% of patients (67% correct). Computed tomography will be helpful in the few patients in whom a series of views produces equivocal interpretation.

Antihyperuricemic properties of amflutizole in gout.

The antihyperuricemic properties of amflutizole were investigated in studies designed to determine its efficacy and mechanisms of action in individuals with gout and hyperuricemia. In a randomized double blind, multiple dose, crossover study of 29 patients, amflutizole caused a significant dose dependent reduction in serum urate concentrations. Mean serum urate concentrations decreased significantly from 9.6 +/- 1.5 mg/dl to 7.2 +/- 1.3 mg/dl with the 500 mg dosage (p less than 0.01). Detailed studies in 5 patients demonstrated evidence for modest xanthine oxidase inhibition. However, the majority of the antihyperuricemic effect was derived from an enhanced renal clearance of uric acid. Although the drug has significant antihyperuricemic properties, these were inadequate to achieve adequate control of the serum urate concentration in hyperuricemia and gout at the doses utilized.

Effect of coexistent serum DNA on qualitative properties of anti-DNA antibodies.

We have explored the possibility that inapparent DNA in serum from patients with systemic lupus erythematosus can occupy anti-DNA combining sites and alter the apparent qualitative properties of such an antibody. DNAse digestion of such sera altered both the association rate of anti-DNA with 125I-DNA and the slope of binding isotherms in Scathchard analysis, although no immunoprecipitable DNA was detected in these sera. The association rate of serum after DNAse digestion was a better correlate of nephritis and disease activity. These findings suggest that DNA not detectable by counterimmunoelectrophoresis may affect assessment of qualitative properties of anti-DNA without affecting overall antibody titer, and that the association rate after DNAse digestion of serum remains one of the best correlates of disease activity. Our data further suggest that future qualitative studies of anti-DNA behavior utilize plasma rather than serum to avoid the artifact reported here.

High prevalence of HLA-Cw1 and Cw2 antigens in spondylarthritis.

HLA-B27 is frequently, but not invariably, found in patients with spondylarthritic diseases. Recently it has been shown that HLA-C-locus antigens w1 and w2 (w1/2) are in linkage disequilibrium with B27. A group of 139 patients with seronegative arthritis or spondylitis has been studied to determine the clinical and radiographic features associated with these antigens. An increased frequency of spondylarthritis was present in HLA-B27-negative, Cw1/2-positive patients when compared with B27- and Cw1/2-negative patients (P less than 0.01). In addition, a large group of patients who did not fulfill accepted criteria for a specific spondylarthritic syndrome were identified; the frequency of both HLA-B27 and Cw1/2 was greater in these individuals than in healthy blood donors. Thus HLA-Cw1/2 are spondylitis-associated antigens. These findings suggest that the critical genetic locus is neither B27 nor Cw1/2 but is a closely linked gene.

Impaired T-cell activation in patients with systemic lupus erythematosus.

Interleukin-2 (IL-2) production was studied in T lymphocytes from 32 patients with systemic lupus erythematosus (SLE) and 27 healthy volunteers. The IL-2 production by phytohemagglutinin (PHA)-stimulated cells from SLE patients was significantly depressed compared to control values, with a correlation between degree of depression and disease activity. The depressed IL-2 production by SLE T cells are largely reversed by the addition of either phorbol ester (PMA) or partially by a calcium ionophore. SLE T cells had significantly lower peak increases in intracellular free calcium [( Ca2+]i) than controls after stimulation by PHA or by a monoclonal antibody against the CD3 antigen. This abnormality was found even in T cells from patients with mild disease activity or in those whose T cells produced normal amounts of IL-2. Calcium ionophore produced similar increases in [Ca2+]i in SLE patients as in normals. These results suggest that a major component of the defect responsible for decreased IL-2 production by SLE lymphocytes is proximal to protein kinase C activation and may involve impaired signal transduction after activation of the antigen receptor complex.

Ketoprofen versus indomethacin in patients with acute gouty arthritis: a multicenter, double blind comparative study.

Fifty-nine patients with acute gouty arthritis entered into a 7-day multicenter, double blind trial of ketoprofen versus indomethacin. Patients were randomly assigned to receive 100 mg of ketoprofen (n = 29 patients) or 50 mg of indomethacin (n = 30 patients) 3 times a day. More than 90% of the patients in each group reported pain relief within the 1st day of treatment. By Day 5, 7 patients in the ketoprofen group and 6 in the indomethacin group discontinued treatment because of complete or substantial pain relief. At the end of the study, most patients in both groups were rated as having marked improvement both by the investigators and by self-assessment. Three patients in each group withdrew prematurely because of drug related gastrointestinal disorders. Ketoprofen compared favorably for efficacy and safety with indomethacin in the treatment of gouty arthritis.

Gouty arthritis: a prospective radiographic evaluation of sixty patients.

A prospective analysis of 60 patients with gout was undertaken to evaluate the radiographic spectrum of gouty arthritis in patients treated in the era of hypouricemic therapy. Twenty-two of these patients were clinically tophaceous; 36 were considered to have radiographic findings diagnostic of gouty arthritis by strict radiographic criteria. Up to 24% of the patients denied symptoms in joints with radiographic changes of gout; 42% with no evidence of tophi on clinical examination had radiographic changes characteristic of gout. Radiographic assessment can be extremely helpful in the management of gout by documenting the degree and extent of bony involvement, particularly in patients with limited symptoms or without clinical tophi.

Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology.

Methotrexate (MTX) has become an important drug in the treatment of rheumatoid arthritis (RA). The American College of Rheumatology convened a committee to assess the risks of development of clinically significant liver disease (CSLD) during MTX treatment, to evaluate the risk and role of surveillance liver biopsies, and to provide recommendations about monitoring patients for liver toxicity. The committee recommends obtaining liver blood tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, albumin, bilirubin), hepatitis B and C serologic studies, and other standard tests including complete blood cell count and serum creatinine tests prior to starting treatment with MTX. A pretreatment liver biopsy should be considered only for patients with a history of prior excessive alcohol consumption, persistently abnormal baseline AST values, or chronic hepatitis B or C infection. At intervals of every 4-8 weeks the AST, ALT, and albumin levels should be monitored. Routine surveillance liver biopsies are not recommended for RA patients receiving traditional doses of MTX. However, a biopsy should be performed if a patient develops persistent abnormalities on liver blood tests. These are defined as elevations (above the upper limit of laboratory normal) in the AST in 5 of 9 determinations within a given 12-month interval (6 of 12 if tests are performed monthly) or a decrease in serum albumin below the normal range. The recommendations for monitoring and selection of patients for liver biopsy identify patients at potential risk for CSLD, and thus significantly reduce the number or patients who would be exposed to this procedure. Close monitoring is essential to reduce the risk of unrecognized serious liver disease. These recommendations should be revised as necessary to reflect new and compelling information.