Lymphocyte ecto-5'-nucleotidase deficiency in agammaglobulinemia.

Fresh peripheral blood lymphocytes from eight patients with congenital agammaglobulinemia demonstrate reduced ecto-5'-nucleotidase activity when compared to the mean activity of normal subjects and patients with other forms of immunoglobulin deficiency. A specific defect of ecto-5'-nucleotidase is further suggested by normal values for lymphocyte ecto-adenosinetriphosphatase and ecto-nonspecific phosphatase. The data provide evidence for an enzyme deficiency in this X-linked, B lymphocyte deficiency syndrome.

Overproduction of uric acid in hypoxanthine-guanine phosphoribosyltransferase deficiency. Contribution by impaired purine salvage.

The contribution of reduced purine salvage to the hyperuricemia associated with hypoxanthine-guanine phosphoribosyltransferase deficiency was measured by the intravenous administration of tracer doses of [8-(14)C]adenine to nine patients with normal enzyme activity, three patients with a partial deficiency of hypoxanthine-guanine phosphoribosyltransferase, and six patients with the Lesch-Nyhan syndrome. The mean cumulative excretion of radioactivity 7 d after the adenine administration is 5.6+/-2.4, 12.9+/-0.9, and 22.3+/-4.7% of infused radioactivity for control subjects, partial hypoxanthine-guanine phosphoribosyltransferase-deficient subjects, and Lesch-Nyhan patients, respectively. To assess relative rates of nucleotide degradation in control and hypoxanthine-guanine phosphoribosyltransferase-deficient patients two separate studies were employed. With [8-(14)C]inosine administration, three control subjects excreted 3.7-8.5% and two enzyme-deficient patients excreted 26.5-48.0% of the injected radioactivity in 18 h. The capacity of the nucleotide catabolic pathway to accelerate in response to d-fructose was evaluated in control and enzyme-deficient patients. The normal metabolic response to intravenous fructose is a 7.5+/-4.2-mmol/g creatinine increase in total urinary purines during the 3-h after the infusion. The partial hypoxanthine-guanine phosphoribosyltransferase-deficient subjects and Lesch-Nyhan patients show increases of 18.6+/-10.8 and 17.3+/-11.8 mmol/g creatinine, respectively. Of the observed rise in purine exretion in control subjects, 40% occurs from inosine excretion and 32% occurs from oxypurine excretion. The rise in total purine excretion with Lesch-Nyhan syndrome is almost entirely accounted for by an elevated uric acid excretion. Increases in urine radioactivity after fructose infusion are distributed in those purines that are excreted in elevated quantities.The observations suggest that purine salvage is a major contributor to increased purine excretion and that the purine catabolic pathway responds differently to an increased substrate load in hypoxanthine-guanine phosphoribosyltransferase deficiency. The purine salvage pathway is normally an important mechanism for the reutilization of hypoxanthine in man.

'Rhupus' syndrome.

Occasionally patients with overlapping features of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), termed "rhupus," have been encountered. We wanted to ascertain the frequency of such patients and determine whether they represent a unique overlap syndrome. Of approximately 7000 new patients evaluated over 11 years, we identified six patients who had, on the average, 6.7 American Rheumatism Association criteria for RA and 4.2 criteria for SLE. Criteria for RA included chronic symmetric arthritis with morning stiffness (six patients); subcutaneous nodules (two patients); positive rheumatoid factors test (four patients); and radiologic erosions (four patients). The criteria for SLE included malar rash (three patients); discoid lupus erythematosus (two patients); biopsy-proved nephritis (one patient); photosensitivity (one patient); leukopenia/thrombocytopenia (four patients); positive antinuclear antibodies or lupus erythematosus cell test (six patients); hypocomplementemia (two patients); and abnormal results from skin biopsy (two patients). During observations of up to ten years, the conditions of three patients were stable or improved, one died, and two were unavailable for follow-up. Patients usually did not have conditions that evolved to classic rheumatic disease patterns. Rhupus was not common and did not occur more frequently (0.09% prevalence among our patients) than expected from chance concurrence of SLE and RA (calculated at 1.2%). These observations confirm that rhupus indeed exists as a syndrome manifested by patients sharing features of probable coincidental concurrence of RA and SLE, but not as a unique clinical pathologic or immunologic syndrome. Appreciation of these patients with rhupus is important since their therapy and outcome differ from those having RA or SLE alone.

Vasculitis associated with malignancy. Experience with 13 patients and literature review.

Vasculitis is a syndrome which may complicate certain infectious, rheumatic, and allergic diseases. We identified 13 patients, over the past 17 years, who had both vasculitis and lympho- or myeloproliferative disorders and relate their clinical, laboratory, histologic, and immunologic features, course, therapy, and outcome. Nine patients were male, 4 female; ages ranged from 28 to 82 years. Ten of 13 patients presented with cutaneous vasculitis antedating malignancy by an average of 10 months. Three of 13 developed cutaneous vasculitis after malignancy. A statistically significant association between cutaneous vasculitis and lympho- or myeloproliferative malignancies was noted when compared with all other tumors. Dermatologic manifestations included palpable purpura (5 patients), maculopapular eruptions (4), urticarial and petechial lesions (3), and ulcers (1). Hepatitis B surface antigen, Coombs antibodies, rheumatoid factor and antinuclear antibodies were not found. Serum cryoglobulins were detected in 3 patients; serum C3 and C4 were normal in 8 of 9 patients evaluated. Histologic examinations revealed necrotizing leukocytoclastic vasculitis with disruption of endothelial integrity, destruction of endothelium, and neutrophil infiltration. Occasional perivascular mononuclear cell invasion was also noted in 4 patients. Immunofluorescent staining for IgG, IgA, IgM, C3, and C4 was negative in all patients studied. Symptoms were, in general, poorly responsive to therapy, which included nonsteroidal antiinflammatory drugs, antihistamines, antiserotonin agents, and corticosteroids. Chemotherapy directed at the underlying malignancy was also generally ineffective, although the vasculitis appeared to lessen in severity. Vasculitis appeared to lessen in severity as bone marrow function deteriorated. Ten patients died, all as a direct result of their malignancy. We have described a unique clinical syndrome of lympho- and myeloproliferative disease presenting with small-vessel vasculitis. Recognition that rheumatic symptoms may reflect or antedate malignancy may permit early diagnosis, aggressive treatment, and elucidation of pathogenesis.

Lesch-Nyhan syndrome: CSF neurotransmitter abnormalities.

Serial determinations of spinal fluid homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were made in four patients with the Lesch-Nyhan syndrome over a 5-year period. Control spinal fluids for age-matched comparison were obtained from 194 neurologic and nonneurologic pediatric patients. A rapid decline in control spinal fluid HVA and 5-HIAA occurs over the first 3 years of life (50 and 60%, respectively), and a more gradual decline persists throughout adolescence. The Lesch-Nyhan subjects have similar age-related changes in their spinal fluid neurotransmitter levels. Sequential 5-HIAA determinations from the four Lesch-Nyhan boys fall within the control range. The Lesch-Nyhan HVA levels are lower than the mean value for the age-matched control group in 18 of 19 samples. Ten of 19 determinations fell below the control range. Our findings provide evidence for altered CNS dopamine metabolism in the Lesch-Nyhan syndrome.

Magnetic resonance imaging of tophaceous gout in the hands and wrists.

The objective of this study was to determine the relative usefulness of physical examination, plain radiographs, and magnetic resonance imaging (MRI) using T1- and T2-weighted spin-echo images in evaluating the extent of urate deposition and soft tissue destruction in gouty arthritis. Seven patients with chronic tophaceous gout of the hands and wrists were examined to identify all clinically apparent tophi. Plain radiographs of the hands and wrist were obtained to further quantify soft tissue and osseous changes. MRI was then performed of the involved areas and a comparison made between soft tissue and bony changes observed by clinical examination and plain radiographs and those observed by MRI. Plain radiographs and physical examination markedly underestimate the size and extent of soft tissue and osseous involvement by tophi when compared with the findings of MRI. MRI also detects early, subclinical tophaceous deposits and indicates that urate deposits appear to spread along compartmental and fascial planes as opposed to the traditional view of strict radial growth. MRI is a useful method of determining the extent of disease in tophaceous gout and may provide information regarding the patterns of deposition and spread of monosodium urate crystals.

Silicone and rheumatic diseases.

Silicone generally has been regarded as a biologically inert material. However, recent reports suggest that inflammatory responses to silicone occur. There is some experimental and clinical evidence of a direct inflammatory response to the presence of liquid or particulate silicone. These include granulomatous skin reaction to injected silicone, synovitis around silicone prosthetic joints, and lymphadenopathy proximal to silicone prostheses. There are case reports of systemic rheumatic disease following silicone prostheses, but no definitive proof of a direct relationship between silicone prostheses and systemic disease. The clinical features of the reported cases following breast augmentation include breast tenderness, axillary adenopathy, sclerodermatous skin changes, arthritis, Raynaud's phenomenon, rheumatoid factors, and ANAs. Prior epidemiologic evidence and the number and consistency of our own and others' clinical findings suggest that silicone may indeed be associated with inflammatory processes and rheumatic diseases.

Immunodeficiencies associated with errors in purine metabolism.

The genetic deficiencies of adenosine deaminase and purine nucleoside phosphorylase lead to blocks in the purine pathway. The intracellular accumulation of deoxynucleosides and deoxynucleotides is toxic to both dividing and nondividing lymphocytes via multiple mechanisms. T-lymphocytes are uniquely sensitive to purine-mediated cytotoxicity because of a functional imbalance of phosphorylating and dephosphorylating enzymatic activities. These inborn errors or purine metabolism are rare disorders. The study of these conditions, however, has uncovered unique enzymatic properties of lymphocytes and lymphocyte subclasses. A better understanding of the mechanisms of lymphocytotoxicity in these two purine enzyme defects may lead to better modes of therapeutic manipulation of the immune system.

Magnetic resonance imaging in patients with inflammatory arthritis of the knee.

Magnetic resonance imaging (MRI) permits visualization of anatomic structures not appreciated by conventional radiographic imaging and may quantify inflammatory disease and its progression with greater sensitivity than available techniques. We therefore compared MRI with clinical evaluation and with radiographic examination of 17 patients with inflammatory arthritis of the knee. We sought to determine anatomic integrity of bone, cartilage, menisci, and ligaments, and to quantify joint effusion and synovial proliferation. Patients studied had rheumatoid arthritis (10 patients), juvenile rheumatoid arthritis (4 patients), ankylosing spondylitis (1 patient), and monoarticular arthritis (2 patients). In all patients MRI revealed clinically important abnormalities not detected by physical or conventional radiographic exams. These included proliferative synovitis (13 patients), cartilage thinning (2 patients), cartilage erosion (8 patients), bone infarction (1 patient), meniscal injury (1 patient), and synovial invagination into bone (1 patient). Also MRI indicated inflammatory disease to be quantitatively greater than had been appreciated on clinical examination or routine X-ray studies--proliferative synovitis (12 patients), erosion (7 patients), effusion (8 patients), cartilage thinning (11 patients), and ligamentous/meniscal damage (1 patient). These findings led to reassessment of anatomic staging and influenced therapeutic decision for these patients. Thus MRI provides clinically important information about joint integrity and inflammatory disease, with a sensitivity and resolution considerably beyond conventional techniques.

Hypoxanthine salvage in man: its importance in urate overproduction in the Lesch-Nyhan syndrome.

1. A daily urinary excretion of 0.8 percent of the administered radioactivity results from the turnover of the labeled adenine nucleotide pool. 2. A 4-fold increase of urinary radioactivity excretion occurs in patients with the Lesch-Nyhan syndrome and support the role of impaired hypoxanthine salvage in the purine overexcretion associated with HGPRT deficiency. 3. Our data do not support the possibility that the increased radioactivity excretion in the HGPRT deficient subjects results from an elevated rate of adenine nucleotide degradation.

Drugs to lower uric acid levels. How to avoid misuse in gouty arthritis.

Several points regarding the use of drugs to lower uric acid levels deserve emphasis. First, these agents are not useful in the management of acute gout. Second, all forms of the drugs should be initiated at low dose with gradual increments to achieve a serum uric acid level between 5 and 6 mg/dL. There are no data to support the widely presumed notion that dropping the uric acid level to a very low range (1 to 3 mg/dL) hastens resorption of tophi or improves joint function. Third, the uricosuric agents probenecid (Benemid) and sulfinpyrazone (Anturane) interact with a number of drugs, and both the patient and physician should be aware of this. Finally, and most important, careful and frequent monitoring is needed during the first several months of therapy with these drugs.

Work productivity loss due to flares in patients with chronic gout refractory to conventional therapy.

OBJECTIVE: Joint pain and swelling during gout flares may lead to considerable morbidity and disability, having an impact on patient work productivity and social participation. The objective of this study was to assess how gout flares affect these activities in patients with chronic gout refractory to conventional therapy. METHODS: A 1-year prospective observational study was conducted among patients with symptomatic disease in the United States in 2001. Inclusion criteria required patients (1) to be age 18 years or older, (2) to have documented, crystal-proven gout, (3) to have symptomatic gout, and (4) to be intolerant or unresponsive to conventional therapy, reflected by SUA ≥ 6.0 mg/dL. Patients were evaluated every 2 months. At each visit, patients completed a gout diary, which included number of flares experienced, duration and severity of each flare, and whether the flare caused: (1) work loss, (2) missed appointments or social events, or (3) impairment of self-care activities. The Short-Form Health Survey (SF-36) was also completed each visit. RESULTS: Analyses were restricted to those who completed the first 6 months of the study (n = 81). Mean number of flares per patient per year was 8.8. Of the patients who were <65 years, 78% reported at least 1 work day lost due to a gout attack during the year. Mean annual work day loss for those <65 years was 25.1 days. A total of 545 of patients reported at least one flare per year that impaired social activities, with a mean of 17.1 social days lost and 52% reported at least one flare per year that compromised normal self-care activities, with a mean of 16.9 days impairment. Correlations between the diary reports and activity-related questions from the SF-36 were significantly positive. LIMITATIONS: The study is limited by small sample size, lack of reference group, and inability to explicitly collect employment information. Age under 65 years was used as a proxy for employment eligibility. CONCLUSION: Flares in patients with chronic gout refractory to conventional therapy significantly affect patient work productivity and social activities.