Threshold Amsler grid as a screening tool for asymptomatic patients on hydroxychloroquine therapy.

BACKGROUND/AIMS: Patients taking hydroxychloroquine (HCQ) are at risk of developing classic bull's eye maculopathy. Currently, the standard Amsler grid (AG) is one of the most useful methods to identify such lesions. However, AG is a suprathreshold target and may not detect relative central scotomas. The aim of this study was to determine if the threshold Amsler grid (TAG) test, which varies light transmission through two cross polarising filters, allows increased detection of scotomas caused by HCQ toxicity. METHODS: 56 rheumatological patients taking HCQ and 12 similar patients not taking HCQ were tested by AG, red Amsler grid (RAG), and TAG. RESULTS: No scotomas were observed in patients never treated with HCQ. Among patients who had been treated with HCQ, AG revealed scotomas in two of 56 (3.64%) patients; in contrast, six (10.7%) and 37 (66.1%) scotomas were identified by RAG and TAG testing respectively. Additionally, the average area of each scotoma detected by all three methods expanded from 34.5 square degrees of central field loss on AG testing to 71 square degrees on RAG and 117 on TAG. CONCLUSION: By decreasing the perceived luminance of the suprathreshold AG, TAG testing provides a novel alternative to detect shallow scotomas and areas of depressed retinal activity secondary to HCQ toxicity.

Synergistic effect between IL-10 and bcl-2 genotypes in determining susceptibility to systemic lupus erythematosus.

OBJECTIVE: To determine whether genes participating in programmed cell death, including bcl-2, IL-10, Fas-L, and CTLA-4, may contribute to the genetic predisposition to systemic lupus erythematosus (SLE). METHODS: First, intragenic markers for the bcl-2, IL-10, Fas-L, and CTLA-4 genes were characterized and their extent of polymorphism in normal populations was determined. The allelic distribution of these gene markers in a large Mexican American SLE cohort of 158 patients and 223 ethnically matched controls was determined using fluorescent-labeled primers and semiautomated genotyping. RESULTS: The bcl-2, Fas-L, and IL-10 loci showed significantly different allelic distribution in SLE patients compared with controls, indicating an association between these genes and SLE. No association was found between SLE and the CTLA-4 gene. Further analysis revealed a synergistic effect between susceptibility alleles of the bcl-2 and IL-10 genes in determining disease susceptibility. Alone, the presence of each of these alleles was associated with a moderate increase in SLE risk, while the occurrence of these alleles together increased the odds of developing SLE by more than 40-fold. CONCLUSION: The results suggest that individuals carrying specific genotypes of both bcl-2 and IL-10 are at significant risk of developing SLE.

Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus.

Genetic susceptibility confers significant risk for systemic lupus erythematosus (SLE). The MHC region and other polymorphic loci have been associated with SLE. Because more compelling evidence for an involvement of a genetic locus includes linkage, we tested a candidate region homologous to a murine SLE susceptibility region in 52 SLE-affected sibpairs from three ethnic groups. We analyzed seven microsatellite markers from the human chromosome 1q31-q42 region corresponding to the telomeric end of mouse chromosome 1, the region where specific manifestations of murine lupus, including glomerulonephritis and IgG antichromatin, have been mapped. Comparing the mean allele sharing in affected sibpairs of each of these seven markers to their expected values of 0.50, only the five markers located at 1q41-q42 showed evidence for linkage (P = 0.0005-0.08). Serum levels of IgG antichromatin also showed evidence for linkage to two of these five markers (P = 0.04), suggesting that this phenotype is conserved between mice and humans. Compared to the expected random distribution, the trend of increased sharing of haplotypes was observed in affected sibpairs from three ethnic groups (P < 0.01). We concluded that this candidate 1q41-q42 region probably contains a susceptibility gene(s) that confers risk for SLE in multiple ethnic groups.

Surgical procedures in the management of Takayasu's arteritis.

Takayasu's arteritis is an inflammatory arteriopathy that often progresses to obliteration of multiple large arteries. Variable results have been reported after medical and surgical management. Twenty female patients with Takayasu's arteritis were treated from 1973 to 1989. Eleven (55%) patients had hypertension. Upper or lower extremity ischemia was present in 12 (60%) patients and cerebrovascular insufficiency in seven (35%). Nine patients initially managed with corticosteroids had no improvement in signs or symptoms of arterial insufficiency. Eleven patients had 16 vascular procedures for the following indications: renovascular hypertension (6), extremity ischemia (5), cerebrovascular insufficiency (2), dilation ascending aorta with aortic insufficiency (1), thoracic aortic aneurysm (1), abdominal aortic aneurysm (1). Procedures included aortorenal bypass (5), carotid-subclavian, axillary, or brachial bypass (4), aorto-carotid bypass (2), aneurysm resection (2), supra-celiac aorto-femoral bypass (1), ascending aorta/aortic valve replacement (1), and nephrectomy (1). Clinical improvement occurred in all patients. There were no operative deaths. All are alive at a mean follow-up of 5.75 years (6 months to 16 years). Revision of the initial reconstruction has been required for recurrent renovascular hypertension in one patient and extremity ischemia in another. The other nine patients remain symptomatically improved. Symptomatic Takayasu's arteritis frequently requires arterial reconstruction. Symptomatic improvement and excellent long-term graft patency can be expected after arterial reconstruction.

Rheumatic diseases and pregnancy: a perspective.

The interaction between certain rheumatic diseases, sex hormones and their wide fluctuation during pregnancy and postpartum may be responsible for the variable course of rheumatic diseases during pregnancy. Important issues include effects on the mother and fetus by the disease, pregnancy and maternal drug therapy.

Pregnancy in mixed connective tissue disease, poly/dermatomyositis and scleroderma.

Pregnancy related problems in mixed connective tissue disease, polydermatomyositis and scleroderma are analysed. Particular attention is also elevated to the therapeutical approach to these diseases during pregnancy and delivery.

Chondritis in systemic lupus erythematosus: clinical and immunopathologic studies.

Three patients with systemic lupus erythematosus (SLE) and relapsing auricular and nasal chondritis are described. Chondritis in SLE is a rare event (less than 1% of our patients), was accompanied by clinical and laboratory evidence of SLE activity and resembled relapsing polychondritis in clinical presentation and pathology. Clinical involvement was limited, cartilage collapse did not occur and response to steroid therapy was prompt. Cartilage inflammation in two ear biopsies was relatively mild, with deposits of IgG and C3 in the chondrofibral junction and adjacent skin vessels. Immune complexes (cryoglobulins) were present in the serum. We postulate an immune complex pathogenesis of this rare manifestation of SLE.

Anticardiolipin antibodies in unselected autoimmune rheumatic disease patients.

Quantitative determination of IgG and IgM antibodies to cardiolipin (anti-CL) was performed with a newly developed sensitive and specific ELISA method. We studied a cohort of 361 unselected patients with various autoimmune rheumatic diseases (ARD), 69 patients with thromboembolic phenomena (TEP) unassociated with ARD, and 267 healthy blood donors (HBD). Anti-CL of at least one immunoglobulin class were found in 42 (11.6%) of the ARD patients, in 3 (4.3%) of the TEP patients (2 with myocardial infarction and 1 with pulmonary emboli), and in 6 (2.3%) of the HBD. In ARD patients anti-CL were more prevalent in patients with systemic lupus erythematosus (SLE) and overlap syndromes. Significant correlations included CNS involvement (particularly seizures) and features of immune hyperreactivity (splenomegaly-lymphadenopathy, ANA, and antibodies to Ro(SSA), U1-nRNP, and double-stranded DNA). No statistical correlation could be demonstrated between the presence of anti-CL and thrombotic events, hematologic disorders, or recurrent abortions in the ARD patients.

Studies on human blood lymphocytes with iC3b (type 3) complement receptors: III. Abnormalities in patients with active systemic lupus erythematosus.

Lymphocytes displaying iC3b (Type 3) complement receptors (CR3) were quantified by flow cytometry in patients with systemic lupus erythematosus. The percentages and absolute numbers were compared to age and sex matched controls. Total CR3+ lymphocytes identified by the monoclonal antibodies OKM1 or Leu 15 were significantly decreased in patients with symptomatic arthritis, serositis or vasculitis and those with lupus nephritis, whereas values for CR3+ lymphocytes in patients with inactive disease were similar to normal donors. The phenotype of CR3+ lymphocytes was markedly different in patients with active SLE. In normals granular lymphocytes bearing Fc receptors for IgG (L cells) comprised two-thirds of CR3+ lymphocytes. However, in SLE this subset was reduced to 20% and there was a corresponding increase in CR3+ lymphocytes co-expressing the T3 marker. Percentages of CR3 T4+ but not CR3+ T8+ lymphocytes were significantly increased in SLE. Although patients with active disease were lymphopenic, absolute numbers of CR3+ lymphocytes co-expressing T cell markers were similar to normal controls. Since L cells are non-specific suppressors of Ig production, the reduction of this subset along with the increase in CR3 T4+ cells could contribute to unregulated antibody production characteristic of SLE.

Unusual paraspinal muscle lesions in ankylosing spondylitis.

Minicore, multicore, core-targetoid and other ultrastructural lesions were found in the paraspinal muscles of patients with AS. The 10 patients studied, all men with AS, showed varying degrees of muscle fibre atrophy, Z band streaming, rod body formation, minicores, multicores and core-targetoid fibres. Central core disease, rod body myopathy, minicore and multicore diseases are recognized clinical entities within the congenital group of structural myopathies. Target fibres are believed to be a feature of reinnervation. It is also known that experimental tenotomy causes core-targetoid changes, rod bodies, minicores and multicores. Therefore, it seems possible that tension is a necessary stimulus for the correct programming of synthetic muscle enzymes, and without this disorganization occurs. It may also be assumed, but in this case for genetic reasons, that similar biochemical systems are disturbed in the group of congenital myopathies.

Esophageal manometric findings in autoimmune rheumatic diseases: is scleroderma esophagus a specific entity?

In order to assess whether distal esophageal hypomotility in scleroderma is unique to this disease or not, we studied 25 normal volunteers and 109 patients with autoimmune rheumatic diseases (27 with primary Sjögren's syndrome, 25 with idiopathic Raynaud's phenomenon, 25 with rheumatoid arthritis, 19 with scleroderma, 5 with undifferentiated connective tissue disease, 3 with systemic lupus erythematosus, 2 with mixed connective tissue disease, 2 with sclerodermatomyositis, and one with morphea). Esophageal dysfunction typical of scleroderma was present in 17 patients (15.6%), of whom 13 had scleroderma (68%) and one each primary Sjögren's syndrome, rheumatoid arthritis, undifferentiated connective tissue disease, and mixed connective tissue disease. Twenty-two percent of all patients had nonspecific esophageal motility changes, clustered among primary Sjögren's syndrome, idiopathic Raynaud's phenomenon, and rheumatoid arthritis. We conclude that lower esophageal hypomotility, although most frequent in scleroderma, is not unique to this disease and can be encountered in several other auto-immune rheumatic diseases.

Renal involvement in mixed connective tissue disease: a longitudinal clinicopathologic study.

Eleven of 30 patients with MCTD, followed for a mean of 10 years, developed immune complex nephropathy (five membranous, two mesangial, one mixed, and one sclerosing) with NS in nine of 11. Another patient had membranous nephropathy at autopsy. Patients with renal disease tended to have more systemic manifestations than those without. NS was at times of abrupt onset, recurrent, and/or persistent. Anti-RNP and serum complement were not helpful in predicting nephritis. Seventy-two percent of nephropathy and 62% of NS episodes resolved or improved after corticosteroid therapy. Five patients became hypertensive, two developed chronic renal failure and required chronic dialysis, and one needed acute dialysis twice. One patient progressed to focal proliferative crescentic nephritis with necrotizing arteritis. Three patients with nephropathy died, two of pulmonary hypertension with acute cor pulmonale and one of overwhelming sepsis. Nephropathy is relatively common in MCTD, is associated with substantial morbidity, and with the risk of hypertension and chronic renal failure.

Cyclosporin a therapy in patients with primary Sjögren's syndrome: results at one year.

We present our experience with small doses of cyclosporine A (CyA), 5 mg/kg/day, in patients with primary Sjögren's syndrome treated for up to 12 months. Subjective improvement in xerostomia occurred at 6 months of treatment, without objective improvement in any sicca parameters. At 12 months, xerostomia improved slightly, but minor salivary gland histology worsened. We conclude that small doses of CyA in patients with primary Sjögren's syndrome for up to 12 months are rather ineffective.

Defective production of interleukin 1 and interleukin 2 in patients with systemic lupus erythematosus (SLE).

The objective of this study was to define some causes of the immunologic impairment characteristic of systemic lupus erythematosus. Blood mononuclear cells from 19 patients were stimulated to produce interleukin 1 and interleukin 2 and compared with controls. A severe defect in both IL 1 and IL 2 activity was observed. The low cytokine levels did not correlate with clinical or serologic activity of disease. These defects could not be explained by concurrent corticosteroid therapy. There was no correlation between a lower number of OKT4+ cells observed in these patients and the levels of IL 2 production, nor did removal of monocytes bring IL 2 to normal. Impaired IL 2 production could not be restored to normal by IL 1. The observed deficiency in these regulatory cytokines may therefore be a primary defect that is important in the pathogenesis of this disorder.

T lymphocyte subsets in systemic lupus erythematosus. Correlations with corticosteroid therapy and disease activity.

The contribution of immune regulation to the etiology of systemic lupus erythematosus (SLE) is poorly understood. Using the monoclonal antibodies OKT4 and OKT8, we quantitated, by flow cytometry, T inducer/helper and T cytotoxic/suppressor cells in patients with SLE. Serologically active patients, who had clinical manifestations such as arthritis or rash and were not receiving prednisone, were characteristically lymphopenic due to a marked reduction in OKT4+ cells. Prednisone therapy produced the same phenomenon. Untreated patients, who were serologically inactive, demonstrated no abnormalities. These studies have thus revealed two presumably independent factors that can produce similar immunoregulatory aberrations.

Septic arthritis due to Arizona hinshawii.

Arizona hinshawii, a gram negative bacillus which bears antigenic similarities to genus Salmonella is an uncommon cause of human disease. We report 3 patients who in an immunocompromised state developed septic arthritis due to Arizona hinshawii. Treatment with systemic antibiotics and repeated joint aspiration was successful. The infection was recurrent in 2 patients and 1 died of septicemia. Previous cases of Arizona hinshawii septic arthritis are reviewed.

Pregnancy in mixed connective tissue disease: comparison with systemic lupus erythematosus.

The risk of pregnancy was evaluated in 31 patients with mixed connective tissue disease (MCTD), 31 patients with systemic lupus erythematosus (SLE) and 51 controls. The fertility rates in MCTD and SLE were unaltered by disease; however, parity was decreased and fetal wastage was increased both before and even more so after onset. It is our observation that pregnancy carries the same risks in MCTD as it does in SLE.

Esophageal dysfunction in patients with mixed connective tissue diseases and systemic lupus erythematosus.

We sought to correlate esophageal symptoms with esophageal motility abnormality in 17 patients with mixed connective tissue disease (MCTD) and in 14 patients with systemic lupus erythematosus (SLE). Heartburn and regurgitation were common symptoms (11/17) in patients with MCTD, and most of the (10/11) exhibited significant manometric abnormalities. Additionally, impairment of esophageal peristalsis was found in four of the remaining asymptomatic patients. Severe esophageal aperistalsis was noted in nine MCTD patients. Patients with SLE also frequently reported esophageal symptoms (8/14), but significant motility abnormalities were seen in only three cases. In both patient groups good correlation between Raynaud's phenomenon and esophageal aperistalsis was found. Our results reveal that, although esophageal symptoms are commonly present in patients with both MCTD and SLE, severe esophageal motility abnormalities are more often found in patients with MCTD than in those with SLE.

Complement fixing antibodies to DS-DNA in systemic lupus erythematosus: a study using the immunofluorescent Crithidia luciliae method.

Crithidia luciliae, a hemoflagellate, was used in an immunofluorescent procedure to assay for antibodies to ds-DNA and their capacity to fix complement. Positive reactions with this method were limited to systemic lupus erythematosus patients, and sensitivity was comparable to the DNA binding assay. Complement fixing activity of antibodies to ds-DNA in 45 sera was determined using kinetoplast ds-DNA of Crithidia luciliae and an antiserum to C3. Complement fixing antibodies to ds-DNA were found in nearly all patients with documented active renal involvement and absent in nearly all patients with no, or inactive renal involvement.