Effect of rheumatoid factor on complement-mediated phagocytosis.

The frequency and amount of IgM rheumatoid factor (RF) in the blood of patients with rheumatoid arthritis (RA) correlate with the severity of the disease and the number of complications. Though previous studies of RF in subacute bacterial endocarditis have shown that RF inhibits phagocytosis of microorganisms by granulocytes, the presence of low levels of complement (C) in blood and synovial fluid of patients with the highest titers of RF suggests that an interaction between RF and C may contribute to the inflammatory process in RA. We thus employed a quantitative methodology to examine the effect of RF on complement-dependent phagocytosis of sheep erythrocytes by rabbit granulocytes. Addition of 2500 molecules of IgM RF to sheep cells heavily coated with IgG antibody (195,000 molecules per cell) resulted in virtually complete inhibition of uptake of C3 (beta(1c)) and prevention of phagocytosis, an effect resulting from inhibition of uptake of C1 by the cells. When erythrocytes coated with only 34,000 molecules of IgG antibody were employed, phagocytosis was similarly inhibited. However the effect of RF on such cells was shown to be primarily mediated through inhibition of C4 rather than C1 uptake. Although the results do not exclude the participation of an IgM RF of higher avidity, present only in the tissues in rheumatoid inflammation, circulating IgM RF probably does not play a potentiating role in rheumatoid inflammation.

Immune complexes in sera and synovial fluids of patients with rheumatoid arthritis. Radioimmunoassay with monocylonal rheumatoid factor.

Evidence for the presence of immune complexes in blood, synovial fluid, and tisues of patients with rheumatoid arthritis (RA) includes low complement levels in blood and effusions, deposition of immunoreactants in tissues and vessel walls, precipitate formation after addition of monoclonal rheumatoid factor (mRF) to serum or synovial fluid. To quantitate immune complex-like material in RA patients, we developed a radioimmunoassay based on inhibition by test samples of the interaction of (125I)aggregated IgG (agg IgG) and mRF coupled to cellulose. This method could measure immune complexes of human antibody with hemocyanine prepared in vitro. The assay was not influenced by presence of polyclonal RF in test samples, nor by freezing and thawing. Normal levels of immune complex-like material in serum were less than 25 mug agg IgG EQ/ML. 12 of 51 RA sera examined (26%) contained more than 25 mug/ml. The presence of this material in RA sera was found to correlate with severity of disease, as measured by anatomical stage and functional class. There was an inverse correlation of the material with serum C4 level. Rheumatoid synovial fluids generally contained higher levels than serum, and five of 23 contained very much higher levels. The frequency of elevated levels of immune complex-like material in sera of patients with systemic lupus erythematosus (2 of 29) and with miscellaneous vasculitides (2 of 21 was much lower than in RA, suggesting that mRF exhibits a specificity for only certain kinds of immune complexes. The reason for this apparent specificity may explain such distinctive features of RA as the high frequency of polyclonal RF, the lack of immune complex nephritis, and the generally normal levels of serum complement.

C3b receptor in normal human skin.

Receptors for C3b in normal skin were studied. C3b was produced by treating normal human serum with cobra venom factor and by partial digestion of purified C3 with trypsin. Cryostat sections of normal human skin were incubated with C3b, followed by a direct immunofluorescent technique using monospecific goat antihuman C3. The histologic localization of C3b fluorescence was ascertained by fixing cryostat sections with glutaraldehyde and staining with hematoxylin and eosin. The following structures showed staining with anti-C3: (1) endothelial cells in capillaries, larger vessels, and arteries, (2) smooth muscle in arrector pilori muscles and artery walls, and (3) myoepithelial cells in the secretory portion of sweat glands. C3b did not bind to the intercellular substance nor to the basement membrane zone in normal human skin. Normal human sera treated with EDTA, EGTA, and heat (56 degrees C for 30 min) were negative, as was purified C3 by itself, thus indicating that native C3 did not bind to these receptors. Specificity for C3/C3b was shown by blocking with both unconjugated rabbit antihuman C3 and purified C3. The endothelial C3b receptor may have an important role in the localization of immune complexes in cutaneous vasculitis.

Measurement of immunoglobulin binding to synovial fibroblast monolayers: comparison of staphylococcal protein A binding to cytotoxic assay methods.

We have studied the binding of rabbit antibody to cultured synovial fibroblasts by 3 methods: complement mediated cell lysis, 125I-labeled staphylococcal protein A ([125I]PrA) and antibody dependent cell mediated cytotoxicity (ADCC). The relative sensitivities of these 3 methods is 1 : 33 : 3300 respectively. The [125I]PrA binding method is shown to quantitatively detect cell bound IgG with a molar stoichiometry of approximately 1 : 1, protein A (PrA) to IgG if PrA is present in excess.

Morbidity impact of rheumatoid arthritis on society.

Classic and definite rheumatoid arthritis affects from 0.5 to 1 percent of the United States' population between the ages of 20 and 80. In the age group of 55 to 75 years, this figure increases to 4.5 percent. In addition to the pain and suffering produced by this disease, family structure is dramatically affected--the divorce rate for patients with rheumatoid arthritis is 70 percent above that for the general population. Rheumatoid arthritis also results in serious economic loss to society. In 1983, the direct cost (out-of-pocket expense for medical care) was $777 million, and the indirect cost (loss of productivity) was $215 million, with a total of approximately $1 billion. The average person with stage III rheumatoid arthritis suffers a 60 percent decline in earnings during the first six years after onset of the disease. Recent studies have indicated that the ability to remain employed depends at least as much on job-related factors as on the extent of disease or success of medical treatment. Job autonomy or the ability to control one's working conditions is the most important factor. Other important variables are education, seniority, and work that is not excessively physically demanding. Good transportation between home and job is also an essential requirement for remaining employed. There are few data available on the cost/benefit ratio of the treatment of rheumatoid arthritis. An 18-month study showed a trend toward greater improvement in patients given optimal care by a team of experts in a medical center as compared with average treatment provided in the community. A study in Scotland on cost of hospitalization of 366 patients (about one half underwent surgery) showed cost benefits of xi 14,000 to xi 131,000 over a five- to 10-year period for those who returned to work. Patients who did not return to work incurred medical costs of xi 100,000. There is little question that more effective medical treatment and better rehabilitation strategies for people with rheumatoid arthritis would provide significant benefits for patients, their families, and society.

Prospective study of immune response to hydralazine and development of antideoxyribonucleoprotein in patients receiving hydralazine.

To examine the relationship between the immune responses to hydralazine, a drug known to induce systemic lupus erythematosus, and to deoxyribonucleoprotein (DNP) we followed prospectively 21 hypertensive patients treated with hydralazine for the first time. Within one year, antibodies to hydralazine developed in 16 of these patients and anti-DNP in seven of these. In one patient whose serum had a positive antinuclear antibody test prior to treatment, a mild hydralazine systemic lupus erythematosus syndrome developed preceded by rises in the levels of both anti-hydralazine and anti-DNP. Studies by radioimmunoassay on serums of three additional patients, not followed in this study but known to have hydralazine-induced systemic lupus erythematosus, revealed no evidence for either (1) cross-reactivity between anti-DNP and anti-hydralazine or (2) antibodies specific for a hydralazine-DNP complex. In some way, perhaps related to the mechanism by which carrier molecules enhance the immunogenuity of haptens, hydralazine increases the antigenicity of DNP. This effect depends on the development of immunity to hydralazine as well.

Immune complexes in primary biliary cirrhosis. Higher prevalence of circulating immune complexes in patients with associated autoimmune features.

A longitudinal study, examining the levels of immune complexes serially for three years, in serum from 88 patients with primary biliary cirrhosis was performed by the Raji cell radioimmunoassay. Studies of the association of autoimmune features in primary biliary cirrhosis and the effect of D-penicillamine therapy in relation to the levels of complexes were carried out. Twenty-two patients (25 percent) were found to have autoimmune features, such as Sjögren's syndrome, rheumatoid-like arthritis, scleroderma, Raynaud's disease, and Hashimoto's thyroiditis. In this subset of patients with primary biliary cirrhosis, a significantly higher prevalence (86 percent) of circulating immune complexes was detected compared with those patients showing no autoimmune features (60 percent). In addition, patients with associated autoimmune features had higher mean levels of immune complexes (259.7 micrograms AHG eq/ml) compared with those without autoimmune features (202.1 micrograms AHG eq/ml). The mean levels of complement C4, reflecting activation of classic complement pathway, were significantly lower in patients with elevated immune complexes and associated autoimmune features. The mean level of immune complexes in 13 patients receiving D-penicillamine, in contrast to the placebo group, decreased at one year but subsequently was greater than the initial level. Patients who had normal levels of immune complexes and received penicillamine therapy continued to have complex levels within the normal range for up to three years of follow-up study, but patients receiving placebo showed significantly elevated levels at subsequent intervals. Thus, levels of immune complexes in primary biliary cirrhosis may reflect the association with autoimmune features.

The turnover in normal dogs of prothrombin and its fragments; effect of induced intravascular coagulation.

When 125I-labeled canine prothrombin was given to normal adult dogs intravenously, it was calculated that 240% of the plasma prothrombin crossed the capillary barrier per day, 410% of the interstitial prothrombin returned to the blood stream daily, and 79% of the plasmatic prothrombin was catabolized per day. These data are in close agreement with those observed for bovine prothrombin in calves by Takeda (1970). When derived from normal dog prothrombin, prethrombin-1 is a mixture of 2 polypeptides, one larger than the other, and both present in about equal amounts. The longer peptide, "prethrombin-1-long," was catabolized twice as fast as prothrombin, and the shorter, "prethrombin-1-short," 4 times faster. Prothrombin fragment-1 was catabolized by the normal dog still more rapidly. The catabolism of prothrombin was not accelerated in 3 dogs receiving continuous infusions of a thromboplastic emulsion of dog brain. Nor was the level of prothrombin in their plasma remarkably altered.

Prothrombin Quick. A newly identified dysprothrombinemia.

The rarest of reported inherited plasmatic coagulopathies involve prothrombin. Only 10 families with significant reductions of this plasma protein (hypoprothrombinemia) have been observed. Even fewer, six families, have been found to have a functionally abnormal prothrombin (dysprothrombinemia) in their blood. An as yet undefined prothrombin abnormally has been recognized in eight other families. One of the first patients previously identified by Quick and his associates as having a defect in her plasma prothrombin has been shown to have about half the normal amount of prothrombin antigen but virtually no prothrombic function. We propose that this dysprothrombin be designated prothrombin Quick. An additional patient also first described by Quick was found to be truly hypoprothrombinemic--that is, to lack both functional and antigenic prothrombin. Briefly summarized are the other five families with dysprothrombinemia, nine with hypoprothrombinemia, and the eight in whom the defect has not been classified.

Hypocomplementemic urticarial vasculitis: association with chronic obstructive pulmonary disease.

Since 1973, we have identified and collected follow-up data on 16 patients with hypocomplementemic urticarial vasculitis. Preliminary diagnostic criteria are the presence of typical urticarial skin lesions and low levels of serum complement (all components), plus two of the following: dermal venulitis, arthritis, glomerulo-nephritis, episcleritis or uveitis, recurrent abdominal pain, and C1q precipitin in plasma. Exclusions are systemic lupus erythematosus, mixed cryoglobulinemia, elevated antinuclear antibody titer, hereditary deficiency of a complement component or of C1 esterase inhibitor, and presence of anti-native DNA or hepatitis B antigen. The renal involvement is relatively benign, and generally the patients do well and respond to specific treatment when this is indicated. Eight of 10 smokers studied had evidence of chronic obstructive pulmonary disease, 1 of whom died of this complication. In three patients, severe chronic obstructive pulmonary disease developed at a young age after relatively low pack-year cigarette smoking histories. Lung disease probably results from the interaction of two major risk factors-smoking and an immunologically mediated process that has not been identified.

Immunologic mechanisms in systemic vasculitis.

Thirty-four patients with systemic vasculitis were studied to determine the possible type and frequency of associated immunologic abnormalities. The patients were divided into three clinical groups--those with systemic vasculitis without respiratory tract involvement, those with systemic vasculitis with respiratory tract involvement (particularly Churg-Strauss vasculitis and Wegener's granulomatosis), and those with limited vasculitis without visceral involvement. A diminished level of serum complement was found in half the patients with systemic vasculitis without respiratory tract involvement. These patients usually had diffuse skin disease that often was associated with the presence of rheumatoid factor and cryoglobulinemia and most likely represented an immune-complex induced disease. The serum IgE often was elevated in patients who had systemic vasculitis with respiratory tract involvement, particularly those with Churg-Strauss vasculitis and Wegener's granulomatosis, and may be a clue to the pathogenesis in this group of patients.

In vivo platelet survival in rheumatoid arthritis.

We studied the in vivo consumption of chromate-labeled platelets in 14 patients with active rheumatoid disease and demonstrated shortened platelet survival in 8. We were unable to find significant relationships between diminished platelet survival and clinical features (including vasculitis), the presence of circulating immune complexes (as measured by both a monoclonal rheumatoid factor and the Raji cell assays), the presence of intravascular coagulopathy with fibrinolysis (as measured by the protamine gel test), other laboratory variables commonly obtained in rheumatoid patients, or various drug regimens.

Development of photosensitivity and an SLE-like syndrome in a patient with psoriasis.

An unusual case of photosensitive psoriasis and systemic lupus erythematosus-related syndrome was characterized by erythroderma, chronic urticaria, angioneurotic edema, intermittent low-grade fever, and polyarthralgias. Investigation revealed no measurable total hemolytic complement and markedly diminished levels of C4, C2, and C3. Microscopic examination of three skin biopsy sections of sun-exposed skin showed psoriasis. Skin biopsy sections of sun-exposed psoriatic plaques and of non-sun-exposed, uninvolved skin (which were stained with fluorescein-tagged anti-IgG, anti-IgM, anti-IgA, and anti-C3) showed granular deposits of IgM and C3 at the dermal-epidermal junction in the sun-exposed plaques, and IgM alone in a granular pattern at the dermal-epidermal junction in uninvolved skin. Antibodies to single-stranded but not double-stranded DNA were detected in the patient's serum. In addition, serum immune complex-like material was detected by sucrose density-gradient ultracentrifugation, standard anticomplementary assays, and radioimmunoassays using both C1q and monoclonal rheumatoid factor.

C2 deficient systemic lupus erythematosus: its association with anti-Ro (SSA) antibodies.

C2 deficiency is the most common complement component deficiency. While individuals with C2 deficiency may be completely normal, a lupus erythematosus-like disease process has developed in some. A 28-year-old woman had a chronic photodermatitis, arthralgias, and mesangial lupus nephritis, She has C2 deficiency associated with an HLA-Dw2 transplantation antigen. Her serum has shown antibodies to the macromolecule Ro (the A antigen in Sjögren's syndrome), while failing to demonstrate antinuclear antibodies in routine laboratory determinations.

The role of the Arthritis Foundation in training of rehabilitation research manpower.

In 1973 the Arthritis Foundation established a research training program for nonphysician health professionals in fields related to nonmedicinal care such as physical therapy, occupational therapy, psychology and health education. This program is primarily designed for individuals performing the research involved in a predoctoral program. For trained investigators in this field the Foundation offers a research grants program as well.

The use of long-acting drugs in the treatment of rheumatoid arthritis.

Experience to date strongly indicates that long-acting drugs currently used in treatment of rheumatoid arthritis are very potent antiinflammatory agents which act in most cases by completely unknown mechanisms. All of them have built in but recognizable toxicity which can usually be prevented by appropriate monitoring. Although most of them offer relatively short term (up to 3 years) benefits, with the probable exception of methotrexate, nonetheless they can offer for a period of time improved function and relief of pain for many individuals. Thus, even though they do not dramatically affect the long-range outcome of the disease, they continue to offer useful benefit for patients with rheumatoid arthritis who are not responding to conservative therapy. Some of the long-acting agents are only slightly more toxic than the widely nonsteroidal antiinflammatory drugs which do have a definite risk of serious upper gastrointestinal bleeding. Currently the use of combinations as well as the continued introduction of new drugs in this class, offer hope that greater benefit than we can currently provide is within reach over the next few years.