A decrease in disease activity score (DAS) level is associated with a decrease in health assessment questionnaire (HAQ) score, independent of follow-up duration, during 5 years of tightly controlled treatment: results from the BeSt study.

OBJECTIVE: To assess the relationship between a decrease in disease activity score (DAS) and functional ability during 5 years of DAS-steered treatment in recent-onset rheumatoid arthritis (RA) patients, taking into account absolute DAS levels and follow-up duration. METHODS: Data from the BeSt study were used, in which treatment was aimed at achieving DAS ≤2.4. The longitudinal relationship between 3-monthly measured DAS and health assessment questionnaire (HAQ) score was assessed using linear mixed modelling during 5 years of treatment, with DAS and HAQ 3 months earlier, change in DAS in last 3 months (delta DAS), time (log-transformed) and their interactions as determinants. RESULTS: Predictors for HAQ were: previous DAS, delta DAS, ln time, the interaction previous DAS×delta DAS, and previous HAQ. The interaction ln time×delta DAS was non-significant, indicating that the association between delta DAS and HAQ was independent of follow-up duration. A decrease from a higher DAS was associated with a smaller HAQ decrease than for a similar decrease from a lower DAS, indicating a non-linear relationship between DAS and HAQ. CONCLUSION: At any time during 5 years of follow-up, a decrease in DAS was associated with a better functional ability. The magnitude of HAQ improvement depends on the DAS decrease and on the absolute DAS level.

Prednisone plus azathioprine treatment in patients with rheumatoid arthritis complicated by vasculitis.

The therapeutic effect of prednisone combined with azathioprine was studied in 28 patients with rheumatoid vasculitis. Nine patients with severe systemic vasculitis were treated initially with 60 mg of prednisone and 2 mg/kg of body weight of azathioprine daily. Clinical signs of vasculitis decreased in all patients. Nineteen patients with only cutaneous vasculitis entered a randomized controlled study comparing prednisone plus azathioprine treatment vs continuation of various conventional antirheumatic drugs. Although measures of both vasculitis and arthritis activity improved to a greater degree in the patients treated with prednisone plus azathioprine in the first 3 months of therapy, no significant differences between the results of the two treatments were observed at the end of the follow-up period. Prednisone plus azathioprine treatment was associated with a low incidence of relapse of vasculitis, few serious complications, and a relatively low mortality. We conclude that the combination of prednisone and azathioprine is effective in the treatment of severe systemic rheumatoid vasculitis; rheumatoid vasculitis with only cutaneous manifestations has a relatively good prognosis, and there is probably no indication for therapy specifically directed at the vasculitic process.

Association of rheumatoid factors in renal transplant recipients with cytomegalovirus infection and not with rejection.

Because rheumatoid factors (RF) were detected in the circulation of the majority of early renal transplant recipients and could be eluted from rejected transplants, RF were hypothesized to be related to antibody responses to the histoincompatible graft. The possibility that RF production might have been related to infection and not rejection has not been considered previously. Therefore, we investigated serial serum samples from 147 adult renal transplant recipients for RF with latex agglutination and radioimmune assays. RF were detected in the sera of 32 patients, 30 of whom had coincident active cytomegalovirus (CMV) infections. Another 45 patients with active CMV infections did not have detectable circulating RF. In contrast, of 74 patients who experienced a total of 103 treated reversible or irreversible rejection episodes in the absence of evidence of active CMV infections, only 2 patients produced RF during their rejection episodes. Nine of the patients who did not produce RF during a rejection episode subsequently produced RF during a later CMV infection. These data indicate that RF production in renal transplant recipients is associated with CMV infection and not rejection. Moreover, RF production was found to be more frequently associated with primary and severe CMV infections than with secondary or milder CMV infections. RF production was not more frequent in patients who were HLA-DR-4-positive., older, or female, characteristics that have been associated with RF production in other populations. All of the sera with detectable RF contained IgM antibodies that were directed to the Fc portion of human IgG, and about half contained additional IgM antibodies directed to Fab. Thus CMV infections may be the stimuli for the IgM anti-Fab antibodies that have been reported in pretransplant serum samples. Eleven patients produced IgG or IgA RF in addition to IgM RF during CMV infections.

Perivascular deposits of IgM in the skin of transplant recipients during active cytomegalovirus infections. Correlation with IgM rheumatoid factors and IgM immune complexes.

Skin biopsies from 30 renal transplant patients were investigated for cellular infiltrates and deposits of IgM, IgA, IgG, C3, and C5-9 neoantigen. Granular perivascular deposits of IgM were detected in biopsies of 8 of 14 patients during active cytomegalovirus (CMV) infections and in none of 16 controls. In 5 biopsies, the IgM deposits were accompanied by little or no IgG, IgA, or C, while in 3 biopsies definite C3 deposits were present. One of the biopsies with C3 deposits also had C5-9 deposits and another had C5-9 and IgA deposits. Three monoclonal antibodies failed to detect early or late nuclear antigens of CMV in the deposits. These deposits were not associated with clinically evident manifestations of vasculitis. A strong correlation was found between IgM deposits in the skin and IgM circulating immune complexes (CIC) and also IgM rheumatoid factor (RF). The deposition of IgM was not more frequent in primary than in secondary CMV infections, and it did not correlate with the production of IgM antibodies that were specific for CMV antigens.

Genetic heterogeneity of rheumatoid arthritis.

In a population survey in The Netherlands we investigated 6584 individuals for the presence of rheumatoid diseases and their determinants. We observed no overall association of rheumatoid arthritis (RA) with HLA-DR4 or GM. This result is in contrast to the marked association of HLA-DR4 with RA found in studies based mainly on hospital rheumatology clinics. The findings thus suggest a genetic basis for the disease heterogeneity. A study of 16 multicase RA families showed a co-segregation of RA with the DR4 carrying haplotype from the unaffected parent, whereas the non-DR4 haplotype was preferentially segregating to the healthy siblings (p = 0.001). These data suggest that HLA-DR4 is associated with disease susceptibility rather than with a disease modifying factor. In a further attempt to define a genetic basis for disease heterogeneity we compared five well-defined clinical groups of patients with RA. Although the frequency of HLA-DR4 was significantly elevated in all patient groups as compared to healthy controls, we observed a preferential association of HLA-DR4 with severe extra-articular manifestations as compared to patients without extra-articular manifestations (p = 0.002). These results provide an immunogenetical basis for the disease heterogeneity observed in RA and further extend the immunological analogy between RA and leprosy.

Membrane attack complex of complement in leukocytoclastic vasculitis of the skin. Presence and possible pathogenetic role.

The presence of the membrane attack complex of complement (MAC) was studied by a two-step immunofluorescence method in 15 patients with leukocytoclastic vasculitis of the skin, using an antibody against MAC neoantigen. Perivascular deposits of MAC were present in 13 specimens of lesional skin and only two specimens of clinically uninvolved skin, suggesting a possible pathogenetic role for MAC in the development of a skin lesion. Control studies were performed on the clinically normal skin of 15 individuals (11 patients with various nonbullous skin diseases and four healthy volunteers) and on skin lesions of seven patients with inflammatory skin diseases. In the clinically normal skin of only one patient, perivascular deposits of MAC were detected. This patient had rheumatoid arthritis and a cutaneous eruption due to the administration of aurothioglucose. We conclude that the activation of the terminal components of the complement system may play an important role in the formation of lesions in leukocytoclastic vasculitis of the skin, but is not an indispensable condition.

Humoral immunity and composition of immune complexes in patients with rheumatoid arthritis, with special reference to IgE-containing immune complexes.

IgE-containing circulating immune complexes (IgE-CIC) were determined with a 2.5% PEG-precipitation assay in 98 patients with classical or definite rheumatoid arthritis (RA). Of the 45 IgE-CIC positive sera, only 4 had elevated total serum IgE. IgE-CIC positive patients had more active disease than patients without IgE-CIC, as determined by their more swollen joints and higher Ritchie indices (p less than 0.04 and 0.02, respectively). Apart from IgE, other immunoglobulin isotypes, rheumatoid factor (RF) of the IgG-, IgA- and IgM-classes, C3 and antinuclear antibodies could be demonstrated in the IgE-containing PEG-precipitates. IgE-RF could not be demonstrated in serum or in IgE-CIC. Anti-IgE of the IgM-class (IgMaIgE) were frequently found (28/45 patients) in the IgE-positive PEG-precipitates. All 14 patients positive for IgGaIgE in the IgE-CIC were also positive for IgMaIgE in the CIC. As in the serum, there was a good correlation in the CIC between the level of IgGaIgE and the level of IgMaIgE (r = 0.64). The correlation between the respective levels of IgGaIgE and IgMaIgE in serum and in CIC was high (r = 0.93 and 0.79, respectively). On the other hand, only 1 patient was positive for IgAaIgE in the IgE-CIC. We conclude that IgE and aIgE of the IgM- and IgG-classes are frequently present in the immune complex form in RA and that they are correlated with the clinical activity of arthritis.

Rapidly progressive glomerulonephritis with glomerular crescent formation in rheumatoid arthritis.

Systemic vasculitis is a well-known complication of rheumatoid arthritis (RA). Rapidly progressive glomerulonephritis is commonly associated with vasculitis syndromes but rarely found in RA. This report describes two RA patients with complicating systemic vasculitis who developed rapidly progressive glomerulonephritis with glomerular crescent formation. One recovered after treatment with corticosteroids and cytostatic drugs and the other died of severe systemic vasculitis despite similar therapy.

IgE-containing immune complexes in synovial fluid of patients with rheumatoid arthritis.

The prevalence and composition of IgE-containing immune complexes in paired synovial fluid and serum of 42 patients with classical or definite rheumatoid arthritis were studied. IgE-containing immune complexes were found in 15/42 synovial fluids; 15 sera were also positive. The correlation between serum and synovial fluid complexed IgE levels was high (r = 0.77). The mean ratio of synovial fluid/serum levels was 1.96, i.e. significantly higher than 0.33, the synovial fluid/serum ratio for alpha-2-macroglobulin (molecular weight 820 kD), which was taken as high molecular weight control protein (p less than 0.0001). Apart from IgE in immune complex form, monomeric IgE was also significantly higher in synovial fluid compared to serum (ratio = 2.94). Other constituents which could be found in the immune complexes, i.e. anti-IgE antibodies, rheumatoid factors and anticollagen antibodies, were also higher in synovial fluid than predicted. Our results suggest intra-articular production of IgE-containing complexes in the synovial fluid, in addition to possible exudation of the complexes from the serum. These findings provide further evidence for the role of IgE-containing immune complexes in rheumatoid synovitis.

[Rheumatic disease as initial symptom of HIV infection]. / Een reumatisch ziektebeeld als eerste uiting van een HIV-infectie.

A 47-year old man presented with general malaise, pain in several joints and muscles, lymphadenopathy, livedo reticularis, an elevated sedimentation rate and mild pancytopenia. A positive ANF, anticardiolipin antibodies and circulating immune complexes raised suspicion of an autoimmune disease. A perivascular infiltrate in muscle and fascia was found, but a specific diagnosis could not be made. The patient appeared to be infected with the human immunodeficiency virus (HIV) type I, with the cellular immunity already decreased. During treatment with zidovudine the symptoms and signs diminished, suggesting a causal relation between the HIV infection and this clinical presentation. The rheumatic manifestations and autoimmune phenomena with which HIV infection can be associated are discussed.

IgM immune complexes, lymphocytotoxins, and rheumatoid factors in renal transplant recipients with CMV disease.

In studying 127 consecutive adult recipients of cadaver renal transplants, we found that the 23 patients who developed CMV disease produced IgM immune complexes as measured by a polyethyleneglycol precipitation (PEG) assay which coincided with symptoms of their illness. In addition to anti-CMV antibodies, PEG precipitated apparently non-specific antibodies such as lymphocytotoxins and rheumatoid factor (RF). The lymphocytotoxins were IgM antibodies that were not directed against HLA antigens and lysed granulocytes as well as lymphocytes but not platelets at 22 degrees C. Lymphocytotoxin production was correlated with HLA-DR 3 and 7 and with graft dysfunction during the CMV disease. The RF also were predominantly IgM antibodies that were detectable for only 3-8 weeks. The production of RF coincided with the initial rise in IgG anti-CMV antibody activity and some reacted with the Fab fragments of IgG raising the possibility that they could modulate the cellular or humoral immune response to CMV. Patients with RF tended to have severe CMV infections with pneumonia and graft dysfunction.

[Comparison of azathioprine and methotrexate in rheumatoid arthritis: an open-randomized clinical study]. / Comparaison de l'azathioprine et du méthotrexate dans la polyarthrite rhumatoïde: une étude clinique ouverte randomisée.

Thirty-eight patients with active rheumatoid arthritis (RA) were entered in an open randomized 24-week study comparing azathioprine (AZA; initial daily dose 1 mg/kg) with methotrexate (MTX; initial weekly dose 7.5 mg). The patients had previously been treated with antimalarials, gold salts and/or D-penicillamine. The groups were well balanced in baseline characteristics. There were three premature withdrawals in each group, all of which were due to toxicity. The present study did not show any significant differences between AZA and MTX in ability to reduce activity in RA after 24 weeks of treatment.

Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): A randomized, controlled trial.

OBJECTIVE: Several treatment strategies have proven value in the amelioration of rheumatoid arthritis (RA), but the optimal strategy for preventing long-term joint damage and functional decline is unclear. We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies, with intense monitoring in all patients. METHODS: In a multicenter, randomized clinical trial, 508 patients were allocated to 1 of 4 treatment strategies: sequential disease-modifying antirheumatic drug monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with tapered high-dose prednisone (group 3), and initial combination therapy with the tumor necrosis factor antagonist infliximab (group 4). Treatment adjustments were made every 3 months in an effort to obtain low disease activity (a Disease Activity Score in 44 joints of < or =2.4). RESULTS: Initial combination therapy including either prednisone (group 3) or infliximab (group 4) resulted in earlier functional improvement than did sequential monotherapy (group 1) and step-up combination therapy (group 2), with mean scores at 3 months on the Dutch version of the Health Assessment Questionnaire (D-HAQ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 (P < 0.001). After 1 year, mean D-HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 (P = 0.009). The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0, 2.5, 1.0, and 0.5 in groups 1-4, respectively (P < 0.001). There were no significant differences in the number of adverse events and withdrawals between the groups. CONCLUSION: In patients with early RA, initial combination therapy including either prednisone or infliximab resulted in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy.

Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial.

OBJECTIVE: Several treatment strategies have proven value in the amelioration of rheumatoid arthritis (RA), but the optimal strategy for preventing long-term joint damage and functional decline is unclear. We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies, with intense monitoring in all patients. METHODS: In a multicenter, randomized clinical trial, 508 patients were allocated to 1 of 4 treatment strategies: sequential disease-modifying antirheumatic drug monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with tapered high-dose prednisone (group 3), and initial combination therapy with the tumor necrosis factor antagonist infliximab (group 4). Treatment adjustments were made every 3 months in an effort to obtain low disease activity (a Disease Activity Score in 44 joints of < or =2.4). RESULTS: Initial combination therapy including either prednisone (group 3) or infliximab (group 4) resulted in earlier functional improvement than did sequential monotherapy (group 1) and step-up combination therapy (group 2), with mean scores at 3 months on the Dutch version of the Health Assessment Questionnaire (D-HAQ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 (P < 0.001). After 1 year, mean D-HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 (P = 0.009). The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0, 2.5, 1.0, and 0.5 in groups 1-4, respectively (P < 0.001). There were no significant differences in the number of adverse events and withdrawals between the groups. CONCLUSION: In patients with early RA, initial combination therapy including either prednisone or infliximab resulted in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy.

The detection of circulating immune complexes containing immunoglobulin G.

An immune complex assay using radiolabelled immunospecific antibodies against human IgG and polyethylene glycol precipitation (IgG-PEG assay) is described. The material reactive in this assay was evaluated using aggregated immunoglobulins, immune complexes prepared in vitro, sera of patients with a variety of disorders and normal human serum. Sucrose density gradient ultracentrifugation showed that only large-sized immune complexes (greater than 25 S) were detected. Comparison of the results of the IgG-PEG assay with those of the C1q binding assay showed a highly significant positive correlation (p less than 0.001). It was found that rheumatoid factors do not influence the results of the IgG-PEG assay. The method described in this study detects specifically immune complexes containing IgG and might be extended to the detection of other constituents of circulating immune complexes.

Rheumatoid arthritis--the clinical significance of histo- and immunopathological abnormalities in normal skin.

Biopsies of normal skin from 64 patients with rheumatoid arthritis (RA) were studied for histological abnormalities in dermal blood vessels. Thirty percent of patients had a moderate or dense infiltrate of mononuclear cells (predominantly T lymphocytes) around the vessel walls not seen in controls. This infiltrate correlated with disease activity and the presence of extraarticular manifestations. Vascular deposits of IgM often with C3 were seen in seropositive patients only and correlated with the amount of cellular infiltrate. No Ig and C deposits were seen in biopsies of seronegative patients and healthy controls. Apart from IgM and C3, IgG and/or IgA were found perivascularly in the areas of skin with leukocytoclastic vasculitis, indicating participation of other classes of immunoglobulins in immune complexes. The histological and/or immunopathological features that we found in uninvolved skin may serve as markers of disease activity and extraarticular manifestations.

IgA containing immune complexes in rheumatoid vasculitis and in active rheumatoid disease.

Serum and synovial fluid (SF) from 68 patients with rheumatoid arthritis (RA) were studied for the presence of immune complexes (IC) and the results correlated with extraarticular features and/or disease activity. IC were measured by the 125I Clq binding assay (ClqBA) and with one detecting IgG, IgA, C3 or C4 in IC. Disease activity correlated significantly with IgG or IgA containing and Clq binding IC. The IgA containing IC were found only in 25% of the patients, including all but one case of rheumatoid vasculitis, but otherwise only in seropositive active RA. C3 and C4 IC did not correlated with disease activity, seropositivity or vasculitis. IC in serum did not correlate with SF levels, but C4 containing IC were more frequent in SF (60%) than in serum (30%). Thus serum IC did not reflect SF levels. Patients with vasculitis showed more IC in the sera than in SF.

Comparison of immune complexes and complement components in arterial and venous blood of patients with rheumatoid arthritis.

Immune complexes (IC) are frequently found in the venous blood and synovial fluid of patients with rheumatoid arthritis (RA). Although IC are claimed to have a pathogenetic role in RA, there is generally poor correlation between different IC tests and between individual tests and clinical features. We have therefore sought differences in the levels of IC detected by the Clq binding assay (ClqBA) and the indirect polymorphonuclear phagocytosis test (IPPT) in the arterial and venous blood of 16 patients with RA and 6 disease control subjects to determine which IC are pathogenetically important. Complement components, IgA, IgG, and rheumatoid factor were also measured. Eight of 10 patients with clinically active RA had higher ClqBA results in arterial blood while IgA IC in the IPPT and most complement components were higher in venous blood. No such differences were seen in patients with inactive RA or controls. These results suggest that IC other than those containing IgA are not formed in limb tissues including the synovium and may explain the variable results previously seen in patients with RA.