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.

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.

Cigarette smoking and pulmonary diffusion defects in rheumatoid arthritis.

The pathogenesis of lung disease in rheumatoid arthritis (RA) has still to be defined. Risk factors associated with lung involvement in RA were investigated by means of pulmonary function studies in 40 RA patients without apparent lung disease. A decreased carbon monoxide (CO) diffusion capacity indicative of interstitial lung disease (ILD) was the main pulmonary function defect found in the first 20 patients. The occurrence was associated with current cigarette smoking. This association was confirmed in a case control study performed subsequently. These data suggest that ILD in RA is stimulated by smoking and provide an additional argument that modification of smoking behaviour in RA patients might lead to less severe complications.

Increased bone mass with pamidronate treatment in rheumatoid arthritis. Results of a three-year randomized, double-blind trial.

OBJECTIVES: Osteoporosis is a frequent complication of rheumatoid arthritis (RA). We therefore investigated the effect of oral pamidronate therapy as a specific bone-sparing agent in RA. METHODS: The study design was a 3-year randomized, double-blind trial of 300 mg oral pamidronate/day compared with placebo in 105 RA patients. Bone mineral density (BMD) measured at 12-month intervals was the primary efficacy parameter. RESULTS: In 3 years, lumbar spine and forearm BMD increased significantly in the pamidronate-treated group (by 8.4 +/- 6.9% [mean =/- SEMI] [P < 0.00011 and 5.2 =/- 6.5% [P < 0.005], respectively), compared with nonsignificant changes in the placebo-treated patients (increase of 0.6 =/- 5.2% and decrease of 1.2 =/- 5.8%, respectively). Femoral neck BMD increased in the pamidronate-treated group (by 2.6 =/- 8.6%) and decreased significantly in the placebo-treated group (by 4.0=/- 1.3% [P < 0.005]). The changes in BMD with time at all 3 measurement sites were significantly different between the treatment groups (P < 0.0001). Changes in radiographic signs of joint damage and in disease activity were similar in the 2 groups. CONCLUSION: The present study provides the first evidence that long-term treatment with an orally administered bisphosphonate overcomes bone loss and increases bone mass when compared with placebo. This finding may have significance with regard to the treatment of patients with RA.

Factors associated with the development of vasculitis in rheumatoid arthritis: results of a case-control study.

OBJECTIVE: To investigate those characteristics of patients with rheumatoid arthritis (RA) that are associated with the development of rheumatoid vasculitis (RV). METHODS: Demographic and clinical data of 69 patients who had been diagnosed as having RV were compared with those of 138 contemporaneous control patients with RA who were not suspected to have vasculitis. Vasculitis was confirmed histologically in 96% of the subjects with RV. RESULTS: Variables associated with the development of RV were: 1) male gender, presence of increased serum concentrations of rheumatoid factor, joint erosions, subcutaneous nodules, number of disease modifying antirheumatic drugs previously prescribed, treatment (ever) with D-penicillamine or azathioprine; 2) presence of nail fold lesions and any other extrarticular feature one year before the time of diagnosis of RV; 3) treatment with corticosteroids at the time of diagnosis of RV. CONCLUSIONS: The development of RV is associated with male gender, extra-articular features, and a severe course of RA as indicated by the presence of joint destruction and need for intensive treatment with antirheumatic drugs. The strongest association was found with the presence of increased concentrations of rheumatoid factor.

The mortality of rheumatoid vasculitis compared with rheumatoid arthritis.

OBJECTIVE: To determine whether the mortality of patients with rheumatoid vasculitis (RV) is increased in comparison with that of patients with rheumatoid arthritis (RA). METHODS: The mortality of all RV patients identified in 1980-1992 (n=61) was compared with that of 244 RA controls matched for the year the diagnosis was made in the RV cases. Hazard ratios (HR) of death were calculated with a multivariate survival analysis, adjusting for age, sex, comorbidity, treatment, and parameters of RA severity. RESULTS: The unadjusted risk of death (HR) in RV patients compared with RA controls was 1.65 (95% confidence interval [95% CI] 1.05-2.58). After adjustment for prognostic factors, the HR was reduced to 1.26 (95% CI 0.79-2.01), mainly due to removal of the effects of age and sex. No excess mortality was seen in RV patients with severe organ involvement when compared with RV patients without severe organ involvement, although the former patients were treated more often with cytostatic and immunosuppressive drugs. Infection was the main cause of death in the RV patients, and cardiovascular disease in the RA controls. Vasculitis was reported as the cause of death in only 1 RV patient. CONCLUSION: After allowance for general risk factors such as age and sex, there remains only a slight excess mortality in RV patients compared with RA controls.

Technetium-99m labelled polyclonal human IgG scintigraphy before and 26 weeks after initiation of parenteral gold treatment in patients with rheumatoid arthritis.

OBJECTIVE: To determine effectiveness of technetium-99m labelled polyclonal human immunoglobulin G (99mTc-IgG) scintigraphy to monitor variation in arthritis activity in patients with rheumatoid arthritis (RA). METHODS: The results of semiquantitative 99mTc-IgG scintigraphy were compared with those of examination before and 26 weeks after initiation of parenteral gold treatment in 19 patients with RA. RESULTS: Clinical and laboratory variables of arthritis activity as well as the scores of 99mTc-IgG scintigraphy were significantly lower after gold treatment compared to the scores before treatment. However, the difference between the mean scores of 99mTc-IgG scintigraphy before and after treatment was statistically significant for more joints than such difference in scores for joint pain and joint swelling. CONCLUSION: 99mTc-IgG scintigraphy is able to reflect variations in arthritis activity in patients with RA.

Value of 99mTc-IgG scintigraphy in the prediction of joint destruction in patients with rheumatoid arthritis of recent onset.

The ability of technetium-99m-labelled polyclonal human immunoglobulin G (99mTc-IgG) scintigraphy to predict joint destruction in patients with rheumatoid arthritis (RA) was investigated in this study. The progression of radiographically determined joint destruction in wrists, hands and feet was compared with the results of physical and laboratory examination, as well as 99mTc-IgG scintigraphy, measured at the beginning of a year-long study on 30 patients with RA of recent onset. The sensitivity of joint swelling in predicting the progression of radiographically determined joint destruction ranged between 57% and 74%. The sensitivity of 99mTc-IgG scintigraphy ranged between 71% and 100%. The specificity and positive predictive value both of joint swelling and 99mTc-IgG scintigraphy were low. Multiple regression analysis showed that for the total joint score, and for the metacarpophalangeal and forefeet joints, progression of radiographically determined joint destruction was primarily predicted by 99mTc-IgG scintigraphy. Joint swelling, ESR and IgM rheumatoid factor did not contribute to this prediction. We concluded that 99mTc-IgG scintigraphy is superior to conventional clinical and laboratory measurements in RA with respect to prediction of joint destruction.

[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.

Bone metabolism in rheumatoid arthritis; relation to disease activity.

Biochemical parameters of bone metabolism were investigated in 105 ambulant, non-steroid treated patients with RA and compared with parameters of disease activity. Urinary calcium (Ca) and hydroxyproline (OHP) excretions, as parameters of bone resorption and serum alkaline phosphatase (AP), as a parameter of bone formation, were positively related to parameters of disease activity. Serum osteocalcin, another parameter of bone formation, was not related to parameters of disease activity. Patients with active disease (ESR > or = 28 mm and Ritchie articular index > or = 8) had a significant higher urinary Ca and OHP excretion (62 and 42% higher, respectively) than patients with inactive disease. Serum AP and OC were slightly higher (19 and 16%, respectively) in patients with active disease. These results suggest that in RA patients bone metabolism is related to disease activity. In active disease bone resorption seems to be increased more than bone formation, suggesting that prolonged disease activity may contribute to generalized and/or localized osteopenia.

99mTc human immunoglobulin scintigraphy--a reliable method to detect joint activity in rheumatoid arthritis.

The ability of 99mtechnetium labelled nonspecific, polyclonal human immunoglobulin G (99mTc-IgG) scintigraphy to depict and quantify synovial inflammation was studied in 30 patients with rheumatoid arthritis (RA). All patients were injected with 350 MBq 99mTc-IgG and imaging was performed 4 h later. This resulted in excellent images of inflamed synovium. Scores for 99mTc-IgG joint scintigraphy correlated highly with scores for joint swelling and C-reactive protein levels, weakly with pain scores and not with radiographic scores of joint destruction. These results suggest that 99mTc-IgG joint scintigraphy may provide an objective test to detect synovitis and measure the activity of the disease.

[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.

Anti-neutrophil cytoplasmic autoantibodies in patients with symptomatic HIV infection.

Antibodies against cytoplasmic antigens of neutrophils, producing perinuclear (p-ANCA) as well as cytoplasmic staining with central accentuation (c-ANCA), have been described in non-HIV-infected patients with specific pathology such as glomerulonephritis and vasculitis. Here, we report on a patient with a vasculitis-like syndrome and a positive ANCA-test who appeared to be infected by HIV. Further analysis revealed that ANCA, p-ANCA as well as c-ANCA without central accentuation can be demonstrated in the serum of HIV+ individuals. In a cross-sectional study on individuals in different stages of HIV infection, we found that the occurrence of ANCA was limited to the symptomatic stages of HIV infection: p-ANCA was found in one out of 10 ARC patients and in two out of 11 AIDS patients with malignancies (AIDS-MAL), but not in AIDS patients with opportunistic infections (AIDS-OI). c-ANCA was found in four of the ARC patients, in two of the 14 AIDS-OI patients and in two AIDS-MAL patients. The presence of ANCA was not related to the degree of hypergammaglobulinaemia nor to specific symptomatology. ANCA containing sera from HIV+ individuals did not react with HEp2 cells nor with cytoplasmic antigens of lymphocytes, natural killer (NK) cells or eosinophils. Five out of the 11 (two p-ANCA and three c-ANCA) sera reacted weakly with cytoplasmic antigens of monocytes. All sera reacted with karyoplasts but not with cytoplasts prepared from neutrophils. These results suggest that HIV-ANCA might be directed against myeloid cell-specific granule constituents. However, sandwich-ELISAs with MoAbs against granule antigens that are frequently the target antigens of ANCA in HIV- individuals were negative. Also immunoprecipitation and immunoblotting, using lysates of neutrophil granules, did not allow further identification of the target antigens of HIV-ANCA.

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.

Uptake and degradation of soluble aggregates of IgG by monocytes of patients with rheumatoid arthritis: relation to disease activity.

Monocytes from patients with rheumatoid arthritis (RA) and rheumatoid vasculitis have a diminished ability to degrade soluble complexes of aggregated IgG in the absence (mediated by Fc receptors) as well as in the presence of complement (C) (mediated by (Fc + C) receptors). To investigate whether a relation exists between the receptor mediated degradation of aggregated IgG by adherent monocytes and disease activity a longitudinal study was performed in 79 patients with RA and rheumatoid vasculitis over a period of 16 months. Adherent monocytes were incubated in vitro with 125I labelled IgG aggregates of restricted size in the absence or presence of fresh serum and the percentage of catabolised IgG aggregates was measured. Cross sectionally the degradation of aggregated IgG by monocytes, mediated by Fc and (Fc + C) receptors, correlated significantly with disease activity as scored by the Ritchie articular index, the presence of extra-articular features, and circulating immune complexes. A high number of Fc receptors on monocytes correlated with diminished degradation, whereas high numbers of complement receptors 1 and 3 correlated with enhanced degradation of aggregated IgG mediated by both Fc and (Fc + C) receptors. The degradation of aggregated IgG by monocytes did not correlate with disease activity in individual patients followed up longitudinally. When patient groups were formed according to the results of longitudinal studies, however, degradation of aggregated IgG mediated by Fc and (Fc + C) receptors was significantly decreased in patients with rheumatoid vasculitis and in patients with active RA in comparison with patients with inactive RA and healthy controls. Patients with active RA and rheumatoid vasculitis also expressed significantly more Fc receptors and less complement receptors on the monocytes than patients with inactive RA. Drug treatment did not correlate with receptor expression or the degradation of aggregated IgG by monocytes either in cross sectional or longitudinal studies. It is concluded that in RA disease activity is related to receptor expression and the degradation of soluble immune aggregates by monocytes.

IgG autoantibodies against C1q are correlated with nephritis, hypocomplementemia, and dsDNA antibodies in systemic lupus erythematosus.

We investigated the association between serum titers of IgG antibodies against C1q (C1qAb) and clinical and laboratory variables of disease activity in systemic lupus erythematosus (SLE). C1qAb were measured by ELISA in serum samples of 88 patients. Thirty patients (34%) had increased C1qAb titers. No correlation between C1qAb titers and a score for general disease activity was found. However, significant positive correlations were found between C1qAb titers and the presence of several clinical and laboratory variables of disease activity. These included nephritis, dermatitis, hypocomplementemia, antibodies against dsDNA, and circulating immune complexes. A negative correlation was found with neurological disease manifestations. The correlations between C1qAb titers and clinical features indicate that the pathogenetic role for C1qAb in certain disease manifestations of SLE deserves further study.