Measurement characteristics of a new rapid anti-CCP2 test compared to the anti-CCP2 ELISA.

OBJECTIVE: Anti-cyclic citrullinated peptide (CCP)2 antibody status is an important diagnostic tool in the work-up of undifferentiated arthritis (UA)/early rheumatoid arthritis (RA) but the results of the enzyme-linked immunosorbent assay (ELISA) are only available a few days after the test. The aim of this study was to assess the measurement characteristics of a rapid anti-CCP2 test compared to the usual anti-CCP2 ELISA test. METHODS: In the first phase, rapid anti-CCP2 (CCPoint) tests were performed in capillary blood obtained by finger puncture (CAP), in venous blood from a clot tube (CLOT) and in serum (SERUM) in consenting RA patients. Anti-CCP2 measured in serum using the anti-CCP2 ELISA (ELISA) was set as the gold standard (reference). In the second phase of the study, specificity versus RA was confirmed in consenting non-RA patients and healthy controls. The anti-CCP2 results were negative (no visible line or anti-CCP2<25 U/mL) or positive (visible line or anti-CCP2> or =25 U/mL). RESULTS: A total of 880 subjects (109 RA patients, 351 non-RA patients and 420 healthy controls) were enrolled in this study. For the RA patients, 5%, 15%, and 1% of CAP, CLOT and SERUM tests, respectively, were inconclusive. The sensitivity and specificity of CAP compared with ELISA were 95% (95% CI 90-100) and 95% (95% CI 89-100), respectively, and the corresponding values for SERUM were 97% (95% CI 93-100) and 98 (95% CI 94-100). The specificity for RA versus non-RA and healthy controls was 99% (95% CI 97-100) and 99% (95% CI 98-100), respectively. CONCLUSION: The CCPoint test is a fast, valid and reliable anti-CCP2 test in both capillary blood and serum but not directly in venous blood.

Observational study on efficacy, safety, and drug survival of anakinra in rheumatoid arthritis patients in clinical practice.

BACKGROUND: The efficacy and safety of anakinra, a recombinant human interleukin 1 (IL1) receptor antagonist used in rheumatoid arthritis, has been documented in five randomised controlled studies. However, long term post-marketing efficacy data are lacking. OBJECTIVE: To evaluate the efficacy, safety, and drug survival of anakinra in clinical practice. METHODS: All patients with rheumatoid arthritis who started anakinra in six hospitals between May 2002 and February 2004 were included in a two year prospective, in part retrospective, cohort study. Efficacy was assessed using the 28 joint disease activity score (DAS28) and the EULAR response criteria. Safety was evaluated using the common toxicity criteria. Drug survival and prognostic factors were analysed using Kaplan-Meier and Cox proportional hazard analyses. RESULTS: After three months, 55% of the patients (n = 146) showed a response (43% moderate, 12% good). A subset of patients continuing anakinra after 18 months had a sustained clinical response compared with patients who switched to other disease modifying antirheumatic drug treatment (DAS28 improvement, 2.46 v 1.79). Drug survival was 78%, 54%, and 14% after three, six, and 24 months, respectively. The reason for discontinuation was lack of efficacy in 78% and adverse events in 22%. Except for higher drug survival in women (odds ratio = 0.51, 95% confidence interval, 0.27 to 0.97), no prognostic factors were found. Adverse events were reported 206 times in 111 patients, the most common being injection site reactions (36%). Serious adverse events occurred in 12% of the patients, with one classified as related. CONCLUSIONS: The short term efficacy and safety profile of anakinra are comparable to those found in randomised clinical studies. However, the drug survival of anakinra after two years is low, mostly because of lack of efficacy.

Radiological and clinical results of longterm treatment of rheumatoid arthritis with methotrexate and azathioprine.

OBJECTIVE: To study whether the reported superior effect of methotrexate (MTX) compared to azathioprine (AZA) in retarding radiologic progression after one year in rheumatoid arthritis was sustained at 2 and 4 years. METHODS: All 64 patients enrolled in the original randomized double blind study were invited for an open extension of followup to 4 years including 4-monthly clinical and laboratory assessments and radiographs of hands, wrists, and feet at 2 and 4 years. RESULTS: After 4 years, 18 patients (58%) from the MTX group and 7 patients (21%) from the AZA group continued the initial study drug. During followup more patients (n = 21) switched from AZA to MTX than vice versa (n = 5). In an intention-to-treat analysis improvement of clinical and laboratory variables at 4 years was more pronounced in the MTX group. Mean radiologic scores increased in both treatment groups during followup. According to an intention-to-treat analysis increase in erosion score at one and 2 years in the MTX group was significantly lower than in the AZA group: after one year MTX group 1.8 versus AZA group 5.3 (p = 0.002); after 2 years MTX 3.5 versus AZA 6.5 (p = 0.05). After 4 years there was a trend toward less progression in the MTX group: MTX 6.8 versus AZA 10.8 (p = 0.09). For the total score, progression in the MTX group was less after one and 2 years. After 4 years marked radiologic progression was observed more often in the AZA group. CONCLUSION: Drug continuation after 4 years of followup was better for MTX than for AZA. In an intention-to-treat analysis the beneficial effect of MTX on radiologic progression compared with AZA was sustained after 2 years of followup. Thereafter differences between treatment groups leveled off, probably mainly due to the greater number of switches from AZA to MTX than vice versa.

Post-streptococcal reactive arthritis: a clinical and serological description, revealing its distinction from acute rheumatic fever.

OBJECTIVE: To follow-up prospectively patients with arthritis after infection with beta-haemolytic streptococci of Lancefield group A (beta HSA), with emphasis on clinical characteristics and serological features. We additionally investigated whether these patients, though often fulfilling the Jones' criteria for acute rheumatic fever (ARF), had a disease with clinical characteristics different from ARF. DESIGN: We performed a systematic prospective observational study of consecutive patients at a Dutch Outpatient Clinic and Department of Rheumatology, with arthritis after throat infection with beta HSA presenting to rheumatologist or internist from September 1992 until September 1996. Main outcome measures were clinical and biochemical characteristics with special reference to carditis. RESULTS: A total of 23 patients (21 Dutch, two Turkish; female/male ratio 15/8; mean (SD) age 42 (14) years) with predominantly non-migratory arthritis were included. A positive throat swab culture was obtained in 17%. All patients showed a significant rise of antistreptolysine-O (ASO; normal < 200 i.u. mL-1) and antideoxyribonuclease-B (anti-DNase-B; normal < 200 i.u. mL-1) titre. The mean (SEM) maximal ASO was 1305 (195) i.u. mL-1, and anti-DNase-B titre 980 (115) i.u. mL-1. Arthritis was present in mean (SEM) 5.4 (0.9) joints: 2.2 (0.7) small, 3.2 (0.4) larger joints. The arthritis was monarticular in 23% of the patients, oligoarticular in 35%, and polyarticular in 43%. Skin abnormalities were present in 12 patients: erythema nodosum in seven patients (30%), and erythema multiforme in five patients (22%). A transient cholestatic hepatitis was found in four patients (17%). In two patients a transient first-degree conduction block was found; however, neither echocardiography nor clinical course supported carditis. All patients were advised to receive monthly penicillin prophylaxis during a period of 2 years. Two patients refused to follow medical advice: in one a non-migratory arthritis recurred 15 months after the first episode of arthritis. CONCLUSION: Commonly, arthritis secondary to beta HSA infection in the Netherlands, a prosperous West-European country with State Welfare, is not accompanied by carditis, contrary to literature on classical ARF. Other factors discriminating it from ARF are the age of onset, the non-migratory character of the arthritis, the high frequency of erythema nodosum and multiforme, as well as the presence of transient hepatitis. As arthritis is the hallmark of this syndrome, post-streptococcal reactive arthritis (PSRA) is the most proper name for this disease entity. Whether penicillin profylaxis is needed in PSRA, as it is in ARF, warrants further prospective investigation.

Antiperinuclear factor and disease activity in rheumatoid arthritis. Longitudinal evaluation during methotrexate and azathioprine therapy.

OBJECTIVE: To study the correlation between antiperinuclear factor (APF) titer and disease activity variables in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) or azathioprine (AZA) and to investigate whether changes are dependent on the drug used. METHODS: Serial measurements of APF titers (2-fold dilutions) and disease activity variables in a 48-week double blind trial comparing MTX and AZA in 64 patients with RA. APF titers at baseline and during followup, and correlations between APF titers and disease activity variables and their changes from baseline were studied in the patient group as a whole and in the 2 treatment groups. RESULTS: The prevalence of the APF at baseline in the MTX group and in the AZA group with undiluted serum was 15/31 (48%) and 19/33 (58%), respectively. With serum diluted 1:10 this was about 25% higher. The APF titer ranged from 1/10 to 1/640. No sustained changes in APF titers were observed during followup. Statistically significant correlations were found between APF titers and 2 of the 4 disease activity variables, as well as for their changes from baseline at some time points and were most pronounced in the AZA group. However, no consistent correlation between APF titers and disease activity variables could be established. APF changed from negative to positive during followup in 4 patients (6.3%) and from positive to negative in 4 (6.3%). Changes in APF titer between 2 consecutive measuring points did not exceed 2 dilution steps. CONCLUSION: The APF titer showed no sustained change during the followup period. There was no consistent correlation between APF titer and disease activity variables. We conclude that serial measurements of the APF in longitudinal studies do not give additional information.

Methotrexate: anti-inflammatory or immunosuppressive?

Low dose methotrexate (MTX) is an effective drug for rheumatoid arthritis, suppressing joint inflammation and even radiographic progression of joint disease. Some disease-specific side effects suggest an immunomodulatory effect of the drug. However, most data currently available suggest a mechanism of action at the level of the non-specific efferent arc of the immuno-inflammatory process rather than on T cells.

Accelerated nodulosis during low dose methotrexate therapy for rheumatoid arthritis. An analysis of ten cases.

OBJECTIVE: To obtain information on the occurrence of accelerated nodulosis during methotrexate (MTX) for rheumatoid arthritis (RA), localization, size and presence in heart and lungs of these nodules, predisposing factors, relationship with other extraarticular manifestations (EAM) and their histological features. METHODS: Ten patients with accelerated nodulosis were studied. Four participated in a double blind study of MTX and azathioprine. Patient characteristics, localization, size and histopathology of new nodules were determined. Echocardiography and chest roentgenograms were performed. RESULTS: Accelerated nodulosis occurred exclusively during treatment with MTX in our double blind study. The estimated incidence was 8%. One patient reported was rheumatoid factor negative. Newly developed nodules were small, and located in the fingers in all patients and in additional sites in 7. Pretreatment nodules were not found in the fingers. In one patient nodules on the mitral valve were found, but this was not likely to be associated with the use of MTX. No new pulmonary nodules were found. Other EAM developed concurrently in 4 patients. Histopathology revealed typical rheumatoid nodules. In 3 patients nodulosis regressed after MTX was stopped. In 2 of them they recurred after a rechallenge. CONCLUSIONS: Accelerated nodulosis during MTX for RA is not rare, and occurs despite good clinical response of polyarthritis. Rheumatoid factor positivity is not a prerequisite. New nodules are small and preferentially located in the fingers. Recurrence after rechallenge with MTX suggests causality.

Neuromuscular hyperexcitability features in patients suffering from musculoskeletal pain: a neuroepidemiologic survey.

We studied the reported frequencies of clinical complaints of neuromuscular hyperexcitability (muscle cramps and fasciculations) in random samples of 527 Dutch adults, who were and 253 Dutch adults, who were not suffering from musculoskeletal pain and tenderness. Data were collected by telephone-interview and by self-administered questionnaire. Muscle cramps and fasciculations were recorded more frequently in the category that suffered from musculoskeletal pain (p less than 0.001). This association warrants further investigation into the possible intrinsic role of neuromuscular hyperexcitability in musculoskeletal pain and primary fibromyalgia.

Methotrexate versus azathioprine in the treatment of rheumatoid arthritis. A forty-eight-week randomized, double-blind trial.

We conducted a double-blind, randomized trial comparing azathioprine (AZA) and methotrexate (MTX) in the treatment of patients with rheumatoid arthritis in whom parenteral gold and/or D-penicillamine treatment had been unsuccessful. Patients were randomly assigned to receive either AZA (100 mg daily) or oral MTX (7.5 mg weekly). After 8 weeks, the dosage was increased depending on the clinical improvement. Sixty-four patients were followed up for 48 weeks (33 AZA, 31 MTX). Comparison of values at week 24 with baseline values revealed significant improvement in 12 of 13 disease variables in the MTX group and in 6 of 13 in the AZA group. Comparison between the 2 treatment groups at 24 weeks, by area-under-the-curve analysis, showed significantly more improvement in the MTX group in terms of the swollen joint count, pain score, erythrocyte sedimentation rate, C-reactive protein level, hemoglobin level, thrombocyte level, and disease activity score. A significant overall clinical improvement (disease activity score) was found in 7 of 20 patients treated with AZA and 18 of 30 patients treated with MTX after 24 weeks of therapy, and in 6 of 12 AZA-treated patients and 19 of 25 MTX-treated patients after 48 weeks. The number of withdrawals due to side effects was significantly higher in the AZA group. After 48 weeks, only 12 patients from the AZA group (36%), but 25 from the MTX group (81%), were still using the initial drug. These results demonstrate MTX to be superior to AZA in the treatment of rheumatoid arthritis, with a more rapid clinical improvement which is sustained after 1 year, accompanied by a lower rate of serious adverse reactions.

Influence of methotrexate and azathioprine on radiologic progression in rheumatoid arthritis. A randomized, double-blind study.

OBJECTIVE: To compare the effects of azathioprine and methotrexate on progression of radiologic damage in patients with rheumatoid arthritis. DESIGN: Double-blind, randomized 48-week trial. PATIENTS: Sixty-four patients with active rheumatoid arthritis who either have not responded to or who have reacted with side effects to at least parenteral gold and D-penicillamine. INTERVENTIONS: Either azathioprine, 100 mg daily, or methotrexate, 7.5 mg weekly, was administered orally. Depending on the clinical effect after 8 weeks, the dosage was increased to either azathioprine, 150 mg, or methotrexate, 15 mg. The dosages for nonsteroidal anti-inflammatory drugs and prednisone were held stable. MEASUREMENTS: Clinical and laboratory assessments were done by the same physician every 4 weeks for the first 24 weeks and every 8 weeks thereafter. Radiographs of hands, wrists, and feet obtained at baseline and after 24 and 48 weeks were scored by one rheumatologist blinded to medication and clinical findings. MAIN RESULTS: Initial radiologic scores were comparable in both groups and correlated with disease duration (r = 0.38). An intention-to-treat analysis after 24 and 48 weeks showed significantly fewer new erosions in the methotrexate group compared with the azathioprine group (difference, 2.0 [95% CI, 0.2 to 3.9] and 3.5 [CI, 1.3 to 5.8], respectively). The change in total joint score was also significantly less pronounced in the methotrexate group compared with the azathioprine group after 24 weeks (difference, 2.8 [CI, 0.2 to 5.2]) and after 48 weeks (difference, 3.9 [CI, 0.3 to 7.4]). Radiologic stabilization after 48 weeks was present in 10% of the azathioprine group compared with 29% of the methotrexate group. CONCLUSIONS: Patients with rheumatoid arthritis treated with low-dose methotrexate showed significantly less radiologic progression than patients treated with azathioprine. This result suggests that methotrexate therapy is clinically superior in these patients.

Azathioprine induced fever, chills, rash, and hepatotoxicity in rheumatoid arthritis.

Within one year three of 25 patients with rheumatoid arthritis treated with azathioprine 100 mg daily developed the following adverse reactions less than two weeks after starting treatment: patient one showed fever with chills, rash, and severe liver function abnormalities suggestive of cholestasis; the second patient had fever, nausea, diarrhoea, and moderately raised liver enzymes; the third patient showed very high fever and severe chills. In two patients the drug was rechallenged, with more rapidly arising and more severe symptoms. In one case raised liver enzymes persisted until seven months after discontinuation of azathioprine. Hypersensitivity reactions and hepatotoxicity of azathioprine are discussed.

Methotrexate therapy in connective tissue diseases: a review of the literature.

Low dose methotrexate (MTX) therapy is now widely used with considerable success in refractory rheumatoid arthritis. Experience with the drug in other connective tissue diseases and vasculitis has been limited. This article reviews hypotheses about the mode of action of MTX, pharmacology and pharmacokinetics, reasons to use cytotoxic agents in the different diseases, and results of MTX therapy. Risk factors, adverse reactions and drug interactions of MTX with other drugs are mentioned. Although based on a small number of patients, data about remarkable clinical improvement in polymyositis, systemic lupus erythematosus and vasculitis suggest that MTX is a potent and effective drug in connective tissue diseases other than rheumatoid arthritis. However, controlled trials are needed to assess the exact value of the drug in these diseases.

Pancytopenia related to azathioprine in rheumatoid arthritis.

Two patients with rheumatoid arthritis developed pancytopenia during treatment with azathioprine 100 mg daily. In one patient this side effect occurred after three weeks, in the other after eight weeks of treatment. Rapid fall of platelets in one patient necessitated platelet transfusion. In the other patient additional treatment with allopurinol was probably responsible for the toxic effect. Haematological side effects of azathioprine are discussed.

Methotrexate in refractory rheumatoid arthritis.

Fourteen patients with severe rheumatoid arthritis refractory to hydroxychloroquine, gold-thioglucose, D-penicillamine and azathioprine completed a 6-month open study with oral methotrexate (2.5 to 5 mg every 12 hours, three doses weekly). Twelve of them were followed up for 12 months. Compared with pretreatment values, there was a significant reduction in duration of morning stiffness (p less than 0.01), in the number of tender or painful joints (p less than 0.02), number of swollen joints (p less than 0.01), visual analog scale, patient's assessment of joint discomfort and overall well-being (p less than 0.01) after 2, 6 and 12 months. Likewise there was an improvement in the erythrocyte sedimentation rate (p less than 0.001) C-reactive protein (p less than 0.01) and the levels of IgG, IgM and IgA (p less than 0.01). Two patients were withdrawn from the study, one for severe diarrhoea and one because of a depression. Adverse reactions during methotrexate therapy included nausea (5/16) and transaminase elevation (4/16). We conclude that this pilot study provides evidence that a weekly low dose of methotrexate is effective in the short-term treatment for patients with rheumatoid arthritis, refractory to hydroxychloroquine, auriothioglucose, D-penicillamine and azathioprine.