PATIENTS AND METHODS

Patients

Over a period of one month we examined patients with RA with active disease before and during treatment with etanercept. Five patients (four female, one male) were recruited from the medical outpatient department and gave informed consent before inclusion in our study.

All patients fulfilled the classification criteria of the American College of Rheumatology for RA and had active erosive disease at the wrist and at multiple metacarpophalangeal (MCP) and proximal interphalangeal joints of both hands.

In patients with active disease, despite combination treatment with at least two disease modifying antirheumatic drugs (DMARDs) (one of which was methotrexate) in appropriate doses and low dose corticosteroids, treatment was started with etanercept (2×25 mg/week subcutaneously). Methotrexate was continued except in one patient because of side effects. Other DMARDs were stopped at least four weeks before study entry. During the study the dose of oral corticosteroids was stable in two of the patients and could be reduced in three of the five patients (for patient data see also table 1). Application of intra-articular corticosteroids was not allowed. Table 1 shows the clinical data of the patients.

Clinical examination

Clinical activity of single finger joints was determined by an independent joint assessor who was not directly involved in the treatment of the patients. The degree of swelling and tenderness was assessed according to a modified index of synovitis activity in a single joint.¹⁰ The rheumatic disease activity index (RDAI) represents the mean value of the parameters swelling and tenderness on a scale from 0 to 3 (where 0 = no, 1 = moderate, 2 = strong, 3 = very strong), determined separately for each patient and each finger joint. Because the ultrasound examination focused only on the MCPII joint of the right hands, besides the total RDAI (referred to as RDAI_total, corresponding to the score of all small finger joints together) we also determined a single joint RDAI for the respective right MCPII joints, referred to as RDAI_II. In addition, a general subjective pain score was determined according to a standard visual analogue scale ranging from 0 (no pain) to 10 (very strong pain) referred to as “subjective pain score” (SPS_total).

Blood chemistry

During the study venous blood samples were drawn from each patient at several defined times (days 0, 8, 16, and 28) to determine the corresponding CRP values, blood sedimentation rates, and other routine parameters (with the exception of CRP values data not shown).

Ultrasound examination

Immediately after clinical examination, US was performed by an experienced radiologist who was not aware of the results of the clinical parameters obtained by the rheumatologists (that is, RDAI, SPS, and serum parameters). Each MCP joint was scanned longitudinally and transversely from the dorsal view, with the joint in 20° of palmar flexion and was documented in the longitudinal and transverse view in B mode and colour mode, as previously described.¹⁰ All data were saved in a digital archiving computer system (ALI UltraPACS; SEPP, Röttenbach, Germany).

In this study we used a Sonoline Elegra Advanced equipped with a multi-D linear array transducer (VFX 13–5, Siemens Medical Systems, Ultrasound Group, Issaquah, WA). For adjustment, we chose constant parameters—that is, a pulse repetition frequency of 551 Hz, a B mode frequency of 12.0 MHz, a colour mode frequency of 9.0 MHz, a gain of 70 dB, and a low filter. Stored images were evaluated on a 21 inch screen.

Intra-articular colour density was quantified in the longitudinal and transverse views within a user defined region of interest (CS/ROI) by computer aided image analysis (Echotech, Hallbergmoos, Germany). On longitudinal and transverse scans, the border of the respective ROIs was defined as previously described (longitudinal scans: tendon of the muscle extensors (top), the joint cavity (base), and the convex articular surfaces of corresponding bones (lateral border); transverse scans: tendons of the muscles extensors (top), the joint cavity (base), and the skin surface (lateral border)⁹). A pannus vessel index was calculated as the sum of all colour signals for each ROI (CS/ROI) from both longitudinal and transverse scans of the MCPII joints.

Baseline US examination was performed before treatment with etanercept. During a one month period the second MCPII joint of the right hand of every patient was examined on days 8, 16, and 28, directly after the rheumatological examination.

Statistics

All data are given as mean (SD). Because of the small number of patients we did not assume normal distribution of the data. Significance between the mean values obtained for RDAI_total, RDAI_II, subjective pain score, CRP, and CS/ROI in the course of our study (days 0, 8, 16, and 28 repeated measurements) was analysed by Kruskal-Wallis test followed by Dunn's multiple comparison test. A p value <0.05 was considered significant. Moreover, Pearson's correlation coefficient was calculated between the RDAI_II and CS/ROI values obtained for each MCPII joint from every patient at defined time points (that is, on days 0, 8, 16, and 28).

RESULTS

Clinical parameters

All patients investigated had active RA lasting more than six months despite treatment with DMARDs in an appropriate dose (table 1). During treatment with etanercept the total disease activity index (RDAI_total) of the MCPII joints decreased significantly only after 28 days of treatment from 19.3 (3.3) to 11.2 (2.8) (p<0.05; fig 2), whereas the single joint RDAI_II rapidly (within eight days of treatment) and constantly decreased from 2.9 (0.2) to 1.2 (0.7) (p<0.05). Similarly, the general subjective pain score improved (from 4.7 (0.4) to 1.8 (0.6); p<0.05) as did serum CRP (from 3.02 (0.9) to 0.24 ± (0.1); p<0.05; fig 2). Note, that parallel treatment with corticosteroids could be reduced in three of the five patients (table 1).

Ultrasound findings

All MCP joints examined could be visualised by US allowing for a further detailed analysis of intra-articular pannus vascularisation. In all patients the MCPII of the right hand had detectable pannus with a high vascularisation as determined by longitudinal and transversal scans (figs 1A and B). Concordant with the clinical and serological findings a gradual decrease of pannus vascularisation of the MCPII joints was seen during treatment with etanercept (figs 1C and D and fig 2). After treatment for 28 days HRUS showed a significant reduction in pannus vascularisation of these joints in all five patients (from 23 602 (5339) to 2907 (1609) CS/ROI; p<0.001). There was quite a good correlation between HRUS and clinical parameters (HRUS_II/RDAI_II: R=0.85 (fig 3, insert); HRUS/SPS: R=0.67).

DISCUSSION

Treatment decisions in RA are based on an estimation of disease progression and responsiveness to treatment.^9,11,12 So far, there is a diagnostic gap between the symptoms of inflammation as determined by clinical examination of the hands and those resulting from imaging methods such as scintigraphy and/or magnetic resonance imaging (MRI).¹³ HRUS seems to be useful in helping to make therapeutic decisions; it allows for detection of pannus and its degree of vascularisation, which have been shown to be associated with the activity of RA.⁹ Hypervascularisation and angiogenesis within the pannus are essential pathogenic mechanisms leading to joint destruction during the chronic phase of RA. Inhibition of vascularisation by drug treatment^14–16 improves symptoms in animal models of RA; in addition, synovial biopsy studies have shown that TNFα blockade improves disease activity¹⁰ through reduction of pannus vascularisation.^4,5

To investigate the effects of TNFα blockade on pannus formation and vascularisation we treated patients with active RA with the soluble TNFα receptor protein etanercept. In general, an ACR20 response was recorded in all five patients within one month of treatment. To compare the results obtained by US with clinically relevant parameters, in this preliminary study we focused on the evaluation of disease activity in the MCPII joint (referred to as RDAI_II), which was chosen as an “index joint”. The clinical effect correlated well with the extent of pannus formation and vascularisation, as determined by HRUS (fig 3). Our observations are in line with a previous study using MRI to monitor patients with RA receiving a TNFα monoclonal antibody.¹³ However, in contrast with MRI, HRUS imaging offers a routinely available, inexpensive bedside method that might enable the examiner to monitor therapeutic effects within a given time period. As a consequence, immunosuppressive treatment could be modified earlier, which might help to prevent further damage. In conclusion, the data from our pilot study are encouraging and show that imaging by HRUS may represent an additional helpful tool for the rheumatologist in the assessment of RA disease activity. The next step is for a larger number of patients to be investigated by HRUS in order to evaluate whether this method should be generally recommended for clinical routine.