Ca Lawson

The impact of ultrasonography on diagnosis and management of patients with musculoskeletal conditions

There is increasing interest in the use of ultrasonography (US) in rheumatology (1). Ultrasonography is noninvasive, safe (uses no ionizing radiation), and can be used repeatedly in an outpatient setting which provides immediate access for patients. Availability of US varies widely between hospitals, with most of the referrals being for specific conditions such as rotator cuff tears. This usually requires a separate visit to the radiology department and then a return visit to the referring physician. There is accumulating evidence that US is more accurate than clinical examination in the detection of synovitis and tenosynovitis in small joints (2,3), and its use in musculoskeletal conditions is becoming increasingly validated (4). There is, however, a paucity of data assessing its actual impact on patient management. This study evaluated the diagnostic and therapeutic impact of musculoskeletal US in rheumatology outpatient clinics. Of 520 consecutive rheumatology outpatients seen, 100 were referred for US, and were enrolled in the study following provision of informed consent. All patients underwent a routine assessment, including a detailed history and clinical examination by experienced physicians. The indication for US, the site of interest, and site-specific diagnosis (SSD; e.g., synovitis, tenosynovitis), which was diagnosed clinically by the attending physician, were documented. The overall diagnosis (OD; e.g., rheumatoid arthritis, gout) and management plan were also recorded. Patients had US performed during the same clinic visit (on the requested sites only) by a rheumatology research fellow experienced in US, using an on-site ATL HDI 3000 machine (Advanced Technology Laboratories, Bothel, Washington). A linear array 10-5 MHz “hockey stick” transducer was used to examine most joints and a curvilinear array 5-3 MHz transducer was used to examine the hip. The referring physician subsequently reviewed the US report for each patient in the same clinic, and any change in the diagnosis or management as a result of US was documented. Of the 100 patients referred for US, 73 were female and the mean age was 50 years (range 17–87 years). Sixty-four patients were referred to confirm a diagnosis alone, while 36 were referred for diagnosis and local corticosteroid injection. Twenty of these 36 patients (56%) had reported a poor response to a previous “blind” corticosteroid injection. A total of 121 sites were examined by US (Table 1). US was requested to confirm the presence or absence of synovitis in 86 of the 121 sites (71%), enthesitis in 11 of 121 sites (9%), and tenosynovitis in 9 of 121 sites (7%). Following review of the US findings, the SSD was changed in 53 of 100 patients (53%) and 60 of 121 sites (50%). In order of frequency, the changes in clinical SSD were synovitis in 43 of 60 sites (72%), tenosynovitis in 7 of 60 sites (12%), and enthesitis in 5 of 60 sites (8%). The frequency of SSD change, by site, is listed in Table 1. The OD was changed in 5 of 100 patients (5%). There were a further 8 of 100 patients (8%) in whom US helped confirm a provisional OD. The management plan was altered in 53 of 100 patients (53%) after US, of which 39 were due to a change in SSD and 14 were a result of US confirming a provisional SSD. The corticosteroid regimen was affected in 43 patients. Planned intraarticular corticosteroid injections were altered in 22 patients, and in 14 patients, a new injection was given after US. Parenteral corticosteroid therapy was affected in 7 patients. Only 14 (39%) of the 36 intended injections were given at the planned intraarticular site. Disease-modifying antirheumatic drug (DMARD) therapy was affected in 13 patients, of which 10 were due to the detection of extensive subclinical synovitis. This study suggests that US has a diagnostic and therapeutic impact in the majority of referred patients who attend rheumatology clinics. When these findings are applied in the context of all patients attending clinics during the study period, US has an impact on diagnosis and management in at least 10% (53 of 520) of all cases. Consistent with previous reports, this study demonstrates a poor correlation between US and clinical examination in the detection of synovitis; the changes to DMARD therapy were mainly a result of detection of subclinical synovitis by US. This would suggest patients with clinically stable disease are often undertreated, and may help explain the continued bone damage reported in this group of patients (5). Response to corticosteroid injections is known to vary considerably, and there is evidence that accurately placed injections result in improved patient outcome (6,7). Interestingly, as a consequence of US, less than half the referred patients received an injection at the preplanned site. The impact of US on corticosteroid injections therefore reflects the limitations of clinical assessment in accurately localizing pathologic sites and may explain, in part, the variation in response to conventionally placed injections. This study also documents the referral pattern when rheumatologists have direct access to US, with most patients referred for assessment of small-joint synovitis and guided injections. After initial capital expenditure, the only running costs Table 1. Sites examined by ultrasonography, with frequency of change in site-specific diagnosis (SSD)

Interleukin-7 deficiency in rheumatoid arthritis: consequences for therapy-induced lymphopenia

We previously demonstrated prolonged, profound CD4+ T-lymphopenia in rheumatoid arthritis (RA) patients following lymphocyte-depleting therapy. Poor reconstitution could result either from reduced de novo T-cell production through the thymus or from poor peripheral expansion of residual T-cells. Interleukin-7 (IL-7) is known to stimulate the thymus to produce new T-cells and to allow circulating mature T-cells to expand, thereby playing a critical role in T-cell homeostasis. In the present study we demonstrated reduced levels of circulating IL-7 in a cross-section of RA patients. IL-7 production by bone marrow stromal cell cultures was also compromised in RA. To investigate whether such an IL-7 deficiency could account for the prolonged lymphopenia observed in RA following therapeutic lymphodepletion, we compared RA patients and patients with solid cancers treated with high-dose chemotherapy and autologous progenitor cell rescue. Chemotherapy rendered all patients similarly lymphopenic, but this was sustained in RA patients at 12 months, as compared with the reconstitution that occurred in cancer patients by 3–4 months. Both cohorts produced naïve T-cells containing T-cell receptor excision circles. The main distinguishing feature between the groups was a failure to expand peripheral T-cells in RA, particularly memory cells during the first 3 months after treatment. Most importantly, there was no increase in serum IL-7 levels in RA, as compared with a fourfold rise in non-RA control individuals at the time of lymphopenia. Our data therefore suggest that RA patients are relatively IL-7 deficient and that this deficiency is likely to be an important contributing factor to poor early T-cell reconstitution in RA following therapeutic lymphodepletion. Furthermore, in RA patients with stable, well controlled disease, IL-7 levels were positively correlated with the T-cell receptor excision circle content of CD4+ T-cells, demonstrating a direct effect of IL-7 on thymic activity in this cohort.

Abnormal T cell differentiation persists in patients with rheumatoid arthritis in clinical remission and predicts relapse

Objectives: An abnormal CD4+ T cell subset related to inflammation exposure (inflammation-related cells, IRC) has been identified in rheumatoid arthritis (RA). Patients with inflammatory and non-inflammatory diseases were used to examine the relationship between inflammation and this T cell subset in vivo. Methods: Blood was collected from healthy controls and patients with RA (active disease or in clinical remission), Crohn’s disease and osteoarthritis. IRC and chemokine receptors were quantified by flow cytometry. Thymic activity and apoptotic factors were measured by real-time polymerase chain reaction. Circulating cytokines were measured by enzyme-linked immunosorbent assay. CXCR4 and SDF1 in synovial biopsies were measured using immunohistochemistry. Results: IRC were identified in patients with RA (p<0.0001) and Crohn’s disease (p = 0.005), but not in those with osteoarthritis. In RA in remission, IRC persisted (p<0.001). In remission, hyperproliferation of IRC was lost, chemokine receptor expression was significantly lowered (p<0.007), Bax expression dropped significantly (p<0.001) and was inversely correlated with IRC (rho = −0.755, p = 0.03). High IRC frequency in remission was associated with relapse within 18 months (OR = 6.4, p<0.001) and a regression model predicted 72% of relapse. Conclusions: These results suggest a model in which, despite the lack of systemic inflammation, IRC persist in remission, indicating that IRC are an acquired feature of RA. They have, however, lost their hyper-responsiveness, acquired a potential for survival, and no longer express chemokine receptors. IRC persistence in remission confirms their important role in chronic inflammation as circulating precursors of pathogenic cells. This was further demonstrated by much higher incidence of relapse in patients with high IRC frequency in remission.

Successful Treatment of ANCA-Negative Wegener's Granulomatosis with Rituximab

Wegeners Granulomatosis (WG) is a systemic vasculitis typically associated with antineutrophil cytoplasmic antibodies (ANCAs). A small proportion of patients are ANCA negative, however, and this is more commonly found in individuals with disease limited to the ears, nose, throat, and lungs, who do not have renal involvement. Rituximab is a monoclonal anti-CD20 antibody that has been demonstrated to be effective in the treatment of autoantibody-associated rheumatic diseases, including systemic WG. We report the case of a patient with ANCA-negative WG who responded well to rituximab, illustrating that even in the absence of detectable autoantibodies, B-cell depletion can be effective.

Cyclosporin treatment in psoriatic arthritis: a cause of severe leg pain

We describe a case of severe leg pain in a young woman receiving cyclosporin. She was referred to our department at the age of 18 with psoriatic arthritis that had started five years previously. Owing to intolerance of sulfasalazine she had been receiving cyclosporin 100 mg twice a day (3.3 mg/kg) for the preceding seven months before review in combination with methotrexate. Two weeks after referral to our department she began to develop non-specific thigh pains, and the possibility of myalgia due to cyclosporin was suggested. Her dose was reduced but with no change in symptoms. At this point she was taking regular opioids in an attempt to ease her symptoms. She was admitted for further assessment. On questioning, her leg pain consisted of a burning sensation radiating from her thighs to her ankles, and was intermittent every one …