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BACKGROUND: The detection of joint swelling caused by synovitis is important for the diagnosis of inflammatory arthritis. Ultrasound (US) and MRI have proven to be more sensitive and reliable than physical examination, but they are time-consuming and expensive. The automated breast volume scanner was developed to acquire serial B-mode pictures of the female breast and these can be analyzed in all three dimensions. OBJECTIVES: To analyze the value of automated B-mode ultrasound employing the ABVS system in detecting synovitis of the finger joints compared to manual ultrasound (mUS) and physical examination, using MRI as the gold standard. METHODS: 19 consecutive patients suffering from active rheumatoid (n=15) or psoriatic (n=4) arthritis were included. Automated and mUS were conducted with a linear array (ACUSON S2000™, 11 MHz). Multiplanar reconstruction enabled examination of the images for the presence of synovitis. RESULTS: 90% of the hand joints were assessable by automated ultrasound. Automated US detected 12.0, mUS 14.2, MRI 13.4, and clinical examination 4.1 positive joints - i. e. joints with synovitis - on average per patient. The inter-observer reliability of both assessors for automated and mUS, MRI, and physical examination, was 66.9%, 72.7%, 95.1%, and 88.9%, respectively. 84.3% of the joints classified as positive on MRI were confirmed by automated ultrasound, 85.5% on mUS, and 36.0 on physical examination. This translated into a sensitivity of 83.5%, 85.5%, and 36.0% for the three methods, respectively. Conclusion: Automated ultrasound is a promising ultrasound method for assessing small joints in patients with inflammatory arthritis.

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BACKGROUND: The impact of physical exercise on joints and tendons is still a matter of debate. The aim of this study was to investigate with ultrasound the acute effects of extreme physical exercise on knee and ankle joints and their surrounding structures in trained athletes. METHODS: Participants of the Munich marathon were examined by arthrosonography before and after long distance running. Ultrasound assessment included grey scale and power Doppler examination of the knee and talocrural joints with surrounding tendons. Findings consistent with joint effusion, tendon and/or entheseal pathologies were documented. In addition to the ultrasound evaluation, information on training habits and past or present arthralgia or joint swelling was gathered. RESULTS: One Hundred Five runners completed both the pre- and post-excercise ultrasound assessments (baseline and follow-up), resulting in the sonographic evaluation of 420 knee and talocrural joints. At baseline, 105 knee (50) and 38 talocrural joints (18.1) showed effusions, compared to 100 knee (47.6) and 33 talocrural joints (15.7 %) at follow-up. The differences were not significant (p > 0.05 each). Effusion size did not correlate with the timepoint of ultrasound assessment and was independent of covariates such as gender, age or running distance. Hypervascularity of the patellar tendon was detected in 21 cases (10.0 %) at follow-up in contrast to one at baseline (p < 0.001). This observation was more frequent in male than in female participants (p < 0.05). CONCLUSIONS: Acute physical stress is significantly associated with hypervascularity of the patellar tendon. No significant changes of synovial effusion were detected in knee and talocrural joints.

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BACKGROUND: Due to diagnostic and therapeutic advances, quality of life of patients with spondyloarthritides (SpA) has improved substantially in recent years. However, little is known about how patients with the SAPHO syndrome, a heterogeneous disease counted among the SpAs, profit from these advances. OBJECTIVE: To investigate current aspects of patient care in a nationwide SAPHO cohort. METHODS: Patients were recruited in a university centre and via a nationwide SAPHO patient support group. Medical records were reviewed and patients were asked to complete a questionnaire on the course of diagnosis, disease burden and treatment regimen. RESULTS: A total of 64 patients were included in the analysis. The mean time from disease onset to diagnosis was 3.8 ± 5.3 years. The patients' overall satisfaction with the course of diagnosis was 23.0 ± 28.9 on a visual analogue scale (VAS) from 0 to 100. Musculoskeletal symptoms had the highest impact on the patients' wellbeing. The mean overall disease burden on a VAS for pain was 45.4 ± 25.9. Limitations in the quality of life were reported mainly in the general health, bodily pain and vitality dimensions of the SF-36 questionnaire. Current treatments consisted of NSAIDs (77%), DMARDs (27%), glucocorticoids (23%), TNF-inhibitors (16%) and bisphosphonates (11%). CONCLUSIONS: The SAPHO syndrome has a high impact on the patients' general health and quality of life. Establishing the diagnosis still takes years and expends multiple medical resources. Effective treatments such as TNF-inhibitors are rarely prescribed and current disease burden is not acceptable.

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OBJECTIVE: To compare the dorsal and palmar ultrasound (US) examination of finger joints in early rheumatoid arthritis (RA) with regard to the concurrence of greyscale (GSUS) and power Doppler (PDUS) positivity, and to correlate both approaches with clinical variables. METHODS: Patients with newly diagnosed RA were assessed by clinical examination and US. GSUS and PDUS of metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints were performed using the dorsal and palmar approach. Findings of synovitis in GSUS and PDUS were graded semiquantitatively from 0 to 3. Clinical and sonographic reevaluation was performed after 6 months. RESULTS: With 44.6% versus 32.2% positive findings, palmar GSUS identified significantly more joints with synovitis than did dorsal GSUS. With 22.1% versus 8.9%, PDUS abnormalities were detected significantly more often from the dorsal side. With 71.2% versus 21.8% for the MCP and 57.5% versus 17.4% for the PIP joints, significantly more GSUS and PDUS double-positive joints were found with the dorsal as opposed to the palmar approach. These differences remained significant at Month 6. Both palmar and dorsal GSUS and PDUS correlated with comparable strength with clinical variables such as the Disease Activity Score 28, Clinical Disease Activity Index, and Simple Disease Activity Index. CONCLUSION: Although the dorsal approach detected fewer GSUS findings than the palmar approach, PDUS signals were significantly more frequently detected by dorsal US. In addition, the prevalence of double-positive joints with concurrent GSUS and PDUS findings was significantly higher with the dorsal approach. These data argue in favor of the dorsal US approach to finger joints in RA.

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OBJECTIVE: To investigate the clinical relevance of grade 1 findings on gray-scale ultrasound (GSUS) of the joints in patients with rheumatoid arthritis (RA). METHODS: We examined the wrists and small joints of 100 patients with early or established RA and 30 healthy controls, using GSUS and power Doppler ultrasound (PDUS). Independent clinical assessment of all joints for tenderness and swelling according to the European League Against Rheumatism examination technique was performed. Joints with grade 1 findings on GSUS were identified, and associations with swelling, pain, and findings on PDUS were assessed. Grade 1 findings on GSUS in patients with early RA were reassessed after 6 months of antirheumatic treatment. RESULTS: Grade 1 results represented the majority of all GSUS findings in patients with RA and were also frequently recorded in healthy controls. Grade 1 GSUS findings were not associated with tenderness, swelling, or positive results on PDUS. In comparison to joints with grade 2 and grade 3 findings on GSUS, joints with grade 1 findings were less likely to respond to treatment. CONCLUSION: The present results indicate that grade 1 findings on GSUS have limited clinical relevance.

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OBJECTIVE: Joint counts are the key outcome measure in rheumatoid arthritis (RA). There is a great variability between different assessors of the same patient; this variability can be reduced by standardized training. The training effect is far less pronounced for the 66/68-joint count compared to the 28-joint count. We evaluated the reason for the higher interrater disagreement in the 66/68 compared to the 28-joint count. METHODS: Participants in joint examination seminars evaluated a patient with RA before and after training in the European League Against Rheumatism technique. Joints were rated positive or negative for tenderness and swelling. The number of positive joints and the variability between examiners before and after the training were compared. Concordance was calculated for every single joint using the Fleiss-Kappa test. RESULTS: In total, 256 health professionals were instructed in the 66/68-joint count and 84 in the 28-joint count. The disagreement between examiners was higher for swelling than for tenderness. After the training, there was a significant reduction of interrater variability, which was more pronounced in the 28 than in the 66/68-joint count. Comparisons between joint counts revealed that the joints of the feet were more likely to be rated negative, yet interrater disagreement was still high. CONCLUSION: Standardization of joint examination significantly reduces variability between assessors. The better performance of the 28-joint count is due to the lower number of joints examined, especially the foot joints, which remain difficult to assess reliably even after training.

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OBJECTIVES: To study the role of interleukin 22 (IL-22) in rheumatoid arthritis (RA). METHODS: IL-22 serum levels were measured in patients with early, treatment-naive RA (n=49) and in 45 age- and sex-matched healthy individuals as controls. Patients were assessed clinically and radiographically at baseline and followed up for 2 years. Correlations of IL-22 serum levels were sought with parameters of disease activity, serological markers, demographic factors and the incidence of erosions. IL-22 production by peripheral blood T cells was investigated by intracellular flow cytometry. RESULTS: 24 of 49 patients with RA demonstrated elevated IL-22 levels compared with the range of healthy controls. At baseline, a high percentage of these patients (8/24, 33%) demonstrated bone erosions, whereas only one patient (4%) from the group with normal IL-22 had erosions. During the 2 years of follow-up, six additional patients with increased IL-22 at baseline developed erosions. In contrast, none of the patients in whom IL-22 levels were normal developed erosions despite similar treatment regimens. Multivariate regression analysis accounting for other parameters predictive for erosions, such as the presence of rheumatoid factor or anti-cyclic citrullinated peptide antibodies and disease activity, showed that elevated IL-22 baseline levels were independently and significantly associated with erosive RA. Cellular analysis demonstrated enhanced expression of IL-22 from CD4 T cells in RA. CONCLUSION: IL-22 is elevated in the serum of half of the patients with RA. Elevated serum IL-22 allows discrimination between patients with different radiographic progression and indicates a possible involvement of IL-22 in the pathophysiology of RA.

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INTRODUCTION: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting. METHODS: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators. RESULTS: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm). CONCLUSIONS: Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.

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OBJECTIVE: To delineate the role of Th17 cells in the pathogenesis of autoimmune arthritides. METHODS: Th17 cells were analyzed in well-defined homogeneous cohorts of patients with the prototypical autoimmune arthritides rheumatoid arthritis (RA) and psoriatic arthritis (PsA), grouped according to patients who had very early active RA (n = 36; mean disease duration 2.8 months, Disease Activity Score in 28 joints 5.0) and those who had very early active PsA (n = 20; mean disease duration 2.3 months), none of whom had received treatment with glucocorticoids or disease-modifying antirheumatic drugs, as well as patients with established RA (n = 21; mean disease duration 68 months) who were considered either responders or nonresponders to therapy. Groups of healthy individuals and patients with osteoarthritis (a noninflammatory arthritis) were used as control cohorts. Expression of T lineage-specific transcription factors (RORC, T-bet, GATA-3, and FoxP3) and the response of CD4 T cells to Th17 cell-inducing conditions were analyzed in vitro. RESULTS: The frequencies of Th17 cells and levels of interleukin-17 strongly correlated with systemic disease activity at both the onset and the progression of RA or PsA. The values were reduced to control levels in patients with treatment-controlled disease activity. Th17 cells were enriched in the joints, and increased frequencies of synovial Th17 cells expressed CCR4 and CCR6, indicative of selective migration of Th17 cells to the joints. The intrinsically elevated expression of RORC, accompanied by biased Th17 cell development, and the resistance of Th17 cells to a natural cytokine antagonist in patients with RA and patients with PsA were suggestive of the underlying molecular mechanisms of uncontrolled Th17 activity in these patients. CONCLUSION: Th17 cells play an important role in inflammation in human autoimmune arthritides, both at the onset and in established disease.

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OBJECTIVE: To reduce the amount of variability among assessors, we conducted joint examination standardization seminars in conjunction with multicenter clinical trials for patients with rheumatoid arthritis (RA). The examination techniques used were based on the recommendations of the European League Against Rheumatism (EULAR). METHODS: To evaluate the effect of standardization, participants at the seminars examined a given patient with RA before and after they were made familiar with the EULAR examination technique. The number of tender and swollen joints as well as the variance among the examiners before and after the training were compared. Joints were rated positive or negative for tenderness and swelling without grading. RESULTS: Overall, 553 individuals from a variety of countries in Europe, North America, Asia, and Australia participated. Examiners included different kinds of health professionals, mainly physicians and nurses. We found a substantial variance among examiners before the training in the standardized method. This variance could be significantly reduced by the training. We also found that the number of joints considered active was markedly reduced after the training. CONCLUSION: Standardized joint examination training significantly reduces variability among different assessors.

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A 31-year-old man with ankylosing spondylitis, receiving treatment with infliximab, presented with a large progressive cutaneous ulcer at the right knee. Biopsies showed Leishmania amastigotes, and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis showed Leishmania infantum as the causative agent. After treatment with miltefosine, the ulcer resolved completely, and infliximab was reinstituted because of progression of spondylitis. After 1 year, there was a recurrent ulcer at the same site being positive for Leishmania DNA by PCR. Local treatment with sodium stibogluconate resulted in complete regression. Cutaneous leishmaniasis should be added to the list of opportunistic infections associated with anti-tumor necrosis factor (TNF) treatment. Despite recurrences, antileish-manial treatment may be effective in cases without alternatives to anti-TNF therapy.

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OBJECTIVE: Some patients with chronic inflammatory diseases such as rheumatoid arthritis (RA) improve rapidly from anti-tumor necrosis factor (anti-TNF) therapy. No sensitive markers are available that might predict outcome of anti-TNF therapy. We undertook this study to investigate the predictive value of hypothalamic-pituitary-adrenal (HPA) axis hormones for clinical improvement during anti-TNF therapy. METHODS: An observational study in 23 RA patients was followed by a validation study in 38 RA patients. The patients receiving anti-TNF antibodies had no glucocorticoid treatment, and we measured baseline serum levels of adrenocorticotropic hormone (ACTH) and cortisol. Improvement during anti-TNF antibody treatment was judged by the Disease Activity Score in 28 joints (DAS28), and serum levels of cortisol were measured at followup. RESULTS: The observational study demonstrated that improvement in the DAS28 correlated negatively with baseline serum levels of cortisol (R=-0.520, P=0.011) and the cortisol:ACTH ratio (R=-0.700, P=0.0002). In the longitudinal part of the study at followup, those patients with good improvement and initially low serum levels of cortisol demonstrated an increase of serum cortisol, in contrast to patients with little or no improvement. Findings in the observational study were supported by those in the validation study in a group of RA patients with less inflammation (correlation of improvement in the DAS28 with cortisol:ACTH ratio: R=-0.320, P=0.025). CONCLUSION: This is the first study in a human chronic inflammatory disease to demonstrate that inflammation-induced TNF interferes with HPA axis integrity, which is linked to the disease outcome. These findings position the HPA axis centrally in the vicious circle of perpetuation of chronic inflammation.

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OBJECTIVE: Tumor necrosis factor (TNF)-neutralizing agents are the most successful means of ameliorating systemic autoimmune inflammation. Neutralization of TNF, however, is often associated with the development of autoantibodies, particularly to nuclear antigens, and the mechanisms of this are unknown. We undertook this study to analyze the effect of TNF and its neutralization on the expression of major histocompatibility complex class II molecules and on the function of antigen-presenting myeloid cells in rheumatoid arthritis (RA). METHODS: Monocytes were isolated from the peripheral blood of RA patients before and after anti-TNF monoclonal antibody (mAb) treatment and from the peripheral blood of controls by negative selection, differentiated in vitro to macrophages, and analyzed by flow cytometry for HLA-DR expression. T cell responses to activation by myeloid cells were assessed in proliferation assays, and messenger RNA (mRNA) levels of the class II transactivator (CIITA) were determined by semiquantitative reverse transcriptase-polymerase chain reaction. RESULTS: HLA-DR expression was significantly reduced on myeloid cells from RA patients with active disease, but was increased to normal levels after anti-TNF mAb treatment. Concordantly, in vitro application of TNF to monocytes from healthy individuals reduced their ability to up-regulate HLA-DR during differentiation to macrophages and, importantly, inhibited their ability to stimulate T cells in mixed lymphocyte reactions. Molecular analysis revealed that the effect of TNF on HLA-DR expression was mediated via suppression of the transcription factor CIITA. CONCLUSION: The data indicate that TNF decreases HLA-DR expression by reducing CIITA mRNA levels in myeloid cells, functionally resulting in a decreased capacity of myeloid cells to stimulate T cells. Concordantly, ameliorating disease activity in chronic inflammatory diseases by neutralizing TNF restores expression of HLA-DR on myeloid cells as well as the ability of myeloid cells to stimulate T cells. Thus, anti-TNF treatment might lead to augmented T cell activation by myeloid cells, thereby promoting immune responses to (auto)antigens and the development of antinuclear antibodies that are frequently associated with anti-TNF therapy.

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Etanercept is a member of a new generation of therapeutic agents referred to as biologics or targeted therapies, which have caused some enthusiasm in the field of autoimmune disorders in recent years. Most of these agents are inhibitors of tumor necrosis factor, a key cytokine in the chronic inflammatory process. Etanercept is a tumor necrosis factor recombinant fusion protein consisting of two molecules of the tumor necrosis factor p75 receptor, which binds to the cytokine and thus antagonizes its effect. This review provides an introduction to the compound and describes its clinical efficacy in the main indications, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis and juvenile rheumatoid arthritis. Focus has been placed on the newest data on long-term efficacy and radiologic outcome parameters. Reports on the use of the drug in other indications are reviewed as well as the actual data on safety issues. The authors will provide their opinion on the current status of the drug and speculate on its rank in the future.

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The combination of cyclophosphamide (CYC) and oral corticosteroids is effective in the majority of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AASV), but it carries substantial risk of drug-related morbidity and mortality. New regimens are desired, especially in refractory cases. The immunosuppressant 15-deoxyspergualin (DSG) is effective in experimental autoimmune disease and transplantation as well as in acute kidney transplant rejection in humans. To assess the efficacy and safety of DSG, an open label multicenter trial was conducted in patients with AASV who were either unresponsive or had contraindications for standard immunosuppressants. Included were 19 cases of Wegener granulomatosis and one case of microscopic polyangiitis. Nine of them had received CYC shortly before study entry without apparent therapeutic success. DSG (0.5 mg/kg per d) was given for 2 to 3 wk until the WBC count dropped to 3000/ micro l followed by a rest until at least a WBC of 4000/ micro l was reached again. This was repeated up to six cycles. During the study, no other immunosuppressants besides steroids were allowed. Disease improvement during treatment with DSG was achieved in 70% of cases (six cases of complete remission; eight cases of partial remission). Leucopenia occurred in each patient in a regular pattern during the cycles and was transient without exception. No mortality or septicemia was observed. Mild to moderate infections mainly in the respiratory tract were observed but resolved under adequate treatment without sequel. It is concluded that treatment with DSG is successful in patients with refractory Wegener granulomatosis under careful monitoring of WBC count.

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PURPOSE: To demonstrate a patient developing multiple bilateral eyelid molluscum contagiosum lesions after initiation of TNFalpha-antibody therapy for rheumatoid arthritis. DESIGN: Single interventional case report. METHODS: Clinical, histopathologic, and immunologic-serological findings are presented. RESULTS: A 67-year-old patient with a 5-year history of rheumatoid arthritis had been treated with prednisone and methotrexate for the last 5 years. After initiation of additional TNFalpha-antibody treatment, complaints from rheumatoid arthritis subsided, but multiple bilateral molluscum contagiosum lesions of upper and lower eyelids occurred despite normal or only slightly reduced CD(4) (420-178/ microl) and CD(8) counts (143-58/microl). Histopathologic evaluation of the excised warts confirmed the clinical diagnosis. Under continued therapy, the warts have been recurring for 12 months. CONCLUSION: TNFalpha-antibody treatment for rheumatoid arthritis may compromise the host response to molluscum contagiosum, especially if methotrexate is given additionally. Patients should be informed about this potential complication.

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Pathogenesis of autoimmune diseases like systemic lupus erythematosus (SLE) is unresolved. Dysregulation of programmed cell death is discussed as a pathogenetic factor. We have previously shown that increased in vitro apoptosis of cultured peripheral blood mononuclear cells (PBMC) is nonspecific for SLE. Importantly, however, in recent experiments with SLE PBMC from patients with infections and fever in vitro apoptosis was strongly accelerated. We therefore hypothesized that regulation of apoptosis might be disturbed in activated SLE lymphocytes. Thus, we generated phytohemagglutinine (PHA)/IL-2 stimulated lymphoblasts in vitro. These lymphoblasts readily undergo apoptosis after culture in cytokine-free medium, and can be rescued by addition of gammac-chain cytokines IL-2, -4, -7, or -15. In lymphoblasts from 60 SLE patients tested in comparison to lymphoblasts from normal donors cultured in parallel, we found significant hyporesponsiveness to gammac-chain cytokines in SLE cells. Minor differences were also seen in lymphoblasts from patients with other systemic autoimmunopathies (mixed connective tissue disease, vasculitis, n=49)and in lymphoblasts from patients with other autoimmune diseases (mainly rheumatoid or reactive arthritis, myositis, n=44). In patients with high erythrocyte sedimentation rate (> 25 mm/h), TNF-alpha (> 6.5 pg/ml) or IL-12 (> 4.7 pg/ml) serum levels or detectable IFN-gamma concentrations hyporesponsiveness to gammac-chain cytokines was even more pronounced in SLE lymphoblasts, but not in lymphoblasts from the other groups. Moreover, increased apoptosis was seen in lymphoblasts from SLE patients with decreased complement (C)4 or elevated dsDNA antibody levels. In conclusion, these data suggest that in SLE patients with increased inflammatory activity and/or Th1 dominance signaling through gammac-chain cytokine receptors is deteriorated, leading to facilitated apoptosis of activated lymphocytes and enlarged onflow of apoptotic material.

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