Jean Marie Berthelot

Interleukin 34 expression is associated with synovitis severity in rheumatoid arthritis patients

Objectives Interleukin (IL) 34 is a new cytokine implicated in macrophage differentiation and osteoclastogenesis. This study assessed IL-34 expression in the tissue of patients with rheumatoid arthritis (RA). Methods Immunohistochemistry was performed in synovial biopsies from patients with RA (n=20), osteoarthritis (n=3) or other inflammatory arthritis (n=4). IL-34 was detected in the synovial fluid by ELISA and its messenger RNA expression was studied by quantitative PCR in rheumatoid synovial fibroblasts after stimulation by tumour necrosis factor α (TNFα) and IL-1β. Wild-type, jnk1−/−–jnk2−/− and nemo−/− murine fibroblasts and pharmacological inhibition were used to determine the involvement of nuclear factor kappa B (NF-κB) and JNK in that effect. Results IL-34 was expressed in 24/27 biopsies, with three samples from RA patients being negative. A significant association was found between IL-34 expression and synovitis severity. Levels of IL-34 and the total leucocyte count in synovial fluid were correlated. TNFα and IL-1β stimulated IL-34 expression by synovial fibroblasts in a dose/time-dependent manner through the NF-κB and JNK pathway. Conclusion This work for the first time identifies IL-34 expression in the synovial tissue of patients with arthritis. This cytokine, as a downstream effector of TNFα and IL-1β, may contribute to inflammation and bone erosions in RA.

Pulmonary Nodulosis and Aseptic Granulomatous Lung Disease Occurring in Patients with Rheumatoid Arthritis Receiving Tumor Necrosis Factor-α-Blocking Agent: A Case Series

Objective. To describe cases of development of pulmonary nodulosis or aseptic granulomatous lung disease in patients with rheumatoid arthritis (RA) receiving anti-tumor necrosis factor-α (TNF-α) therapy. Methods. A call for observation of such cases was sent to members of the French “Club Rhumatismes et Inflammation.” The cases had to occur after introduction of TNF-α-blocking therapy. Results. Eleven cases were examined: 6 patients were treated with etanercept, 2 with infliximab, and 3 with adalimumab. Pulmonary nodular lesions were observed after a mean treatment period of 23.3 ± 15.3 months. Clinical symptoms were observed in 5 cases. Radiographs or computed tomography of the chest showed single or multiple nodular lesions in 10 cases and hilar adenopathies in 1 case. Biopsy of the nodular chest lesions or mediastinal lymphadenopathies were performed in 8 patients, and revealed typical rheumatoid nodules in 4 cases and noncaseating granulomatous lesions in 4 cases. Mycobacterial or opportunistic infections were excluded for all cases. Outcome was favorable for all the patients, with either discontinuation or maintenance of anti-TNF-α treatment. Conclusion. Aseptic pulmonary nodular inflammation corresponding to rheumatoid nodules or noncaseating granulomatous inflammation can occur during anti-TNF-α therapy for RA, mainly etanercept. The mechanism explaining such a reaction is not clear but certainly includes different processes. These cases of pulmonary nodular inflammation generally have a benign course and do not systematically require withdrawal of treatment.

Rheumatic and musculoskeletal features of Whipple disease: a report of 29 cases.

Objective. Whipple disease is a rare infection caused by Tropheryma whipplei. Although patients commonly complain of osteoarticular involvement, musculoskeletal manifestations have been poorly described. We report cases of Whipple disease with rheumatic symptoms and describe their clinical presentation, modes of diagnosis, and outcomes. Methods. This retrospective multicenter study included patients with Whipple disease diagnosed and referenced between 1977 and 2011 in 10 rheumatology centers in France and Italy. Results. Twenty-nine patients were included. The median age was 55 years. The median time to diagnosis from first symptoms was 5 years. Polyarthritis was the most frequent presentation (20/29), and was most often chronic, intermittent (19/29), seronegative (22/23), and nonerosive (22/29). In all cases, the symptoms had led to incorrect diagnosis of inflammatory rheumatic disease and immunosuppressants, including biotherapy, were prescribed in most cases (24/29) without success. The diagnosis of Whipple disease was made by histological analysis, molecular biology tests, or both in 21%, 36%, and 43% of the cases, respectively. Duodenal biopsies were performed in most cases (86%). Synovial biopsies were performed in 18% of cases, but all contributed to diagnosis. The clinical outcomes after antibiotic therapy were good for all patients. Conclusion. Polyarthritis is the main feature observed in cases of Whipple disease; it is seronegative and associated with general and gastrointestinal symptoms. The molecular analysis of duodenal tissue and/or other tissues remains the method of choice to confirm the diagnosis. Reducing the time to diagnosis is important because severe late systemic and fatal forms of the disease may occur.

Is IL-6 an appropriate target to treat spondyloarthritis patients refractory to anti-TNF therapy? A multicentre retrospective observational study.

IntroductionThe aim of this study was to evaluate, under real-life conditions, the safety and efficacy of tocilizumab in patients having failed anti-TNFα therapy for spondyloarthritis.MethodsFrench rheumatologists and internal-medicine practitioners registered on the Club Rhumatismes et Inflammations website were asked to report on patients given tocilizumab (4 or 8 mg/kg) to treat active disease meeting Assessment of SpondyloArthritis International Society (ASAS) criteria for axial or peripheral spondyloarthritis, after anti-TNFα treatment failure. Safety and efficacy after 3 and 6 months were assessed retrospectively using standardised questionnaires.ResultsData were obtained for 21 patients, 13 with axial spondyloarthritis (46% men; median age, 42 years; disease duration, 11 years; HLA-B27-positive, 92.3%) and eight with peripheral spondyloarthritis (25% men; median age, 40 years; disease duration, 10 years; HLA-B27-positive, 62.5%). No patients with axial disease had at least a 20 mm decrease in the BASDAI, nor a BASDAI50 response or major ASAS-endorsed disease activity score improvements after 3 or 6 months; an ASAS-endorsed disease activity score clinically important improvement was noted at month 3 in five of 13 patients and at month 6 in one of four patients. A good DAS28 response was achieved in four patients with peripheral disease, including one in EULAR remission at month 3. Four patients were still taking tocilizumab at month 6, including one in EULAR remission and one with a good DAS28 response. Tocilizumab was well tolerated, with no serious adverse events. Initially elevated acute-phase reactants declined during tocilizumab therapy.ConclusionIn patients having failed anti-TNFα therapy, tocilizumab decreased acute-phase reactants but failed to substantially improve axial spondyloarthritis and was inconsistently effective in peripheral spondyloarthritis.

Alternative use of bisphosphonate therapy for rheumatic disease.

Bisphosphonates are widely use for pathologies such as osteoporosis, Pagets disease or bone metastasis. However, their potent antiresorptive properties open new therapeutic opportunities for other conditions associated with an increased focal or systemic bone remodelling. Moreover, apart from their antiresorptive activity, bisphosphonates could also have others properties through a specific analgesic or anti-inflammatory effect. Thus, rheumatic diseases like rheumatoid arthritis, spondylarthritis or SAPHO syndrome (acronym for synovitis, acne, pustulosis, hyperostosis and osteitis) that are associated with systemic and sometimes focal bone loss could be good candidates for bisphosphonate therapy. Other non-inflammatory rheumatic diseases like bone osteonecrosis, algodystrophy, fibrous dysplasia or neuropathic osteoarthropathy are also associated with pain and an increase of focal bone remodelling. Several studies have shown that bisphosphonate could have promising therapeutic potential in these inflammatory or non-inflammatory diseases where therapeutic options are usually few. This review will focus on the new potential alternative indications for bisphosphonate in rheumatic diseases.

A comparison between bisphosphonates and other treatments for osteoporosis.

Since their development 30 years ago, bisphosphonates are now one of the standard therapy in the management of osteoporosis. Improvements in terms of anti-resorptive potency have leaded to new molecules available either orally or intravenously, from weekly to yearly administration. Overall tolerance of bisphosphonates is good with regards to the risk of mandibular necrosis, not comparable with those observed in cancer treatment, and with no causal link yet established in osteoporotic patients. Compliance remains poor and should be improved by a better education of the patients about their treatment. Other treatments like teriparatide, raloxifene or strontium ranelate are now also available and give more therapeutic options but also more questions on the best molecule to choose for each patient. There is currently no valid basis for distinguishing in a formal and objective manner the different new-generation bisphosphonates, in terms of efficacy against either vertebral, peripheral or hip fractures. In a same way, comparison between bisphosphonates and the other treatments available for osteoporosis is hard in absence of proper randomised controlled study. This review gives an overview of the recent data on the efficacity and tolerance of bisphosphonates in the different forms of osteoporosis and compares them to the other treatments currently available.

Second-line drugs used in recent-onset rheumatoid arthritis in Brittany (France)

OBJECTIVE The management of recent-onset rheumatoid arthritis (RA) is not well standardized. We conducted a survey of drugs prescribed to RA patients in Brittany at presentation and during the first 1 to 3 years of follow-up. METHODS A cohort of 270 patients with recent-onset inflammatory joint disease was recruited between 1995 and 1997. The evaluation at presentation included a medical history, a thorough physical examination, and a standard battery of investigations. Follow-up at 6-month intervals was offered. At the last visit, between June and December 1999, a panel of five rheumatologists established that 98 patients had RA. RESULTS At presentation, hydroxychloroquine and injectable gold were the most widely used second-line drugs, and only two patients were offered a combination of second-line drugs. At the last visit, the most commonly used drugs were methotrexate, injectable gold, and hydroxychloroquine (23, 23, and 21 patients, respectively); only three patients were on more than one second-line drug and 38 (38/98, 39%) patients were on glucocorticoid therapy. CONCLUSION Rheumatologists in Brittany prefer monotherapy with hydroxychloroquine or injectable gold as the initial treatment. Later, they rely mainly on methotrexate, injectable gold, and hydroxychloroquine, often in combination with glucocorticoid therapy.

Assessing polymyalgia rheumatica activity when C-reactive protein is unavailable or uninterpretable

Objective The PMR activity score (PMR-AS) includes the CRP value, which may be lacking or invalid owing to anti-IL-6 therapy. Our objective was to develop alternatives to PMR-AS that do not require CRP. Methods We used the Club Rhumatisme et Inflammation (CRI; 89 patients with PMR) and the Tolerance and Efficacy of tocilizumab iN pOlymyalgia Rheumatica (TENOR; 20 patients with recent-onset PMR naive to glucocorticoid who received three tocilizumab infusions, at weeks 0, 4 and 8, followed by prednisone from weeks 12 to 24) cohorts. In the CRI cohort, we evaluated correlations between PMR-AS items to select the best item for imputing CRP. Then we calculated the PMR-AS with (PMR-AS) and without (clin-PMR-AS) CRP and we used the linear regression between PMR-AS and clin-PMR-AS to obtain CRP-imputed (CRP-imp) PMR-AS. Finally, we evaluated agreement between clin-PMR-AS, CRP-imp PMR-AS, PMR-AS and ESR-PMR-AS in the TENOR cohort during tocilizumab therapy. Results In the CRI cohort, agreement between PMR-AS and clin-PMR-AS was excellent (κ = 0.90). Linear regression between PMR-AS and clin-PMR-AS [CRP-imp PMR-AS = 1.12(clin-PMR-AS)+0.26] allowed us to build the CRP-imp PMR-AS. Mean (s.d.) values were as follows: 8.40 (9.76) for PMR-AS, 7.24 (8.58) for clin-PMR-AS and 7.84 (9.61) for CRP-imp PMR-AS. CRP-imp PMR-AS agreed more closely with PMR-AS than did clin-PMR-AS. The results in the TENOR cohort confirmed that CRP-imp PMR-AS or ESR-PMR-AS could be used. Conclusion Alternatives to the PMR-AS obtained without CRP can be used to monitor PMR activity in everyday practice in patients without available CRP values and in those receiving IL-6 antagonist therapy.

SAT0509 Three-Dimensional Versus Two-Dimensional Ultrasonography in the Assessment of Peripheral Enthesitis in Spondylarthritis

Background Power Doppler ultrasonography (PdUS) is widely used for the evaluation of the entheses in spondylarthritis (SpA). PdUS has been shown to be useful for the diagnosis and the evaluation of the disease activity. However, it can be time-consuming and its intra and interobserver reproducibility depends on the experience of the sonographer. Three-dimensional (3D) US has already demonstrated a good reliability and operator independency in the evaluation of rheumatoid arthritis wrist and reduces the time needed to perform this examination (1). Objectives The aim of this study was to compare the reliability of 3D and conventional two-dimensional (2D) US in the scoring of enthesitis in SpA. Methods Sixteen patients with SpA according to ASAS criteria were included. The readers were 2 rheumatologists, one experimented in musculoskeletal US (reader 1) and one beginner (reader 2) (respectively mean experience 6 years and 6 months). They performed independently a 2D US scoring of the entheses using the MASEI score followed by a 3D acquisition of the same entheseal sites. The assessment of the 3D US was performed a minimum of 1 week apart using the images stored on the US unit. Intra-observer reliability was evaluated by a second reading of the same images. The duration of 2D US scanning, 3D US acquisition and reading was recorded. The quality of 3D US acquisitions was scored between 0 and 3. For the reliability analysis, we used the two-way, mixed-effect model (absolute agreement) single-measure intraclass correlation coefficients (ICCs)and results are given with 95% confidence interval (CI). Results They were 12 men and 4 women, mean age 45.7 years (range 26-70) and mean disease duration 11 years (0-33). The mean ASDAS was 2.4 (0.4-5.8). The mean MASEI score was 10 (+/-7). Intra-observer reproductibility was good to excellent for 2D US and good for 3D US (ICC (95%CI) 2D US: 0.776 (0.471-0.916) and 0.96 (0.892-0.986) and ICC (95%CI) 3D US: 0.796 (0.498-0.921) and 0.703 (0.325-0.886) for reader 1 and 2 respectively). Inter-observer reliability was slightly better for 3D US than for 2D US (ICC (95%CI) 0.776 (0.471-0.916) for 3D US versus 0.641 (0.221-0.859) for 2D US). Finally a good correlation was found between 2D and 3D US (ICC (95%CI) 0.705 (0.329-0.887) for reader 1 and 0.756 (0.444-0.906) for reader 2). The mean time (+/-SD) for 2D US scanning was 23 minutes (+/-4) whereas the mean time for 3D US volume acquisition and reading was 16.5 min (+/-2.6) (p<0.001) (with a mean 7.3 min (+/-0.9) for the acquisition and a mean 9.2 minutes (+/-2.2) for the review of the images). The mean score (+/-SD) for quality of 3D US acquisitions was 2.4 (+/0.1)/3 with no significant difference between the entheseal sites. Conclusions This study demonstrates a good intra and interobserver reliability of 3D US assessment of enthesitis in SpA. We also found a good correlation between the 2D US and 3D US scoring. It can be performed by a non-experimented examiner without loss of reliability. Finally, 3D US significantly shortened the time of scanning. References Filipucci et al. Ultrasound imaging for the rheumatologist. Sonographic assessment of hand and wrist joint involvement in rheumatoid arthritis : comparison between two- and three-dimensional ultrasonography. Clin Exp Rheumatol 2009;27:197-200. Disclosure of Interest None Declared

SAT0421 Location of Disk Herniation (Median or Lateral) Affects Clinical Features, but not the Outcome of Lumbar Radiculalgia in Patients without Lumbar Spinal Stenosis.

Background It has been claimed that lumbar radiculalgia induced by foraminal disk herniations had poorer outcomes and different clinical features, including: 1-more progressive onset; 2-more severe radiculalgia; 3-less frequent/severe back pain; 4-less limitation of straight leg raising (SLR); 5-more frequent neurological deficits; 6-poorer outcome (Ref 1). Objectives We wished to check whether patients with median disk herniations but no spinal stenosis (either central of foraminal) had indeed different features and outcome than patients with more lateral disk herniations. Methods Patients whose lumbar radiculalgia required hospitalization were included in this prospective study each time TDM or MRI had already been performed and showed a clear disk prolapsus or herniation, but no features of spinal stenosis (either central of foraminal). Disk herniations were classified as median, mostly located in recess, in foramen, or extra-foraminal. Patients with median disk herniations were then compared to patients with more lateral herniations, their outcome being assessed by a phone call using a standardized questionnaire, at least 6 months after baseline. Results 59 patients (31 males) were included (49 sciatica): 31 (53%) had median disk herniations, and 28 (47%) more lateral herniations (within recess in 3, foraminal in 20, and extra-foraminal in 5). No significant differences according to the location of herniations were noticed for the speed of radiculalgia onset, back pain (both lying or standing), and leg pain (both lying or standing), but significant differences (t test < 0.05) were observed for other items: the 28 patients with more lateral herniations were 8 years older (53.4 +/- 15.8 Vs 45.2 +/- 12.6); their herniations involved disks from upper levels (above L4-L5: 7/28 Vs 3/31); motor weakness was more frequent (25% Vs 3%); SLR was less restricted (65.0 +/- 24.5° Vs 51.1 +/- 25.7°); DN4 score of neuropathic pain was higher (4.4 +/- 2.1 Vs 3.2 +/- 1.8); anxiety was higher (10.3 +/- 4.1 Vs 7.9 +/- 3.2); the use of opioids was more frequent (39% Vs 22%); length of hospital stay was longer (5.7 +/- 2.4 Vs 4.5 +/- 1.4 days); and physician’s prognosis of a good outcome was poorer (6.6 +/-2.2 Vs 8.0 +/- 1.6). However, at the end of follow up (12.2 +/- 3.3 months) outcomes were similar: 37% (Vs 41% for median herniations) had transiently relapsed, 66% felt improved (Vs 63%), 27% felt cured (Vs 22%), and walking capacity was nearly identical (3.7 +/- 1.8 kms, Vs 4.1 +/- 1.6), despite only 21% had to be operated (Vs 37% of those with median herniations). Conclusions Despite slight clinical differences, the outcome of radiculalgia induced by lateral lumbar disk herniations seems even better than the outcome of those induced by median disk herniations. Previous claims of poorer outcomes in foraminal herniations might be explained by the inclusion of patients with associated foraminal stenosis. Thus, surgery should not be requested earlier just because the disk herniation is more lateral, moreover as motor weakness had disappeared in all cases at the end of follow-up. References Lejeune JP, et al. Spine (Phila Pa 1976) 1994:19:1905-8. Disclosure of Interest None Declared