RAPID3? Aptly named!

The RAPID3 score is the sum of three 0-10 patient self-report scores: pain, functional impairment on MDHAQ, and patient global estimate. It requires 5 seconds for scoring and can be used in all rheumatologic conditions, although it has mostly been used in rheumatoid arthritis where cutoffs for low disease activity (<6/30) or high disease activity (>12/30) have been set. A RAPID3 score of ≤ 3/30 with 1 or 0 swollen joints (RAPID3 ≤ 3 + ≤ SJ1) provides remission criteria comparable to Boolean, SDAI, CDAI, and DAS28 remission criteria, in far less time than a formal joint count. RAPID3 performs as well as the DAS28 in separating active drugs from placebos in clinical trials. RAPID3 also predicts subsequent structural disease progression. RAPID3 can be determined at short intervals at home, allowing the determination of the area under the curve of disease activity between two visits and flare detection. However, RAPID3 should not be seen as a substitute for DAS28 and face to face visits in routine care. Monitoring patient status with only self-report information without a rheumatologist's advice (including joints and physical examination, and consideration of imaging and laboratory tests) may indeed be as undesirable for most patients than joint examination without a patient questionnaire. Conversely, combining the RAPID3 and the DAS28 may consist in faster or more sensitive confirmation that a medication is effective. Similarly, better enquiring of most important concerns of patients (pain, functional status and overall opinion on their disorder) should reinforces patients' confidence in their rheumatologist and treatments.

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-1ß. 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-1ß 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-1ß, may contribute to inflammation and bone erosions in RA.

Rituximab therapy for systemic vasculitis associated with rheumatoid arthritis: Results from the AutoImmunity and Rituximab Registry.

OBJECTIVE: Rituximab improves articular symptoms in rheumatoid arthritis (RA) and it recently has been shown to be an effective induction therapy for antineutrophil cytoplasmic antibody-associated vasculitis. We assessed the efficacy and safety of rituximab in a real-life clinical setting among patients with systemic rheumatoid vasculitis (SRV). METHODS: We analyzed data from the AutoImmunity and Rituximab registry, which includes patients with autoimmune diseases treated with rituximab. RESULTS: Of the 1,994 patients with RA enrolled in the registry, 17 were treated with rituximab for active SRV. At baseline, the mean Birmingham Vasculitis Activity Score for RA (BVAS/RA) was 9.6, with a mean prednisone dosage of 19.2 mg/day. After 6 months of rituximab therapy, 12 patients (71%) achieved complete remission of their vasculitis, 4 had a partial response, and 1 died with uncontrolled vasculitis. Mean BVAS/RA was reduced to 0.6 and mean prednisone dosage to 9.7 mg/day. At 12 months, 14 patients (82%) were in sustained complete remission. Severe infection occurred in 3 patients, corresponding to a 6.4 per 100 patient-years rate. In the 6 patients who received further rituximab as maintenance therapy between months 6 and 12, no relapse of vasculitis was observed. However, among the 9 patients who did not, a relapse was observed in 3 patients who were treated with methotrexate alone. Remission was reestablished by reintroducing rituximab in 2 cases. CONCLUSION: Complete remission of SRV was achieved in nearly three-fourths of patients receiving rituximab in daily practice, with a significant decrease in daily prednisone dosage and an acceptable toxicity profile. Rituximab represents a suitable therapeutic option to induce remission in SRV, but maintenance therapy seems to be necessary.

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.

Alternative use of bisphosphonate therapy for rheumatic disease.

Bisphosphonates are widely use for pathologies such as osteoporosis, Paget's 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.

Lymphoma in patients treated with anti-TNF: results of the 3-year prospective French RATIO registry.

OBJECTIVE: To describe cases of lymphoma associated with anti-TNF therapy, identify risk factors, estimate the incidence and compare the risks for different anti-TNF agents. METHODS: A national prospective registry was designed (Research Axed on Tolerance of bIOtherapies; RATIO) to collect all cases of lymphoma in French patients receiving anti-TNF therapy from 2004 to 2006, whatever the indication. A case-control analysis was conducted including two controls treated with anti-TNF per case and an incidence study of lymphoma with the French population was used as the reference. RESULTS: 38 cases of lymphoma, 31 non-Hodgkin's lymphoma (NHL) (26 B cell and five T cell), five Hodgkin's lymphoma (HL) and two Hodgkin's-like lymphoma were collected. Epstein-Barr virus was detected in both of two Hodgkin's-like lymphoma, three of five HL and one NHL. Patients receiving adalimumab or infliximab had a higher risk than those treated with etanercept: standardised incidence ratio (SIR) 4.1 (2.3-7.1) and 3.6 (2.3-5.6) versus 0.9 (0.4-1.8). The exposure to adalimumab or infliximab versus etanercept was an independent risk factor for lymphoma in the case-control study: odds ratio 4.7 (1.3-17.7) and 4.1 (1.4-12.5), respectively. The sex and age-adjusted incidence rate of lymphoma was 42.1 per 100 000 patient-years. The SIR was 2.4 (95% CI 1.7 to 3.2). CONCLUSION: The two to threefold increased risk of lymphoma in patients receiving anti-TNF therapy is similar to that expected for such patients with severe inflammatory diseases. Some lymphomas associated with immunosuppression may occur, and the risk of lymphoma is higher with monoclonal-antibody therapy than with soluble-receptor therapy.

Validity of the polymyalgia rheumatica activity score in primary care practice.

OBJECTIVE: To evaluate the validity and reliability of the polymyalgia rheumatica (PMR) activity score (PMR-AS) for relapse diagnosis by general practitioners (GPs) who manage a large proportion of patients with PMR. METHODS: Seven clinical vignettes of PMR were used, for which 35 rheumatologists previously made a diagnosis of relapse or no relapse with greater than 80% agreement. These vignettes were submitted to 163 GPs, who were asked to assess disease activity using a visual analogue scale (VASph), this being the only physician-dependent component of the PMR-AS. The 1116 available vignette-GP combinations were used to assess differences in VASph assessed by GPs versus rheumatologists. Statistical associations linking a relapse diagnosis by the rheumatologists (the reference standard) to the value of the GP-assessed PMR-AS or its components (GP-assessed VASph, visual analogue scale pain score, C-reactive protein, morning stiffness and elevation of upper limbs) were evaluated. RESULTS: No significant differences were found between VASph scores by GPs versus rheumatologists for any of the vignettes. A relapse diagnosis was strongly associated with PMR-AS values of 7 or more (sensitivity 99.4%; specificity 93.3%; agreement 95.9% (95% CI 94.5% to 97.0%) with kappa = 0.92). Of the 590 GP-vignette combinations with PMR-AS values lower than 7, all but three (0.5%) had no relapse diagnosis. Of 510 combinations with PMR-AS values of 7 or more, only 42 (8%) had no flare diagnosis. CONCLUSIONS: This study supports the validity of the PMR-AS in primary care practice and provides evidence that a good scoring system can be useful to guide clinical and therapeutic decisions.

Characteristics and survival of 26 patients with paraneoplastic arthritis.

OBJECTIVE: To date, only a few series of patients with paraneoplastic arthritis have been published. The charts of patients with cancer-associated arthritis were collected in order to describe characteristics of this rheumatism. METHODS: A questionnaire was created for this study and validated by experts based on specific criteria of inclusion and exclusion. Histology of neoplasia was included. RESULTS: In all, 16 males and 10 females with a mean (range) age of 57.5 years (28-85) were recruited from 17 nationwide centres in France. Patients presented with symmetric polyarthritis involving wrists and hands (85%) and extra-articular symptoms were frequent (84%). There was no specific biologic or radiographic feature. The mean (range) delay between the diagnosis of rheumatism and neoplasia was 3.6 months (0-21.2). Tumours were usually diagnosed after articular symptoms occurred (88.5%). Twenty patients had a solid cancer, and six a haematological malignancy. Adenocarcinoma of the lungs was the most frequent type of solid cancer (60%). Tumours were diagnosed at an early stage, which may explain the good median survival of 1.21 years (range 0.64-present) with a mean follow-up of 1.9 years (range 0.16-10). The percentage of articular symptoms resolution was significantly higher in patients with solid tumours, as compared to patients with haemopathy (p = 0.007). In cases of tumour relapse, rheumatic symptoms did not recur for 75% of patients. CONCLUSIONS: Underlying neoplasia should be considered in male patients with new onset polyarthritis, smokers, and particularly in patients chronically ill. Additional investigations should then be performed to diagnose cancer at an early stage.

Clinical practice decision tree for the choice of the first disease modifying antirheumatic drug for very early rheumatoid arthritis: a 2004 proposal of the French Society of Rheumatology.

OBJECTIVE: To elaborate a clinical practice decision tree for the choice of the first disease modifying antirheumatic drug (DMARD) for untreated rheumatoid arthritis of less than six months' duration. METHODS: Four steps were employed: (1) review of published reports on DMARD efficacy against rheumatoid arthritis; (2) inventory of the information available to guide DMARD choice; (3) selection of the most pertinent information by 12 experts using a Delphi method; and (4) choice of DMARDs in 12 clinical situations defined by items selected in step 3 (28 joint disease activity score (DAS 28): < or =3.2; >3.2 and < or =5.1; >5.1; rheumatoid factor status (positive/negative); structural damage (with/without)-that is, 3 x 2 x 2). Thus, multiplied by all the possible treatment pairs, 180 scenarios were obtained and presented to 36 experts, who ranked treatment choices according to the Thurstone pairwise method. RESULTS: Among the 77 items identified, 41 were selected as pertinent to guide the DMARD choice. They were reorganised into five domains: rheumatoid arthritis activity, factors predictive of structural damage; patient characteristics; DMARD characteristics; physician characteristics. In the majority of situations, the two top ranking DMARD choices were methotrexate and leflunomide. Etanercept was an alternative for these agents when high disease activity was associated with poor structural prognosis and rheumatoid factor positivity. CONCLUSIONS: Starting with simple scenarios and using the pairwise method, a clinical decision tree could be devised for the choice of the first DMARD to treat very early rheumatoid arthritis.

[Chronic lower back pain: a new therapeutic approach]. / Lombalgies chroniques: une autre approche thérapeutique.

Lower back pain is a common complaint of patients seen in our consultations. Despite progress, surgical procedures are still often unsuccessful in relieving pain. Blocks performed in the epidural spaces or more often in the articular facets have provided poor relief of chronic lower back pain. The pain has vegetative components. Considering anatomic findings, we describe the innervation of the peridiscal tIssues which suffer during degenarative conditions. We analyze the course of the autogenic nerves mediating lumbar pain, and select the site of the blocks necessary to obtain optimal selective pain relief. A well-defined block at the level of the communicating rami is described.

Could rheumatoid arthritis result from an abnormal T cell response towards lubricin/superficial zone protein?

The lack of some suppressor T cells (including TCD4+CD25+(high) positively selected first in thymic medulla) specific to a restricted set of autoantigens may be the common link between all patterns of rheumatoid arthritis. In other words, instead of a 'peak' of TCD4+ effector T cells common to all patients with rheumatoid arthritis (which has so far never been demonstrated), a 'hole' in TCD4+CD25+(high) responses towards a limited set of autoantigens responsible for the normal maintenance of tolerance within the joints may be shared by many patients with rheumatoid arthritis. The hallmark of this disorder is the involvement of tissues subjected to friction stress bathed in a lubricating fluid (rheumatoid nodules and bursae, tendinous sheaths, pleura, pericardium, sclera, and joints covered by hyaline cartilage). Consequently, autoantigens shared by all forementioned places may be better candidates than autoantigens restricted to the hyaline cartilage (like collagen II). Tenosynovitis, bursitis and rheumatoid nodules can herald rheumatoid arthritis, and rheumatoid pericarditis is very frequent at the histological level. Lubricin and superficial zone protein (SZP), which are closely related products of the megacaryocyte stimulating factor (MSF) gene, are among the best candidate autoantigens for such a positive selection of suppressor T cells. Lubricin is responsible for most of the lubricating properties of synovial fluid, and SZP (expressed by the superficial articular chondrocytes from diarthrodial cartilages and lining cells of synovial villi) also shares lubricating and cytoprotective properties. Moreover, the expression of lubricin is very probable in pericardium and pleura, and can be induced by friction stress. Although this mucinous glycoprotein may already share close similarities at the antigenic levels with mucins previously demonstrated in Hassall's corpuscles of the thymus, evidence for the ectopic expression of lubricin/SZP within normal human thymus may further support this hypothesis. The prenatal positive selection within the thymus of a functional pool of TCD4+CD25+(high) clones specific for most peripheral tissues is critical (at least in mice) for the quality of tolerance for the rest of the organism's lifespan. Therefore, a poor expression of lubricin/SZP early in life within the human thymus may also favour a lack of suppressor T cells specific to tissues bathed with synovial fluid, i.e. the onset of rheumatoid arthritis later on in life. As studies of human thymus long before the onset of rheumatoid arthritis are hampered for obvious reasons, studies of murine thymus could be a first step. In as much as the human counterpart of lubricin is expressed in the thymic medulla of mice, the generation of knocked-out mice for its expression within the thymus could be one of the best models to test the above hypothesis. The stimulation of TCD4+CD25+(high) clones specific for immunodominant epitopes from the joints/synovial fluid (belonging perhaps to lubricin or SZP) could help restore a normal balance between effector T cells and suppressor T cells in rheumatoid arthritis patients.

Psoriatic arthritis as a mountain.

The concept of psoriatic arthritis (PsA) is not yet universally accepted. Indeed, few of the features said to be characteristic for PsA are pathognomonic, and a same patient can be classified as RA, SpA or PsA depending on the physician seen. The heterogeneity of PsA, the lack of significant differences in early-arthritis with and without psoriasis, and a pathogenesis somewhat different in PsA and psoriasis, also argue against the originality of PsA. Nevertheless, although PsA is possibly "just" a syndrome depending on the combination of numerous co-factors (perhaps shared with SpA and/or RA), its more achieved forms deserve to be segregated from other SpA and RA. Indeed, PsA best bridges the gap with SAPHO syndromes. Moreover, the profile of synovial cytokines seems somewhat different in PsA as compared to RA and SpA, and a special pattern of vascularisation has been confirmed by several teams which could account for the demonstrated link between trauma and some PsA onsets. Both the greater familial risk for PsA than for RA or psoriasis alone and the excessive paternal transmission of PsA strongly suggest a genetic background, although so far only MICA-A9 (expressed on gut epithelial cells) seems to be associated with susceptibility to PsA independently from psoriasis. To make further genetics studies informative, a careful selection of unequivocal cases of PsA is needed, which requires criteria selecting patients at the "top of the mountain" of PsA. One can expect that the sets of criteria proposed by McGonagle or Fournié could satisfy this wish.

Confidence in the diagnosis of early spondylarthropathy: a prospective follow-up of 270 early arthritis patients.

OBJECTIVE: To study the confidence of office-based rheumatologists (OBR) and a college of 5 experts in their diagnosis of spondylarthropathy (SpA) for early arthritis after more than 2 years of follow-up; to determine whether at that time the degree of confidence was improved by the fulfilment of the ESSG criteria. METHODS: 270 patients with early-onset (< 1 year) arthritis were prospectively followed-up for 29+/-11 months. At the final examination, OBR and the college of 5 experts rated their confidence in the diagnosis of SpA on a 0-10 analogue scale and on a 1-4 Likert scale, respectively. RESULTS: After 29+/-11 months OBR had classified 56 patients (21%) as SpA, while a collegial diagnosis of probable (N = 32) or certain SpA (N = 14) was made for 46 patients (17%). At the final examination OBR confidence in their diagnosis (gold standard) was only 6.7+/-2.4 for all 56 cases of SpA. The cumulative fulfilment of ESSG criteria for SpA after 29+/-11 months correlated with the confidence of OBR and the experts in SpA, but improved only slightly the final confidence of OBR (7.1+/-2.3 versus 6.7+/-2.4 for all 56 SpA). Similarly, OBR confidence for the 18/56 SpA patients positive for HLA-B27 was only 7.1+/-2.0. Only 21 of these 56 patients were considered as SpA at baseline, although 37/56 (66%) had fulfilled ESSG criteria since thefirst examination. CONCLUSION: This study indicates a probable lack of consensus on the nosology of early SpA and the limited help provided by the ESSG criteria to differentiate early SpA from otherforms of arthritis at baseline.

[Rhizomelic pseudopolyarthritis: update]. / Pseudopolyarthrites rhizoméliques: mise au point.

PURPOSE: Update of recent works on polymyalgia rheumatica (PMR). CURRENT KNOWLEDGE ANS KEY POINTS: In polymyalgia rheumatica (PMR) unassociated with giant cell arteritis (GCA) (twice as frequent as GCA without PMR) several recent works demonstrated by MRI or echography that synovitis and/or subacromial bursitis accounted for most of the painful shoulders and could be relieved by steroid injections. Peripheral synovitis can also occur in 10-20% of PMR, and lead to consideration of other diagnoses, mostly RA or the RS3PE syndromes for those cases of PMR with peripheral edema. PMR with asymmetrical onset are often difficult to diagnose early, and the classification criteria for PMR are not widely accepted. When clinical signs suggestive of GCA are lacking, temporal biopsy is positive in only 1 to 5% of PMR cases. Several studies on PMR with so-called 'normal' ESR (below 30 mm, first hour) have cast doubts on the value of this biological sign (although 'normal ESR' should only stand for values below 11 mm). Hence it would be worthwhile to study whether CRP and even SAA deserve to be added to future sets of criteria for PMR. A defect in hypothalamic axis response is often noticed and could play a part in PMR pathogenesis, thus explaining why PMR is quite exclusively noticed after ages 50 or 60. Two-thirds of patients can stop prednisone within 2 years after the onset of treatment. The lack of a prompt response within the first days should suggest differential diagnoses, including some myelodysplastic disorders. FUTURE PROSPECTS AND PROJECTS: The search for genetic factors common or specific to PMR and GCA could enhance our understanding of these overlapping syndromes. Studies of the transcriptosomes of lymphocytes infiltrating the target tissues (arterial wall in GCA, synovium in PMR) might also prove informative. Controlled studies of new biological treatments like cytokine inhibitors (anti-TNF-alpha, anti-interferon gamma) could demonstrate a clear sparing effect in steroids, a goal not yet achieved by the use of current DMARDs, including MTX.

Differences in understanding and application of 1987 ACR criteria for rheumatoid arthritis and 1991 ESSG criteria for spondylarthropathy. A pilot survey.

OBJECTIVES: To determine areas of agreement and disagreement among experts in the interpretation of the published criteria for RA (ACR) and spondylarthropathies ( ESSG). METHODS: Thirty-two experts (16 from France and 16 from 10 other countries) replied anonymously to a mailed questionnaire. RESULTS: Tenosynovitis and 'sausage-like' painless swelling of the toes were considered as criteria for RA by 18 and 14 experts, respectively. The definition of symmetry differed widely among experts (symmetry of only one group of joints was sufficient for 13). Twenty-five experts considered erosions of other joints than the wrists and fingers as a criterion for RA, 17 thought that fulfilment of criteria could be achieved cumulatively, and 19 would appreciate clarifications of the current criteria. Among possible clarifications for RA, it was frequently recommended that morning stiffness and nodules be eliminated and that new marker antibodies, X-rays of the feet, and exclusion criteria be added. Twenty-three of the 29 experts who gave an opinion (79%) agreed with the notion of SP in the absence of axial signs and sacroiliitis, 26/31 (84%) indicated that a patient can have both RA and SP, and 19/30 (63%) thought that RA and SP could be regarded as syndromes more than diseases. Only 5/32 experts relied more on the criteria than on their clinical judgement in diagnosing RA. CONCLUSIONS: There would seem to be a needfor the optimisation of RA and ESSG criteria, particularly within the context of early arthritis.