[Aphthous mouth ulcers as an initial manifestation of sécukinumab-induced inflammatory bowel disease]. / Ulcérations buccales aphtoïdes inaugurales d'une maladie inflammatoire chronique de l'intestin induite par le sécukinumab.

BACKGROUND: Secukinumab, a humanized monoclonal antibody targeting interleukin 17A, has been associated with the development of inflammatory bowel diseases. We report a case of a female patient developing recurrent oral ulcers prior to inflammatory bowel disease induced by secukinumab. The patient had developed similar oral ulcers 6 years earlier while on tocilizumab (targeting IL6R), suggesting an immunological link between the two episodes. PATIENTS AND METHODS: A 36-year-old female patient had refractory spondylarthrosis. In 2010, she had presented oral aphthous ulcers during treatment with tocilizumab. In 2011, tocilizumab was stopped and the ulcers resolved. In 2016, secukinumab was introduced and led to recurrence of oral aphthous ulcers followed by ileitis-pancolitis. Corticosteroids and ustekinumab resulted in partial remission. DISCUSSION: The patient developed inflammatory bowel disease during treatment with secukinumab, preceded by recurrent oral aphthous ulcers. She had presented similar oral ulcers 6 years earlier while on a treatment targeting IL6R. IL6 is a pleiotropic cytokine that may activate the Th17 pathway. Thus, tocilizumab could have induced an "anti-IL17-like" effect, accounting for the occurrence of oral aphthous ulcers, possibly related to mild inflammatory bowel disease. CONCLUSION: The occurrence of oral ulcers during treatment with secukinumab may herald inflammatory bowel disease. In patients with a previous history of recurrent aphthous stomatitis, especially where induced by previous biologics, consideration must be given to the risk-benefit ratio of prescribing an anti-IL17 antibody.

[Immunogenicity of biopharmaceuticals: Which consequences during the treatment of rheumatoid arthritis?]. / Immunogénicité des biomédicaments : quelles conséquences au cours du traitement de la polyarthrite rhumatoïde ?

The biopharmaceuticals used in rheumatology are monoclonal antibodies, chimeric (-ximab), humanized (-zumab) or fully human (-[m]umab), or fusion proteins. The immunogenicity, that is the ability to develop an immune response towards biopharmaceuticals and leading to the production of anti-drug antibodies (ADA), may be observed in nearly 30% of patients with monoclonal antibodies, more rarely with fusion proteins. The immunogenicity may lead to an increase of clearance, a reduction of half-life and serum concentration of biopharmaceuticals, a decrease of clinical response and therapeutic maintenance, as well as the occurrence of immuno-allergic reactions. However, we must relativize the importance of this phenomenon because in registers with anti-TNFα, the survival curve of monoclonal antibodies is much closed to that of fusion proteins. The immunogenicity is only one of the factors allowing to explain the clinical response, or the lack of response, with biopharmaceuticals. This phenomenon may explain some clinical situations (secondary failures, adverse reactions), but other factors (weight, inflammatory activity, combination with an immunosuppressive agent, etc.) may influence, more importantly than immunogenicity, the dose-response relationship with biopharmaceuticals.

Rituximab-induced T cell depletion in patients with rheumatoid arthritis: association with clinical response.

OBJECTIVE: Rituximab, a monoclonal antibody specifically targeting CD20, induces B cell depletion and is effective in the treatment of rheumatoid arthritis (RA). This study was undertaken to evaluate whether routine monitoring of lymphocyte subpopulations, especially T cells, may be useful in patients receiving rituximab for RA. METHODS: We examined data on all RA patients receiving rituximab between July 2007 and November 2012 in our center. Peripheral blood CD3+, CD4+, CD8+, CD3-CD56+, and CD19+ lymphocyte counts before and during the first course of rituximab were measured by flow cytometry. The Mann-Whitney nonparametric test was used to compare lymphocyte subpopulation counts before and during treatment. RESULTS: Data on 52 patients were examined. Rituximab induced unexpected and substantial depletion of T cells, mainly CD4+ cells, in most patients. The CD4+ cell count decreased by a mean ± SD of 37 ± 33% as compared to baseline at week 12, reaching <200 cells/µl in 3 patients. Importantly, lack of CD4+ cell depletion was associated with no clinical response. Therefore, the mechanism of action of rituximab may depend at least in part on T cells. CONCLUSION: Rituximab induces substantial T cell depletion, mainly of CD4+ cells, which is associated with the clinical response in RA. Routine monitoring of T cells may be useful in the clinical setting of RA.

[Persistent aphthous mouth ulcers associated with tocilizumab: two cases]. / Ulcérations buccales aphtoïdes persistantes associées au tocilizumab: deux cas.

BACKGROUND: Tocilizumab, a humanized monoclonal antibody that blocks interleukin-6 receptor, is approved for use in rheumatological diseases. The most frequent adverse events reported are infections. We describe for the first time the occurrence of recurrent aphthous mouth ulcers in two patients on TCZ. PATIENTS AND METHODS: Two patients were treated with TCZ for rheumatological disease. A few weeks after administration of TCZ, they presented with multiple painful mouth ulcers that would not heal until TCZ had been withdrawn. In both cases, the oral ulcers resolved 6 to 7weeks after withdrawal of TCZ and readministration of the drug led to recurrence of oral ulcers within 10days in both patients. DISCUSSION: We describe for the first time the occurrence of aphthous mouth ulcers induced by TCZ. The causative role of TCZ was established by positive rechallenge. These cases were similar to a recently reported case of multiple intestinal aphthous ulcers occurring during TCZ treatment. Such mucosal side effects may be explained by similar inflammatory mechanisms but appear paradoxical because TCZ inhibits a pro-inflammatory cytokine, interleukin 6. TCZ treatment can be maintained if necessary, in combination with colchicine, as reported for one of our patients.

Effectiveness of adalimumab in treating patients with active psoriatic arthritis and predictors of good clinical responses for arthritis, skin and nail lesions.

OBJECTIVES: To evaluate the effectiveness of adalimumab in patients with psoriatic arthritis (PsA) and identify predictors of good clinical response for joint and skin lesions. METHODS: Patients received adalimumab 40 mg every other week in addition to standard therapy in this prospective, 12-week, open-label, uncontrolled study. Four definitions of good clinical response were used: > or =50% improvement in American College of Rheumatology response criteria (ACR50), good response according to European League Against Rheumatism (EULAR) guidelines, a > or =3-grade improvement in Physician Global Assessment of psoriasis (PGA) and a > or =50% improvement in the Nail Psoriasis Severity Index (NAPSI). Response predictors were determined by logistic regression with backward elimination (selection level was 5%). RESULTS: Of 442 patients, 94% completed 12 weeks of treatment. At week 12, 74%, 51% and 32% of the patients had achieved ACR20, 50 and 70, respectively; 87% and 61% experienced moderate and good responses according to EULAR criteria, respectively. The percentage of patients with PGA results of "clear/almost clear" increased from 34% (baseline) to 68%. The mean NAPSI score was reduced by 44%. No new safety signals were detected. A lower Health Assessment Questionnaire Disability Index (HAQ-DI) score, greater pain assessment, male sex and absence of systemic glucocorticoid therapy were strongly associated with achievement of ACR50 and good response according to EULAR criteria. In addition, greater C-reactive protein concentration and polyarthritis predicted ACR50, and non-involvement of large joints predicted a good response according to EULAR criteria. CONCLUSIONS: Adalimumab was effective in patients with PsA. Lower impairment of physical function, greater pain, male sex and no systemic treatment with glucocorticoids were factors that increased the chance of achieving a good clinical response.

Single, intra-articular treatment with 6 ml hylan G-F 20 in patients with symptomatic primary osteoarthritis of the knee: a randomised, multicentre, double-blind, placebo controlled trial.

OBJECTIVES: The primary objective was to compare a single, 6 ml, intra-articular injection of hylan G-F 20 with placebo in patients with symptomatic knee osteoarthritis. The safety of a repeat injection of hylan G-F 20 was also assessed. METHODS: Patients with primary osteoarthritis knee pain were randomly assigned to arthrocentesis plus a 6 ml intra-articular injection of either hylan G-F 20 or placebo in a prospective, double-blind (one injector/one blinded observer) study. RESULTS: were evaluated at 4, 8, 12, 18 and 26 weeks post-injection. The primary outcome criterion was change from baseline over 26 weeks in Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index A pain. Secondary outcome measures included WOMAC A1 and C, patient global assessment (PGA) and clinical observer global assessment (COGA) and Outcome Measures in Rheumatology, Osteoarthritis Research Society International responder rates. A 4-week, open, repeat treatment phase evaluated safety only. Results: A total of 253 patients (Kellgren-Lawrence grade II or III) was randomly assigned. Patients receiving hylan G-F 20 experienced statistically significantly greater improvements in WOMAC A pain scores (-0.15, SE 0.076, p = 0.047), and several of the secondary outcome measures (WOMAC A1, PGA and COGA), than patients receiving placebo. There was no difference between the safety results of the two groups. No increased risk of local adverse events was observed in the open, repeat treatment phase. CONCLUSIONS: This placebo-controlled study demonstrated that, in patients with knee osteoarthritis, a single 6 ml intra-articular injection of hylan G-F 20 is safe and effective in providing statistically significant, clinically relevant pain relief over 26 weeks, with a modest difference versus placebo.

Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three-year prospective French Research Axed on Tolerance of Biotherapies registry.

OBJECTIVE: Tuberculosis (TB) is associated with anti-tumor necrosis factor (anti-TNF) monoclonal antibody (mAb) therapy, but whether this association is drug-specific remains a concern. Our objective was to describe cases of TB associated with anti-TNF mAb therapy, identify risk factors, and estimate the incidence. METHODS: We conducted an incidence study and a case-control analysis to investigate the risk of newly diagnosed TB associated with the use of anti-TNF agents. As part of the French Research Axed on Tolerance of Biotherapies (RATIO) registry, for 3 years we collected cases of TB among French patients receiving anti-TNF mAb therapy for any indication; for each case, 2 patients treated with anti-TNF agents served as control subjects. RESULTS: We collected 69 cases of TB in patients treated for rheumatoid arthritis (n = 40), spondylarthritides (n = 18), inflammatory colitis (n = 9), psoriasis (n = 1) and Behçet's disease (n = 1) with infliximab (n = 36), adalimumab (n = 28), and etanercept (n = 5). None of the patients had received correct chemoprophylactic treatment. The sex- and age-adjusted incidence rate of TB was 116.7 per 100,000 patient-years. The standardized incidence ratio (SIR) was 12.2 (95% confidence interval [95% CI] 9.7-15.5) and was higher for therapy with infliximab and adalimumab than for therapy with etanercept (SIR 18.6 [95% CI 13.4-25.8] and SIR 29.3 [95% CI 20.3-42.4] versus SIR 1.8 [95% CI 0.7-4.3], respectively). In the case-control analysis, exposure to infliximab or adalimumab versus etanercept was an independent risk factor for TB (odds ratio [OR] 13.3 [95% CI 2.6-69.0] and OR 17.1 [95% CI 3.6-80.6], respectively). Other risk factors were age, the first year of anti-TNF mAb treatment, and being born in an endemic area. CONCLUSION: The risk of TB is higher for patients receiving anti-TNF mAb therapy than for those receiving soluble TNF receptor therapy. The increased risk with early anti-TNF treatment and the absence of correct chemoprophylactic treatment favor the reactivation of latent TB.

Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the clinical response, safety, and tolerability of a single intraarticular injection of anakinra in patients with symptomatic osteoarthritis (OA) of the knee. METHODS: Patients with OA of the knee were enrolled in a multicenter, double-blind, placebo-controlled study and randomized 2:1:2 to receive a single intraarticular injection of placebo, anakinra 50 mg, or anakinra 150 mg in their symptomatic knee. Patients were evaluated for 12 weeks postinjection. The primary end point was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score from baseline to week 4. Safety assessments included the evaluation of adverse events (AEs), laboratory tests, and vital signs. Pharmacokinetic parameters were assessed in a subset of patients. RESULTS: Of 170 patients who enrolled, 160 (94%) completed the study. The mean improvements from baseline to week 4 in the WOMAC score were not statistically different between the placebo group and the patients who received 50 mg of anakinra (P = 0.67) or 150 mg of anakinra (P = 0.77). Anakinra was well tolerated. No withdrawals due to AEs or serious AEs, and no serious infections or deaths were reported. No clinically significant trends were noted in laboratory values or vital signs. Pharmacokinetic parameters demonstrated that the mean terminal half-life of anakinra in serum after intraarticular injection was approximately 4 hours. CONCLUSION: Anakinra was well tolerated as a single 50-mg or 150-mg intraarticular injection in patients with OA of the knee. However, anakinra was not associated with improvements in OA symptoms compared with placebo.

[What are the risks of not intensively treating a chronic inflammatory disease?]. / Quels sont les risques à ne pas traiter intensivement une maladie inflammatoire chronique?

With more than 10 years of experience in rheumatology and thousands of patients treated, the infectious and oncological risks of TNF-alpha blocking agents are well known. The efficacy of biotherapies in rheumatismal diseases has been largely demonstrated. The recent review of publications and communications shows that biotherapies benefit the comorbidities associated with inflammatory rheumatisms (uveitis, Crohn disease, hemorrhagic rectocolitis, stroke, myocardial infarction). They can even reduce the excess mortality of chronic rheumatoid inflammatory diseases.

Radiological damage in patients with rheumatoid arthritis on sustained remission.

OBJECTIVE: To assess the radiological damage progression in patients with recent rheumatoid arthritis in sustained remission. METHODS: A cohort of 191 patients with active early (<1 year) rheumatoid arthritis was prospectively assessed at baseline, 3 and 5 years by the Disease Activity Score (DAS) and the Sharp-van der Heijde Score (SHS) for radiographic damage. Patients in remission (DAS<1.6) at the 3-year and 5-year time points were compared with patients with a persistently active rheumatoid arthritis by Wilcoxon's signed rank test. RESULTS: 57 patients died, were lost to follow-up or had incomplete data; 30 (15.7% of those who completed) patients were in remission at 3 and 5 years. The SHS in these two groups was not significantly different at baseline (p = 0.15), but was lower in the remission group at 5 years (p = 0.0047). The median (IQR) radiographic score increased from 0.5 (0-7) at baseline to 2.5 (0-14) after 5 years for the remission group (p = 0.18) and from 2 (0-7) to 13 (3-29) in the group with active rheumatoid arthritis (p<0.001). 5 (16.7%) patients in remission had relevant progression of radiographic damage (ie, progression >4.1 points) and 6 (20%) presented new erosions in a previously unaffected joint between the third and the fifth years. CONCLUSION: Patients with early rheumatoid arthritis in sustained remission did not present statistically significant radiographic degradation at the group level; nevertheless, 16.7% of these patients did present degradation. Absence of progression should be part of the remission definition in rheumatoid arthritis.

Prognostic factors for remission in early rheumatoid arthritis: a multiparameter prospective study.

OBJECTIVE: To determine prognostic factors for remission in early rheumatoid arthritis. METHODS: 191 patients with rheumatoid arthritis whose disease duration was less than one year were followed up prospectively for five years. Remission, defined by a disease activity score (DAS) of <1.6, was used as the outcome measure. Baseline clinical, laboratory, genetic, and radiographic data (with radiographic scores determined by Sharp's method, modified by van der Heijde) were obtained. RESULTS: 48 patients (25.1%) fulfilled the remission criteria at the three year follow up visit, and 30 (15.7%) at three and five years. On univariate analysis by Fisher's exact test, remission at three years and persistent remission at five years were closely correlated with baseline DAS values, C reactive protein level, Ritchie score, health assessment questionnaire score, duration of morning stiffness, and to a lesser extent baseline total radiological scores and rheumatoid factor negativity. No significant correlation was found with sex, age, extra-articular manifestations, erythrocyte sedimentation rate, anti-cyclic citrullinated protein antibodies, anti-keratin antibodies, anti-HSP 90, anticalpastatin antibodies, antinuclear antibodies, or HLA-DRB1* genotypes. Logistic regression analysis showed that the baseline independent variables predictive of remission were low DAS, Ritchie score, morning stiffness duration, and total radiographic score. CONCLUSIONS: Baseline prognostic factors for remission in early rheumatoid arthritis were mainly clinical markers of disease activity and radiological scores.

Long term structural effects of combination therapy in patients with early rheumatoid arthritis: five year follow up of a prospective double blind controlled study.

OBJECTIVE: To evaluate whether early combined therapy with methotrexate (MTX) and sulfasalazine (SSZ) during the first year in early rheumatoid arthritis (RA) induces long term beneficial effects, compared with monotherapy, when the further treatment strategy is a free choice. STUDY DESIGN: five year multicentre prospective longitudinal trial. PARTICIPANTS: 146/205 patients with RA previously included in a one year prospective randomised trial comparing the effects of treatment with MTX, SSZ, or a combination of both. Criteria for inclusion: patients with early RA (< or =1 year duration). Follow up: between the end of years 1 and 5, patients were followed up and treated by their own rheumatologist, who was allowed to indicate any treatment. OUTCOME MEASURES: disease activity score (DAS), health assessment questionnaire (HAQ), and Sharp/van der Heijde radiological score at baseline and after five years of follow up. ANALYSIS: comparison of the five year follow up DAS, HAQ, and radiological scores in patients given combined and single treatment during the first year. RESULTS: At the end of the five years of follow up, the patients primarily receiving single or combined treatment had similar mean DAS, HAQ, and radiographic scores. CONCLUSION: Treatment of patients with early RA using combined therapy with MTX and SSZ during the first year did not influence the long term inflammatory status, or disability, or structural changes, compared with single disease modifying antirheumatic drug treatment.

Epidural corticosteroid injections for sciatica: a randomised, double blind, controlled clinical trial.

OBJECTIVE: To determine the efficacy of epidural corticosteroid injections for sciatica. METHODS: Three epidural injections (two day intervals) of 2 ml prednisolone acetate (50 mg) or 2 ml isotonic saline were administered to patients with sciatica presumably due to a disk herniation lasting 15-180 days. Self evaluation was the main judgment criterion at day 20. Patients who recovered or showed marked improvement were considered as success. Pain measured by VAS, the SLR test, Schober's test, Dallas pain questionnaire, and the Roland-Morris index were evaluated at days 0, 5, 20, and 35. Only analgesics were authorised, patients requiring non-steroidal anti-inflammatory drugs (NSAIDs) before day 20 were considered as failure. RESULTS: 42 patients were included in the control group (CG), 43 in the steroid group (SG). On an intention to treat analysis 15/42 (36%) in the CG and 22/43 (51%) in the SG (p=0.15) were considered as success (difference 15.5%, 95% CI (-5.4 to 36.3)). Among the 48 failures, 14 patients (6 CG, 8 SG) required NSAIDs, 3 (2 CG, 1 SG) required surgery, and 7 (3 CG, 4 SG) other treatments. On analysis according to protocol, in 74 remaining patients 12/35 (34%) in the CG and 22/39 (56%) in the SG (p=0.057) were considered as success (difference 22.1%, 95% CI (0.0 to 44.2)). For all secondary end points intragroup improvement with time was significant, but intergroup differences were not. CONCLUSION: The efficacy of isotonic saline administered epidurally for sciatica cannot be excluded, but epidural steroid injections provide no additional improvement.

Prognostic factors for radiographic damage in early rheumatoid arthritis: a multiparameter prospective study.

OBJECTIVE: To determine prognostic factors of radiologic damage and radiologic progression in early rheumatoid arthritis (RA). METHODS: A cohort of 191 patients with RA whose disease duration was shorter than 1 year were prospectively followed up for 3 years. Radiologic scores (as determined by Sharp's method, modified by van der Heijde) and radiologic progression were used as outcome measures. Numerous baseline clinical, laboratory, genetic, and radiographic data were obtained. RESULTS: The change in the total radiologic score for the patients followed up over 3 years was a mean +/- SD increase of 6.1 +/- 6.2. Radiologic progression was observed in 71 of the 172 patients for whom there were data at the end of the study. By univariate analysis with Fisher's exact test, radiologic scores and progression at followup were closely correlated with the baseline values of the erythrocyte sedimentation rate (ESR), C-reactive protein level, IgM and IgA rheumatoid factor positivity, antiperinuclear antibody positivity, radiologic scores, duration of morning stiffness, and RA-associated HLA-DRB1*04 genes. No correlation was demonstrated with sex, age, Disease Activity Score, swollen or tender joint counts, extraarticular manifestations, Health Assessment Questionnaire score, Ritchie Articular Index, patient's assessment of pain, positivity for anti-heat-shock protein 90-kd antibodies, anticalpastatin antibodies, anti-RA33 antibodies, antinuclear antibodies, YKL-40, or antikeratin antibodies, and HLA-DRB1*01 genes. The logistic regression analysis revealed that the only baseline values that were predictive of the 3-year radiologic scores were IgM rheumatoid factor positivity, DRB1*04 genes, pain score, and total radiologic score. Progression of joint damage was predicted by the ESR, IgM rheumatoid factor positivity, DRB1*04 genes, and erosions score at baseline. CONCLUSION: Prognostic factors for radiographic damage in early RA were identified. A combination of these baseline values allowed us to draw up a predictive arithmetic score that could be used to predict radiologic damage at 3 years and radiologic progression in individual patients.

Factors predicting radical treatment after in-hospital conservative management of disk-related sciatica.

OBJECTIVE: To determine predictive factors for radical treatment (nucleolysis or surgery) after in-hospital conservative management of low back pain with sciatica (LBPS). PATIENTS AND METHODS: A standardized form was used to collect data on 134 patients admitted for conservative treatment of LBPS. Subsequent radical procedures were recorded 11 to 24 months after discharge. RESULTS: Forty-seven patients required radical treatment after discharge. Significant risk factors for radical treatment in the univariate analysis were taller stature, use of a lumbar support, more preadmission epidural injections, a positive straight leg-raising test, and a disk herniation diameter of at least 50% of the spinal canal diameter. Protective factors were onset within the month preceding admission and normal range of motion of the lumbar spine. In the multivariate analysis, symptom duration longer than one month, use of a lumbar support prior to admission, and a positive straight leg-raising test were associated with radical treatment. A positive straight leg-raising test was the only significant clinical risk factor in the subset of patients investigated by computed tomography (CT). When CT findings were added to the model, only size of the herniation was significant. CONCLUSION: Sixty-five percent of patients admitted for conservative treatment of LBPS do not receive radical treatment during a mean follow-up of 18 months. Several factors are associated with the likelihood of radical treatment.

Magnetic resonance imaging: a valuable method for the detection of synovial inflammation in rheumatoid arthritis.

OBJECTIVE: Clinical assessment of rheumatoid arthritis (RA) based on pain and swelling and physical examination is limited by observer error and interpretation. We compared magnetic resonance imaging (MRI) and clinical examination to detect synovitis in RA. METHODS: Twelve patients with active RA were assessed according to Ritchie index, swollen joint count and score, swollen joint count of hands and wrists [2 wrists, 10 metacarpophalangeal (MCP), 10 proximal interphalangeal (PIP)], morning stiffness, pain intensity, Disease Activity Score (DAS), erythrocyte sedimentation rate, and C-reactive protein. MR images of hands and wrists were obtained with an adapted device, on T1 weighted (T1W) spin echo (SE) coronal images before and after gadolinium DTPA, TIW SE axial images with gadolinium DTPA, T2* gradient echo recall coronal and axial sequences, and assessed by 2 radiologists (O = no synovitis, 1 = synovitis). RESULTS: The swollen joint count on hands and wrists was 59 on clinical examination (mean 5.08 +/- 3.15 per patient; 20/24 wrists, 7/120 MCP, 32/120 PIP) and 162 on MRI (mean 13.50+/- 5.65; 22/24 wrists, 70/120 MCP, 70/120 PIP). Statistically significant correlations were found between MRI synovitis count and swollen joint count (p = 0.015) and score (p = 0.019), Ritchie Index (p = 0.035), DAS (p = 0.02) and morning stiffness (p = 0.07). MRI revealed synovitis significantly more often than clinical examination (162 vs 59; p = 0.00002) [2-fold in PIP (70/32) and 10-fold in MCP (70/7)]. Clinical examination and MRI were concordant for 157/264 joints (59.5%). The association of normal MRI with synovitis on clinical examination was observed in 2 cases, the opposite in 105. CONCLUSION: MRI is more sensitive than clinical examination to detect synovitis of hands and wrists in RA, especially for MCP and PIP joints, and is valuable for assessment of inflammation in hands and wrists in RA.