The impact of an in-department pharmacist on the prevention of drug iatrogenesis in a rheumatology department.

INTRODUCTION/OBJECTIVES: The primary objective was to evaluate the impact of an in-department pharmacist on the prevention of drug iatrogenesis in a rheumatology department. Secondary objectives were to determine (i) if medication history discrepancies were detected more frequently in the elderly or not, and (ii) if the mean number of treatments at admission had an impact on the number of medication history discrepancies. METHODS: Implementation of a clinical-pharmacy program based on medication reconciliation and medication review of prescription for all patients admitted to a rheumatology department between January and June 2017. The analytical approach was mainly descriptive and data were expressed as mean ± standard deviation (i.e., number of treatments at admission, number of medication reconciliations) and as proportions (i.e., acceptance rate, impact). Chi-squared tests and Student's test were performed to determine if there was a significant difference in outcomes. RESULTS: Three hundred twelve patients were included in the study, 517 medication history discrepancies in 243 (77.8%) patients and 196 pharmaceutical interventions in 133 (42.6%) patients. A significant difference was found in the number of medication history discrepancies and pharmaceutical interventions between the two age groups and in the mean number of treatments at admission between patients with or without medication history discrepancies. 15.4% of study patients had major medication history discrepancies and major pharmaceutical interventions. All patients and practitioners reported the usefulness of an in-department pharmacist. CONCLUSION: This program was found effective in terms of safety and improvement in the continuity of care. Key Points • This clinical-pharmacy program with an in-department pharmacist had a positive impact on the prevention of drug iatrogenesis in one rheumatology department. • 15.4% (n = 48) of study patients had major medication history discrepancies and major pharmaceutical interventions. • All practitioners and patients were satisfied with this clinical-pharmacy program.

Crizotinib-induced osteitis mimicking bone metastasis in a stage IV ALK-rearranged NSCLC patient: a case report.

BACKGROUND: Targeted therapies are a standard of care for first-line treatment of Anaplastic lymphoma kinase (ALK)-rearranged non small cell lung cancer (NSCLC). Giving the rapid pace of drug discovery and development in this area, reporting of adverse effects of ALK inhibitors is crucial. Here, we report a case of osteitis induced by an ALK inhibitor mimicking bone metastasis, a previously undescribed side effect of crizotinib. CASE PRESENTATION: A 31-year-old woman with stage IV ALK-rearranged NSCLC presented with back pain after 3 months of crizotinib treatment. Diagnostic work-up showed osteitis on the 4th and 5th thoracic vertebrae, anterior soft tissue infiltration and epiduritis, without any sign of infection. Spinal cord decompression, histological removal and osteosynthesis were performed. Histologic examination showed necrosis with abundant peripheral neutrophils, no microorganism nor malignant cell. Symptoms and Computarized Tomography-abnormalities rapidly diseappeared after crizotinib withdrawal and did not recur after ceritinib onset. CONCLUSIONS: This is the first report of crizotinib-induced osteitis. Crizotinib differs from other ALK inhibitors as it targets other kinases as well, which may have been responsible for the osteitis. Crizotinib can induce rapidly extensive osteitis, which can mimic tumor progression.

Pre-silencing of genes involved in the electron transport chain (ETC) pathway is associated with responsiveness to abatacept in rheumatoid arthritis.

BACKGROUND: In the current context of personalized medicine, one of the major challenges in the management of rheumatoid arthritis (RA) is to identify biomarkers that predict drug responsiveness. From the European APPRAISE trial, our main objective was to identify a gene expression profile associated with responsiveness to abatacept (ABA) + methotrexate (MTX) and to understand the involvement of this signature in the pathophysiology of RA. METHODS: Whole human genome microarrays (4 × 44 K) were performed from a first subset of 36 patients with RA. Data validation by quantitative reverse-transcription (qRT)-PCR was performed from a second independent subset of 32 patients with RA. Gene Ontology and WikiPathways database allowed us to highlight the specific biological mechanisms involved in predicting response to ABA/MTX. RESULTS: From the first subset of 36 patients with RA, a combination including 87 transcripts allowed almost perfect separation between responders and non-responders to ABA/MTX. Next, the second subset of patients 32 with RA allowed validation by qRT-PCR of a minimal signature with only four genes. This latter signature categorized 81% of patients with RA with 75% sensitivity, 85% specificity and 85% negative predictive value. This combination showed a significant enrichment of genes involved in electron transport chain (ETC) pathways. Seven transcripts from ETC pathways (NDUFA6, NDUFA4, UQCRQ, ATP5J, COX7A2, COX7B, COX6A1) were significantly downregulated in responders versus non-responders to ABA/MTX. Moreover, dysregulation of these genes was independent of inflammation and was specific to ABA response. CONCLUSION: Pre-silencing of ETC genes is associated with future response to ABA/MTX and might be a crucial key to susceptibility to ABA response.

Association between RANK, RANKL and OPG polymorphisms with ACPA and erosions in rheumatoid arthritis: results from a meta-analysis involving three French cohorts.

OBJECTIVES: The RANK/RANKL/osteoprotegerin (OPG) system plays a central role in the pathogenesis of bone erosions in rheumatoid arthritis (RA). The aim of this study was to test the association between 11 single-nucleotide polymorphisms (SNPs) located on RANK, RANKL and OPG genes and anticitrullinated peptide antibody (ACPA) presence or erosions in RA. PATIENTS: This work was performed on three independent samples of French patients with RA: the Etude de Suivi des PolyArthrites Indifférenciées Récentes (ESPOIR) (n=632), Rangueil Midi-Pyrénées (RMP) (n=249) and French Rheumatoid Arthritis Genetic Consortium (FRAGC) (n=590) cohorts. Genotyping: the genotyping of 11 SNPs located on RANK, RANKL and OPG were performed by PCR. STATISTICAL ANALYSES: The association between the genotypes with ACPA or erosions was first tested in the ESPOIR cohort using a χ(2) test and, in the case of significant association, replicated in the RMP and FRACG cohorts. A meta-analysis on the three cohorts was performed using the Mantel-Haenszel method. RESULTS: One SNP on RANK (rs8086340) and three SNPs on RANKL (rs7984870, rs7325635, rs1054016) were significantly associated with ACPA presence, while one SNP on OPG (rs2073618) and one SNP on RANKL (rs7325635) were significantly associated with erosions in the ESPOIR cohort. Following meta-analysis performed on the three samples, the SNP on RANK and the GGG haplotype of the three SNPs located on RANKL were both significantly associated with ACPA presence, while only the SNP on OPG remained significantly associated with erosions. CONCLUSIONS: This study identified one SNP located on RANK, one haplotype on RANKL associated with ACPA presence, and one SNP located on OPG associated with erosions in three different samples of French patients with RA.

Long term outcome of patients with low level of cryoglobulin (<0.05g/L).

OBJECTIVES: To date, no studies have yet assessed the characteristics of non-HCV patients with low level of cryoglobulin (≤0.05 g/L). The aims of the current study were thus to: 1) determine the prevalence of cryoglobulin ≤0.05 g/L in patients with non-HCV cryoglobulin; and 2) compare clinical features and long term outcome, including organ complications and mortality rate, between non-HCV patients with cryoglobulin level ≤0.05 g/L and those exhibiting cryoglobulin level >0.05 g/L. METHODS: Among 6379 cryoglobulin testing, cryoglobulin was detected in 618 patients (9.69% of cases); of these 618 patients, 453 non-HCV patients were included in the study. The medical records of these patients were reviewed. RESULTS: Of the 453 non-HCV cryoglobulin-positive patients, 265 (58.6%) exhibited cryoglobulin level ≤0.05 g/L. We showed that patients with cryoglobulin level ≤0.05 g/L had: 1) less commonly: palpable purpura (p<0.001), digital ulcers (p=0.006), peripheral neurologic involvement (p=0.03) and renal impairment (p=0.03); and 2) lower median values of ESR (p<0.001) and C-reactive protein (p=0.001). The patients with cryoglobulin level ≤0.05 g/L less often experienced infections (p=0.04) and hematological malignancies (p=0.01); both groups did not differ regarding prevalence of connective tissue diseases and solid tumors. Mortality rate was as high as 13.6% in patients with cryoglobulin level ≤0.05 g/L; death was mainly due to: solid tumors (16.6%), cardiovascular complications (13.8%), hematological malignancies (11.1%), infections (8.3%), pulmonary/renal complications of cryoglobulin (8.3%) and connective tissue diseases (8.3%). CONCLUSION: Our study shows a high prevalence of cryoglobulin level ≤0.05 g/L in clinical practice. Our findings further underscore that non-HCV cryoglobulin level ≤0.05 g/L may be responsible for severe renal and neurological complications, leading to high morbidity and mortality in these patients. Thus, our data suggest that both appropriate therapy and close follow-up may be required to improve such patients' outcome.

Rheumatoid Factor and Disease Activity Are Independent Predictors of Lymphoma in Primary Sjögren's Syndrome.

OBJECTIVE: To define parameters predictive of lymphoma development in patients with primary Sjögren's syndrome (SS). METHODS: A multicenter case-control survey was performed to identify predictors of lymphoma. Cases were patients who developed lymphoma after diagnosis of primary SS and were mainly recruited through the Club Rhumatismes et Inflammation network. For each case, 2 controls (matched for disease duration and age) were randomly selected among patients with primary SS and without lymphoma. Cases and controls were compared using univariate analysis and then using multivariate analysis to identify independent predictors of lymphoma. RESULTS: One hundred one patients with primary SS and lymphoma were included. Eighty-seven patients were women (86.1%), and the mean ± SD age at lymphoma diagnosis was 57.4 ± 12.6 years. The most frequent histologic type was B cell non-Hodgkin's lymphoma (NHL) in 99 of 101 patients, with marginal-zone lymphoma in 76 of the 99 patients (76.8%) including 58 (58.6%) with lymphoma of the mucosa-associated lymphoid tissue type. Lymphomas were most frequently located in the salivary glands (43 patients). A specific treatment was initiated at diagnosis in 87 patients with B cell NHL, and 61 patients (61.6%) achieved complete sustained remission after the first line of treatment. In the multivariate analysis, salivary gland enlargement, the presence of rheumatoid factor (RF), low C4, cryoglobulinemia, lymphopenia, and disease activity according to the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (excluding the lymphoma domain) were found to be predictors of lymphoma. No previous treatment for primary SS was associated with any effect on lymphoma occurrence. CONCLUSION: In addition to previously known factors predictive of lymphoma occurrence, the independent roles of RF and disease activity were demonstrated in this case-control study of primary SS-associated lymphoma. Our findings highlight the roles of chronic antigenic stimulation and disease activity in the development of this severe complication.

[Psoriatic arthritis during rituximab treatment of granulomatosis with polyangiitis: a new paradoxical side effect?]. / Rhumatisme psoriasique au cours d'un traitement par rituximab pour une polyangéïte avec granulomatose : une nouvelle réaction paradoxale ?

INTRODUCTION: Rituximab is a monoclonal antibody targeting the CD20 molecule of the B lymphocyte. Its efficacy has been recently reported in ANCA-associated vasculitis. We report a case of psoriatic arthritis that occurs during a treatment with rituximab in granulomatosis with polyangiitis. CASE REPORT: A 66-year-old woman, without past history of psoriasis, presented with a relapsing granulomatosis with polyangiitis in July 2010 with sinus and lung involvement. Treatment with rituximab was started, allowing a complete remission in 6 months. Two months after the first two infusions of rituximab she developed asymmetric arthritis of 3 distal interphalangeal joints. A few months later, the clinical presentation showed asymmetrical arthritis of the hands and wrists and dactylitis. Standard radiographs and MRI showed an inflammatory impairment according with psoriatic arthritis. CONCLUSION: Accountability of rituximab was retained in the development of the disease given the chronology of psoriatic arthritis development. It may be a paradoxical reaction, by analogy to those observed in anti-TNFα.

Usefulness of monitoring of B cell depletion in rituximab-treated rheumatoid arthritis patients in order to predict clinical relapse: a prospective observational study.

Our objective was to evaluate the contribution of monitoring B cell subset depletion after rituximab in patients with rheumatoid arthritis (RA) in order to guide reintroduction to forestall relapse. This prospective, monocentre study included all RA patients receiving two 1-g rituximab infusions at a 15-day interval. The patients were followed clinically and biologically every 2 months until rituximab reintroduction. The physician was blinded to lymphocyte-typing results to diagnose relapse and, hence, retreatment. Among the 39 patients included between March 2010 and December 2011 and followed until April 2013, seven received two rituximab cycles, yielding a total of 46 cycles for analysis. After the two rituximab cycles, the total number of CD19(+) B cells decreased significantly (0·155 versus 0·0002 G/l, P < 0·0001), with complete depletions in all patients of CD19(+) CD38(++) CD24(++) (transitional) (P < 0·0001) and CD19(+) CD27(+) (memory) B lymphocytes. A significant majority of patients relapsed within the 4 months following repopulation of total B (P = 0·036), B transitional (P = 0·007) and B memory (P = 0·01) lymphocytes. CD19(+) B lymphocyte repopulation preceded clinical RA relapse and enabled its prediction 4 months in advance. Hence, monitoring of CD19(+) B lymphocytes could serve as a tool to predict those relapses.

[Therapeutic update in rheumatoid arthritis]. / Actualités thérapeutiques dans la polyarthrite rhumatoïde.

The treatment of rheumatoid arthritis (RA) was revolutionized by the introduction of the biologics. Their power and their good safety profile have allowed to define new objectives and procedures to reach them; it is the "treat to target" concept. New recommendations were published by EULAR or ACR to obtain the remission as soon as possible. Disease-modifying antirheumatic drugs, in particular the methotrexate (MTX), remain the cornerstone of RA treatment in association with symptomatic treatments. The use of corticosteroids can be necessary to control the disease activity in the waiting time of the DMARDs efficiency or to control a flare. The absence of remission after 3months after initiation of MTX should prompt the rheumatologist to intensify the treatment with biologics. The increasing number of biologics targeting different mechanisms (5 anti-tumor necrosis factor-α, antagonist of interleukine-1 [IL-1] receptor, antagonist of IL-6 receptor, anti-CD20, anti-cytotoxic T-lymphocyte antigen 4) asks the question of the strategy in their prescription. Besides, all the registers or meta-analysis plead in favor of a good safety subject to a moderate prescription and to a greater vigilance. Except the opportunist infections, it is more the comorbidities or the associated treatments such as corticoids or MTX, which would favor the infections than anti-TNFα. There is no indication that biologics may increase the risk of solid cancer compared with a population of RA patients not exposed to anti-TNFα. However, biologics could increase the risk of cutaneous cancers, including melanoma.

Clinical manifestations and outcome of anti-PL7 positive patients with antisynthetase syndrome.

BACKGROUND: The aims of the present study were to determine both clinical manifestations and outcome of anti-PL7 patients with antisynthetase syndrome (ASS). METHODS: The medical records of 15 consecutive anti-PL7 patients with biopsy proven ASS were retrospectively analyzed without prior selection. RESULTS: Anti-PL7 patients exhibited polymyositis (n=14) and dermatomyositis (n=1); extra-pulmonary manifestations of ASS included: Raynaud's phenomenon (40%), mechanic's hands (33.3%), joint impairment (26.7%), pericardial effusion (20%) and esophageal/gastrointestinal involvement (20%). The outcome of myositis was as follows: remission/improvement (91.7%) and deterioration (8.3%). Fourteen patients (93.3%) experienced interstitial lung disease (ILD). ILD preceded ASS diagnosis (n=5), was identified concomitantly with ASS (n=8) and occurred after ASS diagnosis (n=1). Patients could be divided into 3 groups according to their presenting lung manifestations: acute onset of lung disease (n=1), progressive onset of lung signs (n=11) and asymptomatic patients exhibiting abnormalities consistent with ILD on PFT and HRCT-scan (n=2). No patient had resolution of ILD, whereas 64.3% and 35.7% experienced improvement and deterioration of ILD, respectively. ILD resulted in respiratory insufficiency requiring O2 therapy in 14.3% of cases. Two patients died. Predictive parameters of ILD deterioration were: DLCO<45% at ILD diagnosis and HRCT-scan pattern of usual interstitial pneumonia (UIP). CONCLUSION: Our series mainly underscores that ILD is frequent in anti-PL7 patients, leading to high morbidity. Our study further suggests that patients with predictive factors of ILD deterioration may require more aggressive therapy, especially the group of patients with DLCO<45% at ILD diagnosis and UIP pattern on HRCT-scan.

European League Against Rheumatism Sjögren's Syndrome Disease Activity Index and European League Against Rheumatism Sjögren's Syndrome Patient-Reported Index: a complete picture of primary Sjögren's syndrome patients.

OBJECTIVE: The European League Against Rheumatism (EULAR) Sjögren's Syndrome (SS) Disease Activity Index (ESSDAI) and the EULAR SS Patient-Reported Index (ESSPRI) were recently developed. We aimed to determine whether patients' symptoms differed between patients with and without systemic involvement and if the disease-specific indices correlated with each other in primary SS. METHODS: Fifteen French centers included 395 primary SS patients in the Assessment of Systemic Signs and Evolution in Sjögren's Syndrome Cohort. At enrollment, physicians completed the ESSDAI, the SS Disease Activity Index (SSDAI), and the Sjögren's Systemic Clinical Activity Index (SCAI), and patients completed the ESSPRI, the Sicca Symptoms Inventory, and the Profile of Fatigue and Discomfort. All scores were compared between patients with and without systemic involvement. Correlations between scores of systemic activity and patients' symptoms were obtained. RESULTS: At enrollment, 120 (30.4%) patients had never experienced systemic complication and 155 (39.2%) patients and 120 (30.4%) patients had, respectively, only past or current systemic manifestations. Past or current systemic patients had higher levels of symptoms, except dryness. The ESSDAI did not correlate with the patient-scored ESSPRI (rho = 0.06, P = 0.30), whereas the SSDAI and the SCAI, which include subjective items, did correlate (rho = 0.28 and 0.25, respectively; P < 0.0001 for both). CONCLUSION: Alterations of common patient-reported outcomes are present in all patients with primary SS, including those with systemic complications. However, patient symptoms and systemic complications are 2 different facets of primary SS. Therefore, the use of both systemic and patients' indices, such as the ESSDAI and ESSPRI, are useful. Since these 2 facets weakly overlap, one should identify which of both components is the main target of the treatment to test, when designing clinical trials in primary SS.

Interstitial lung disease in anti-Jo-1 patients with antisynthetase syndrome.

OBJECTIVE: To assess the outcome of interstitial lung disease (ILD) in anti-Jo-1 patients with antisynthetase syndrome, determine predictive variables of ILD deterioration in these patients, and compare features of anti-Jo-1 patients with and without ILD. METHODS: Ninety-one anti-Jo-1 patients were identified by medical records search in 4 medical centers. All of these patients had undergone pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) scans. RESULTS: Sixty-six patients (72.5%) had ILD. Patients could be divided into 3 groups according to their presenting lung manifestations: acute onset of lung disease (n = 12), progressive onset of lung signs (n = 35), and asymptomatic patients exhibiting abnormalities consistent with ILD on PFTs and HRCT scans (n = 19). Sixteen patients had resolution of ILD; 39 and 11 patients experienced improvement and deterioration of ILD, respectively. ILD led to decreased functional status, since 29.8% of patients exhibited a marked reduction of activities due to ILD and 13.6% had respiratory insufficiency requiring oxygen therapy; 5 of 6 patients died due to ILD complications. Predictive parameters of ILD deterioration were HRCT scan pattern of usual interstitial pneumonia, respiratory muscle involvement, and age ≥55 years. Furthermore, anti-Jo-1 patients with ILD, compared with those without, more frequently exhibited mechanic's hands and lower creatine kinase levels. CONCLUSION: Our findings confirm that ILD is a frequent complication in anti-Jo-1 patients, resulting in high morbidity. We suggest that patients with predictive factors of ILD deterioration may require more aggressive therapy. Finally, anti-Jo-1 patients with ILD, compared with those without, may exhibit a particular clinical phenotype.

Comparison of long-term outcome between anti-Jo1- and anti-PL7/PL12 positive patients with antisynthetase syndrome.

The aims of the present study were to: compare the characteristics between antisynthetase syndrome (ASS) patients with anti-Jo1 antibody and those with anti-PL7/PL12 antibody. The medical records of 95 consecutive patients with ASS were reviewed. Seventy-five of these patients had anti-Jo1 antibody; the other patients had anti-PL7 (n=15) or anti-PL12 (n=5) antibody. At ASS diagnosis, the prevalence of myalgia (p=0.007) and muscle weakness (p=0.02) was significantly lower in the group of anti-PL7/PL12-positive patients than in those with anti-Jo1 antibody; median value of CK (p=0.00003) was also lower in anti-PL7/PL12 patients. Anti-Jo1 positive patients developed more rarely myositis resolution (21.3% vs. 46.2%); in addition, the overall recurrence rate of myositis was higher in anti-Jo1 positive patients than in patients with anti-PL7/PL12 antibody (65.9% vs. 19.4%). Anti-Jo1-positive patients, compared with those with anti-PL7/PL12 antibody, more often experienced: joint involvement (63.3%vs. 40%) and cancer (13.3% vs. 5%). By contrast, anti-PL7/PL12 positive patients, compared with those with anti-Jo1 antibody, more commonly exhibited: ILD (90% vs. 68%); in anti-PL7/PL12 positive patients, ILD was more often symptomatic at diagnosis, and led more rarely to resolution of lung manifestations (5.6% vs. 29.4%). Finally, the group of anti-PL7/PL12 positive patients more commonly experienced gastrointestinal manifestations related to ASS (p=0.02). Taken together, although anti-Jo1 positive patients with ASS share some features with those with anti-PL7/PL12 antibody, they exhibit many differences regarding clinical phenotype and long-term outcome. Our study underscores that the presence of anti-Jo1 antibody results in more severe myositis, joint impairment and increased risk of cancer. On the other hand, the presence of anti-PL7/PL12 antibody is markedly associated with: early and severe ILD, and gastrointestinal complications. Thus, our study interestingly indicates that the finding for anti-Jo1 and anti-PL7/PL12 antibodies impacts both the long-term outcome and prognosis of patients with ASS.

[Azathioprine-associated severe myelosuppression: indication of routine determination of thiopurine S-methyltransferase variant?]. / Aplasie médullaire induite par l'azathioprine: intérêt de la recherche systématique d'une mutation du gène de la thiopurine S-méthyltransférase ?

INTRODUCTION: Myelotoxicity is a well-known adverse effect of azathioprine, leading mainly to leukopenia. Other azathioprine associated hematological adverse effects are uncommon. CASE REPORT: We report a 49-year-old woman with rheumatoid arthritis and acquired hemophilia, who presented a severe myelosuppression occurring 3 weeks after an increase of her azathioprine regimen (at a daily dose of 150 mg). The patient had a heterozygous mutation of the thiopurine S-methyltransferase gene (TPMT*3A). Azathioprine therapy was discontinued and she recovered at 3 weeks. The patient had no relapse of pancytopenia after a 1 year follow-up. CONCLUSION: Routine measurement of TPMT activity or determination of TPMT variant allele may be useful tests, in order to identify the subgroup of patients who are at risk to develop azathioprine induced severe myelosuppression.

[Idiopathic inflammatory myopathies with anti-PM-Scl antibodies: case series and literature review]. / Myopathies inflammatoires et anticorps anti-PM-Scl: à propos d'une série et revue de la littérature.

PURPOSE: The objectives of this study were to evaluate: (1) the prevalence of anti-PM-Scl antibodies within the framework of antinuclear antibodies detection; and (2) the clinical features and outcome of patients with isolated polymyositis/dermatomyositis. METHODS: Nine thousand and sixty-four consecutive antinuclear testing data allowed us to evaluate anti-PM-Scl antibody prevalence. Second, we also assessed the characteristics of patients with isolated dermatomyositis/polymyositis and associated anti-PM-Scl antibody. RESULTS: Over 9064 consecutive antinuclear samples tested for antinuclear antibodies, 3263 (36%) were positive; anti-PM-Scl antibody were positive in nine patients: 0.1% of all sera, 0.2% of sera positive for antinuclear antibodies, 1.2% of sera positive for anti-ENA antibodies. Four of the nine patients with anti-PM-Scl antibody had dermatomyositis (n=3) and polymyositis (n=1). Patients with dermatomyositis/polymyositis and anti-PM-Scl antibody exhibited severe complications, as follows: ventilatory insufficiency (n=2) requiring mechanical ventilation in one case, esophageal involvement requiring enteral feeding (n=1); also, two of these patients had cancer. CONCLUSION: Our case series suggests that the presence of anti-PM-Scl antibody is not a favorable prognostic factor in patients with dermatomyositis/polymyositis. This type of antibody appears to be associated with lung and esophageal involvement; in addition, anti-PM-Scl antibody may co-exist with malignancy in PM/DM patients. Taken together, we suggest that patients with dermatomyositis/polymyositis and anti-PM-Scl antibody require both initial evaluation for lung/digestive manifestations and cancer and close surveillance.

[Acute reactive arthritis after intravesical instillation of bacillus Calmette-Guérin. Two case reports and literature review]. / Arthrites réactionnelles secondaires à la BCG-thérapie. Deux observations et revue de la littérature.

INTRODUCTION: Intravesical bacillus Calmette-Guérin (BCG) therapy-associated articular complications are uncommon, occurring in only 0.5 to 1% of the patients. OBSERVATIONS: We report two patients who were given intravesical BCG therapy for superficial bladder cancer. Both patients developed polyarthritis and fever related to intravesical BCG instillation. The outcome of articular manifestations was favorable after administration of nonsteroidal anti-inflammatory therapy. CONCLUSION: Intravesical BCG therapy-associated articular complications should not be overlooked, as they may result in high morbidity. Nevertheless, the diagnosis of intravesical BCG therapy-related reactive arthritis should be discussed after excluding infectious arthritis due to Mycobacterium bovis. Therefore, joint fluid microbiological tests (cultures, PCR) are required in the patients receiving intravesical BCG who develop arthritis.

Impact of three anti-TNFalpha biologics on existing and emergent autoimmunity in rheumatoid arthritis and spondylarthropathy patients.

OBJECTIVE: The objective of this study was to analyze the effects of 3 anti-TNFalpha agents on markers of autoimmunity in rheumatoid arthritis (RA) and spondylarthropathy (SPA) patients. METHODS: First-time anti-TNFalpha biologics (infliximab, etanercept, or adalimumab) were prescribed to 156 RA and 95 SPA (58 ankylosing spondylarthritides, 37 psoriatic arthritides). During 1-2 years of follow-up, clinical, biological [antinuclear (ANA) and anti-double-stranded (dsDNA) antibodies, rheumatoid factors (RF), and anti-cyclic citrullinated peptide (CCP) for RA], and therapeutic data were collected biannually. RESULTS: ANA appeared or ANA and anti-dsDNA titers increased significantly (P < 0.001) more under infliximab than etanercept in both rheumatisms and than adalimumab in RA patients. During the 2-year follow-up, ANA appeared more in RA patients taking adalimumab than etanercept (P = 0.003), but independently of the anti-TNFalpha used; anti-dsDNA titers rarely became positive. Under etanercept or infliximab, ANA and anti-dsDNA were not influenced by the underlying pathology nor were they affected by infliximab intensification over 18 months. Only one case of cutaneous lupus was observed in a patient having IgG anti-dsDNA. The therapeutic responses were independent of ANA and anti-dsDNA titers for all rheumatisms and biologics. In RA patients, RF titers, but not anti-CCP levels, declined with the therapeutic response for all biologics. CONCLUSION: This is the first study that has evaluated the impact of three TNFalpha blockers on ANA and anti-dsDNA antibodies in RA and SPA patients. Autoimmunity was more induced with infliximab than etanercept and to a lesser degree to adalimumab but, more importantly, this emergent autoimmunity was exceptionally associated to clinical manifestations of lupus.

Contribution of PTPN22 1858T, TNFRII 196R and HLA-shared epitope alleles with rheumatoid factor and anti-citrullinated protein antibodies to very early rheumatoid arthritis diagnosis.

OBJECTIVES: To evaluate the predictive value of TNFRII 196R, PTPN22 1858T and HLA-shared epitope (SE) alleles, RFs and anti-citrullinated protein antibodies (ACPAs) for RA diagnosis in a cohort of patients with very early arthritis. METHODS: We followed up 284 patients who had swelling of at least two joints that had persisted for longer than 4 weeks but had been evolving for <6 months. At 2 yrs, patients were classified as having RA or non-RA rheumatic diseases according to the ACR criteria. Patients were genotyped with respect to TNFRII 196M/R and PTPN22 1858C/T polymorphisms and HLA-SE. The presence of IgA, IgG and IgM RF isotypes and ACPA was sought in sera collected at disease onset. RESULTS: HLA-SE alleles alone, concomitant presence of TNFRII 196R and PTPN22 1858T alleles, IgA, IgG and IgM RF alone and ACPA were found to be significantly associated with RA diagnosis. Using logistic regression analysis, the concomitant presence of RF and ACPA at disease onset was the best association to predict RA diagnosis. In patients (n = 34) who did not fulfil the ACR criteria for RA at inclusion but who progressed to ACR positivity, the study of the genetic risk markers did not contribute to predict RA diagnosis at 2 yrs. CONCLUSIONS: PTPN22 1858T, TNFRII 196R and HLA-SE alleles do not improve the predictive value of RF and ACPA for RA diagnosis in our cohort, and do not contribute to an earlier diagnosis in undifferentiated patients initially negative for RF and ACPA.

Anti-annexin II antibodies in systemic autoimmune diseases and antiphospholipid syndrome.

OBJECTIVES: The objective of this study were (1) to evaluate the prevalence of anti-annexin II antibodies in patients with various autoimmune diseases and antiphospholipid syndrome and (2) to correlate anti-annexin II antibodies with anti-phospholipid antibodies. MATERIALS AND METHODS: Anti-annexin II antibodies and anti-phospholipid were detected, using an enzyme-linked immunosorbent assay, in the serum of patients with primary antiphospholipid syndrome (n = 16), systemic lupus erythematosus (n = 53), primary Sjögren syndrome (n = 71), systemic sclerosis (n = 17), systemic vasculitis (n = 18), and rheumatoid arthritis (n = 119). Healthy blood donors (n = 99) were used as controls. RESULTS: Anti-annexin II antibodies were significantly more prevalent in patients with connective tissue diseases (8.5%), especially antiphospholipid syndrome (14.8%) and rheumatoid arthritis (10%), than in controls (2%). An inverse correlation was observed between anti-annexin II antibodies and antiphospholipid antibodies. CONCLUSION: Annexin II can be recognized by antibodies in serum from patients with systemic autoimmune disorders. Further studies are required to determine the clinical significance of anti-annexin II antibodies in rheumatoid arthritis and to determine their diagnostic value in discriminating clinical subgroups of patients with antiphospholipid syndrome.