Factors associated with disease flare following SARS-CoV-2 vaccination in people with inflammatory rheumatic and musculoskeletal diseases: results from the physician-reported EULAR Coronavirus Vaccine (COVAX) Registry.

OBJECTIVES: To investigate the frequency and factors associated with disease flare following vaccination against SARS-CoV-2 in people with inflammatory/autoimmune rheumatic and musculoskeletal diseases (I-RMDs). METHODS: Data from the European Alliance of Associations for Rheumatology Coronavirus Vaccine physician-reported registry were used. Factors associated with flare in patients with I-RMDs were investigated using multivariable logistic regression adjusted for demographic and clinical factors. RESULTS: The study included 7336 patients with I-RMD, with 272 of 7336 (3.7%) experiencing flares and 121 of 7336 (1.6%) experiencing flares requiring starting a new medication or increasing the dosage of an existing medication. Factors independently associated with increased odds of flare were: female sex (OR=1.40, 95% CI=1.05 to 1.87), active disease at the time of vaccination (low disease activity (LDA), OR=1.45, 95% CI=1.08 to 1.94; moderate/high disease activity (M/HDA), OR=1.37, 95% CI=0.97 to 1.95; vs remission), and cessation/reduction of antirheumatic medication before or after vaccination (OR=4.76, 95% CI=3.44 to 6.58); factors associated with decreased odds of flare were: higher age (OR=0.90, 95% CI=0.83 to 0.98), non-Pfizer/AstraZeneca/Moderna vaccines (OR=0.10, 95% CI=0.01 to 0.74; vs Pfizer), and exposure to methotrexate (OR=0.57, 95% CI=0.37 to 0.90), tumour necrosis factor inhibitors (OR=0.55, 95% CI=0.36 to 0.85) or rituximab (OR=0.27, 95% CI=0.11 to 0.66), versus no antirheumatic treatment. In a multivariable model using new medication or dosage increase due to flare as the dependent variable, only the following independent associations were observed: active disease (LDA, OR=1.47, 95% CI=0.94 to 2.29; M/HDA, OR=3.08, 95% CI=1.91 to 4.97; vs remission), cessation/reduction of antirheumatic medication before or after vaccination (OR=2.24, 95% CI=1.33 to 3.78), and exposure to methotrexate (OR=0.48, 95% CI=0.26 to 0.89) or rituximab (OR=0.10, 95% CI=0.01 to 0.77), versus no antirheumatic treatment. CONCLUSION: I-RMD flares following SARS-CoV-2 vaccination were uncommon. Factors associated with flares were identified, namely higher disease activity and cessation/reduction of antirheumatic medications before or after vaccination.

Response to Biologic Drugs in Patients With Rheumatoid Arthritis and Antidrug Antibodies.

Importance: There are conflicting data on the association of antidrug antibodies with response to biologic disease-modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis (RA). Objective: To analyze the association of antidrug antibodies with response to treatment for RA. Design, Setting, and Participants: This cohort study analyzed data from the ABI-RA (Anti-Biopharmaceutical Immunization: Prediction and Analysis of Clinical Relevance to Minimize the Risk of Immunization in Rheumatoid Arthritis Patients) multicentric, open, prospective study of patients with RA from 27 recruiting centers in 4 European countries (France, Italy, the Netherlands, and the UK). Eligible patients were 18 years or older, had RA diagnosis, and were initiating a new bDMARD. Recruitment spanned from March 3, 2014, to June 21, 2016. The study was completed in June 2018, and data were analyzed in June 2022. Exposures: Patients were treated with a new bDMARD: adalimumab, infliximab (grouped as anti-tumor necrosis factor [TNF] monoclonal antibodies [mAbs]), etanercept, tocilizumab, and rituximab according to the choice of the treating physician. Main Outcomes and Measures: The primary outcome was the association of antidrug antibody positivity with EULAR (European Alliance of Associations for Rheumatology; formerly, European League Against Rheumatism) response to treatment at month 12 assessed through univariate logistic regression. The secondary end points were the EULAR response at month 6 and at visits from month 6 to months 15 to 18 using generalized estimating equation models. Detection of antidrug antibody serum levels was performed at months 1, 3, 6, 12, and 15 to 18 using electrochemiluminescence (Meso Scale Discovery) and drug concentration for anti-TNF mAbs, and etanercept in the serum was measured using enzyme-linked immunosorbent assay. Results: Of the 254 patients recruited, 230 (mean [SD] age, 54.3 [13.7] years; 177 females [77.0%]) were analyzed. At month 12, antidrug antibody positivity was 38.2% in patients who were treated with anti-TNF mAbs, 6.1% with etanercept, 50.0% with rituximab, and 20.0% with tocilizumab. There was an inverse association between antidrug antibody positivity (odds ratio [OR], 0.19; 95% CI, 0.09-0.38; P < .001) directed against all biologic drugs and EULAR response at month 12. Analyzing all the visits starting at month 6 using generalized estimating equation models confirmed the inverse association between antidrug antibody positivity and EULAR response (OR, 0.35; 95% CI, 0.18-0.65; P < .001). A similar association was found for tocilizumab alone (OR, 0.18; 95% CI, 0.04-0.83; P = .03). In the multivariable analysis, antidrug antibodies, body mass index, and rheumatoid factor were independently inversely associated with response to treatment. There was a significantly higher drug concentration of anti-TNF mAbs in patients with antidrug antibody-negative vs antidrug antibody-positive status (mean difference, -9.6 [95% CI, -12.4 to -6.9] mg/L; P < 001). Drug concentrations of etanercept (mean difference, 0.70 [95% CI, 0.2-1.2] mg/L; P = .005) and adalimumab (mean difference, 1.8 [95% CI, 0.4-3.2] mg/L; P = .01) were lower in nonresponders vs responders. Methotrexate comedication at baseline was inversely associated with antidrug antibodies (OR, 0.50; 95% CI, 0.25-1.00; P = .05). Conclusions and Relevance: Results of this prospective cohort study suggest an association between antidrug antibodies and nonresponse to bDMARDs in patients with RA. Monitoring antidrug antibodies could be considered in the treatment of these patients, particularly nonresponders to biologic RA drugs.

Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium.

BACKGROUND: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. METHODS AND FINDINGS: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings. CONCLUSION: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.

Non-TNF-Targeted Biologic vs a Second Anti-TNF Drug to Treat Rheumatoid Arthritis in Patients With Insufficient Response to a First Anti-TNF Drug: A Randomized Clinical Trial.

IMPORTANCE: One-third of patients with rheumatoid arthritis show inadequate response to tumor necrosis factor α (TNF-α) inhibitors; little guidance on choosing the next treatment exists. OBJECTIVE: To compare the efficacy of a non-TNF-targeted biologic (non-TNF) vs a second anti-TNF drug for patients with insufficient response to a TNF inhibitor. DESIGN, SETTING, AND PARTICIPANTS: A total of 300 patients (conducted between 2009-2012) with rheumatoid arthritis, with persistent disease activity (disease activity score in 28 joints-erythrocyte sedimentation rate [DAS28-ESR] ≥ 3.2 [range, 0-9.3]) and an insufficient response to anti-TNF therapy were included in a 52-week multicenter, pragmatic, open-label randomized clinical trial. The final follow-up date was in August 2013. INTERVENTIONS: Patients were randomly assigned (1:1) to receive a non-TNF-targeted biologic agent or an anti-TNF that differed from their previous treatment. The choice of the biologic prescribed within each randomized group was left to the treating clinician. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients with good or moderate response according to the European League Against Rheumatism (EULAR) scale at week 24. Secondary outcomes included the EULAR response at weeks 12 and 52; at weeks 12, 24, and 52; DAS28ESR, low disease activity (DAS28 ≤3.2), remission (DAS28 ≤2.6); serious adverse events; and serious infections. RESULTS: Of the 300 randomized patients (243 [83.2%] women; mean [SD] age, 57.1 [12.2] years; baseline DAS28-ESR, 5.1 [1.1]), 269 (89.7%) completed the study. At week 24, 101 of 146 patients (69%) in the non-TNF group and 76 (52%) in the second anti-TNF group achieved a good or moderate EULAR response (OR, 2.06; 95% CI, 1.27-3.37; P = .004, with imputation of missing data; absolute difference, 17.2%; 95% CI, 6.2% to 28.2%). The DAS28-ESR was lower in the non-TNF group than in the second anti-TNF group (mean difference adjusted for baseline differences, -0.43; 95% CI, -0.72 to -0.14; P = .004). At weeks 24 and 52, more patients in the non-TNF group vs the second anti-TNF group showed low disease activity (45% vs 28% at week 24; OR, 2.09; 95% CI, 1.27 to 3.43; P = .004 and 41% vs 23% at week 52; OR, 2.26; 95% CI, 1.33 to 3.86; P = .003). CONCLUSIONS AND RELEVANCE: Among patients with rheumatoid arthritis previously treated with anti-TNF drugs but with inadequate primary response, a non-TNF biologic agent was more effective in achieving a good or moderate disease activity response at 24 weeks than was the second anti-TNF medication. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01000441.

Step-down strategy of spacing TNF-blocker injections for established rheumatoid arthritis in remission: results of the multicentre non-inferiority randomised open-label controlled trial (STRASS: Spacing of TNF-blocker injections in Rheumatoid ArthritiS Study).

UNLABELLED: Tumour necrosis factor (TNF)-blocker tapering has been proposed for patients with rheumatoid arthritis (RA) in remission. OBJECTIVE: The trial aims to compare the effect of progressive spacing of TNF-blocker injections (S-arm) to their maintenance (M-arm) for established patients with RA in remission. METHODS: The study was an 18-month equivalence trial which included patients receiving etanercept or adalimumab at stable dose for ≥1 year, patients in remission on 28-joint Disease Activity Score (DAS28) for ≥6 months and patients with stable joint damage. Patients were randomised into two arms: maintenance or injections spacing by 50% every 3 months up to complete stop. Spacing was reversed to the previous interval in case of relapse, and eventually reattempted after remission was reachieved. The primary outcome was the standardised difference of DAS28 slopes, based on a linear mixed-effects model (equivalence interval set at ±30%). RESULTS: 64 and 73 patients were included in the S-arm and M-arm, respectively, which was less than planned. In the S-arm, TNF blockers were stopped for 39.1%, only tapered for 35.9% and maintained full dose for 20.3%. The equivalence was not demonstrated with a standardised difference of 19% (95% CI -5% to 46%). Relapse was more common in the S-arm (76.6% vs 46.5%, p=0.0004). However, there was no difference in structural damage progression. CONCLUSIONS: Tapering was not equivalent to maintenance strategy, resulting in more relapses without impacting structural damage progression. Further studies are needed to identify patients who could benefit from such a strategy associated with substantial cost savings. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT00780793; EudraCT identifier: 2007-004483-41.

Rituximab treatment for spondyloarthritis. A nationwide series: data from the AIR registry of the French Society of Rheumatology.

OBJECTIVE: To evaluate the efficacy and safety of rituximab (RTX) in several subsets of spondyloarthritis (SpA) using the data of the AIR (Autoimmunity and Rituximab) registry. METHODS: All patients receiving RTX for SpA, and prospectively included in the AIR registry from September 2005 to September 2010, were retrospectively analyzed. The response to treatment was evaluated by the Bath Ankylosing Spondylitis Disease Activity Index for axial disease, joint count for peripheral disease, and C-reactive protein reduction. RESULTS: Among the 595 patients included in the AIR registry, 26 patients with SpA from 13 centers were reported: ankylosing spondylitis (10), undifferentiated SpA (7), and psoriatic arthritis (9). Mean disease duration was 8.8 years (range 1-40). The extraarticular features found were psoriasis, 12 cases; uveitis, 4 cases; and Crohn's disease, 3 cases. The mean number of disease-modifying antirheumatic drugs before RTX was 2.4; previous anti-tumor necrosis factor (TNF) agents were taken in 23 cases. The mean number of RTX courses was 1.5 (range 1-5), with a total of 35.6 patient-years. Efficacy was noted in 11/23 cases: 3 out of 3 anti-TNF-naive patients and 8 out of 20 anti-TNF nonresponder patients. No predictive factors of response could be identified, particularly in diagnosis subsets or clinical presentation (axial or peripheral). CONCLUSION: In this nationwide study of several subsets of SpA, RTX had only a moderate efficacy that was more marked in patients who were anti-TNF-naive.

Onset of action of etanercept in rheumatoid arthritis based on patient-reported outcomes.

BACKGROUND: Onset of action is considered to be a key characteristic of the treatment of rheumatoid arthritis. The efficacy of TNF blockers is usually evaluated after 2 to 4 weeks of therapy. EULAR-RAID is a valid patient-reported outcome composite index. OBJECTIVES: To evaluate the onset of action of etanercept in rheumatoid arthritis patients according to the EULAR-RAID score. METHODS: An open-label, single-arm (etanercept 50 mg/week), 12-week study was carried out in patients with active rheumatoid arthritis. Patients were asked to fill in the RAID score questionnaire each day for the first 14 days of the study and at the 4-week and 12-week visits. Onset of action was evaluated by considering: a) changes over time of the EULAR-RAID score; b) the percentage of patients achieving an 'acceptable' condition according to the EULAR-RAID score (e.g. a score ≤3.00). RESULTS: Of the 120 screened patients, 108 (female: 75%), age 54±13 years, disease duration 8±7 years) were enrolled. At baseline, patients had active rheumatoid arthritis (DAS: 5.4±0.8; CRP: 18.±30mg/l). Eleven patients dropped out of the study. A statistically significant decrease in the EULAR-RAID score was observed by day 1 of therapy. Kaplan-Meier estimates of the proportion of patients achieving an acceptable RAID score were 29.8 [% 95% C.I. 23.8-X42.6], 50 % [95% C.I. 41-60.9], 51.9% [95% C.I. 43.8-63.7], 56% [95% C.I. 49.5-69.1, after 1, 2, 4 and 12 weeks of therapy respectively. The median time to achieve an acceptable EULAR-RAID score was 14.5 days. CONCLUSIONS: This open-label study suggests that patients can perceive a clinically relevant improvement by the first week of etanercept therapy.

The influence of the definition of patient global assessment in assessment of disease activity according to the Disease Activity Score (DAS28) in rheumatoid arthritis.

OBJECTIVE: Patient global assessment (PGA) is one of the 4 items included in the Disease Activity Score (DAS28) for evaluation of activity of rheumatoid arthritis (RA). We studied the influence of the use of 3 different techniques of PGA on the assessment of disease activity. METHODS: We evaluated 3 different DAS28 according to the technique of PGA in 108 patients with active RA before and after 12 weeks of etanercept therapy. RESULTS: The reliability (intraclass coefficient of correlation) between screening and baseline was very high and similar for the 3 DAS28. The percentage of patients in the different states of disease (from remission to higher disease activity) and the sensitivity to change across the 3 DAS28 scales were very similar. CONCLUSION: The different techniques of collection of PGA to be included in the DAS calculation yield similar results. However, an accepted, unequivocal technique should be encouraged in order to reduce heterogeneity in scoring DAS among patients with RA.

Etanercept compared to intraarticular corticosteroid injection in rheumatoid arthritis: double-blind, randomized pilot study.

OBJECTIVE: To compare etanercept (anti-tumor necrosis factor-α) with intraarticular (IA) corticosteroid injections to treat rheumatoid arthritis (RA). METHODS: Patients with RA who had persistent monoarthritis received etanercept or IA corticosteroid injections. Efficacy was compared at Weeks 4 and 24. RESULTS: Thirty-four patients were included (8 dropped out). Mean age was 58.8 years. No difference between groups was found at Weeks 4 or 24, but both groups showed significant improvement at Weeks 4 and 24 compared to baseline. CONCLUSION: Etanercept and IA steroid injections resulted in significant improvement at Week 4 that persisted to Week 24. There was no significant difference in outcome between the groups.

Comparison of two etanercept regimens for treatment of psoriasis and psoriatic arthritis: PRESTA randomised double blind multicentre trial.

OBJECTIVES: To compare the efficacy over 12 weeks of two different etanercept regimens in treating the skin manifestations of psoriasis in patients who also have psoriatic arthritis and to evaluate efficacy and safety over an additional 12 weeks of open label etanercept treatment. Design Randomised double blind multicentre outpatient study. SETTING: 98 outpatient facilities in Europe, Latin America, and the Asia Pacific region. Participants 752 patients with both psoriasis (evaluated by dermatologists) and psoriatic arthritis (evaluated by rheumatologists). INTERVENTIONS: During the blinded portion of the study, participants were randomised to receive etanercept 50 mg twice weekly (n=379) or 50 mg once weekly (n=373) for 12 weeks by subcutaneous injection. All participants then received open label etanercept 50 mg once weekly for 12 additional weeks, while remaining blinded to the regimen. MAIN OUTCOME MEASURES: The primary efficacy end point was the proportion of participants achieving "clear" or "almost clear" on the physician's global assessment of psoriasis at week 12. Secondary efficacy analyses included psoriasis area and severity index, American College of Rheumatology responses, psoriatic arthritis response criteria, and improvement in joint and tendon disease manifestations. RESULTS: At week 12, 46% (176/379) of participants receiving etanercept 50 mg twice weekly achieved a physician's global assessment of psoriasis of "clear" or "almost clear" compared with 32% (119/373) in the group treated with 50 mg once weekly (P<0.001). In contrast, an equally high percentage of participants in both groups achieved psoriatic arthritis response criteria (77% (284/371) in the twice weekly/once weekly group versus 76% (282/371) in the once weekly/once weekly group). Participants treated with 50 mg twice weekly/once weekly had greater mean reductions from baseline in the psoriasis area and severity index at week 12 compared with those who received 50 mg once weekly/once weekly (71% v 62%, P<0.001), with less difference at week 24 (78% v 74%, P<0.110). Joint and tendon disease manifestations improved from baseline in both groups to a similar extent. No new safety signals were seen in either etanercept treatment group, and no significant difference in the safety profiles was observed. CONCLUSIONS: In participants with active psoriasis and psoriatic arthritis, initial treatment of the psoriasis with etanercept 50 mg twice weekly may allow for more rapid clearance of skin lesions than with 50 mg once weekly. A regimen of 50 mg once weekly seems to be appropriate for treatment of joint and tendon rheumatic symptoms. The choice of regimen should be determined by the clinical needs of the individual patient. TRIAL REGISTRATION: Clinical trials NCT00245960.

Effect of discontinuing TNFalpha antagonist therapy in patients with remission of rheumatoid arthritis.

OBJECTIVE: The objective of this study was to determine the time to relapse after tumor necrosis factor alpha (TNFalpha) antagonist discontinuation in patients with remission of rheumatoid arthritis (RA). METHODS: Among 304 patients taking TNFalpha antagonist therapy for RA, 21 achieved a remission and were taken off the TNFalpha antagonist. Remission was defined as DAS28<2.6 for at least 6 months without nonsteroidal inflammatory drugs or more than 5 mg of prednisone per day but with disease-modifying antirheumatic drug (DMARD) therapy if needed. The same TNFalpha antagonist was restarted in the event of a relapse (DAS28>3.2). RESULTS: The 21 patients had a mean age of 61 years, a mean disease duration of 11.3 years, and a mean remission duration at TNFalpha antagonist discontinuation of 19.2 months. The TNFalpha antagonist was infliximab in 2 patients, adalimumab in 5, and etanercept in 14; and 14 patients were taking a concomitant DMARD. The number of patients still in remission after TNFalpha antagonist discontinuation was 9/20 after 6 months and 5/20 after 12 months. Mean time to relapse was 14.7 weeks. While off TNFalpha antagonist therapy, 3 of the 5 relapse-free patients after 12 months were on DMARD therapy, compared to 11 of the 15 patients who relapsed. Compared to the 15 patients who relapsed, the 5 relapse-free patients had a longer time on TNFalpha antagonist therapy (56 months vs. 35 months, P=0.012) and a longer time in remission on TNFalpha antagonist therapy (35 months vs.14.5 months, P=0.04). The 15 patients who relapsed consistently achieved a remission after resuming TNFalpha antagonist therapy; the remission occurred within 2 months in 13 patients. CONCLUSION: TNFalpha antagonist discontinuation in patients in remission of RA was followed by a relapse within 12 months in 75% of cases. Relapsing patients responded well to resumption of the same TNFalpha antagonist.

TNFalpha antagonist continuation rates in 442 patients with inflammatory joint disease.

OBJECTIVE: To evaluate TNFalpha antagonist continuation rates in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), or psoriatic arthritis (PsA). METHODS: We retrospectively reviewed the charts of patients treated with etanercept, infliximab, or adalimumab at our teaching hospital. Drug continuation was evaluated using Kaplan-Meier survival curves. The logrank test was used to compare continuation rates. RESULTS: We identified 442 patients who were prescribed 571 TNFalpha antagonist treatments between August 1999 and June 2005. Among them, 304 had RA, 92 AS, and 46 PsA. In the RA group, continuation rates were high with etanercept (n=157; 87% after 12 months and 68% after 24 months) and adalimumab (n=43, 83% and 66%) but significantly lower with infliximab (n=104, 68% and 46%; P=0.0001 vs. etanercept and P=0.01 vs. adalimumab). In the AS group, in contrast, infliximab (n=53) showed significantly higher continuation rates (89% and 83%) than did etanercept (n=39; 76% after 12 months: P=0.03). Overall continuation rates were higher in AS than in RA (P=0.01). CONCLUSION: Continuation was better with etanercept than with infliximab in patients with RA, whereas the opposite was noted in patients with AS.

New-onset psoriatic palmoplantaris pustulosis following infliximab therapy: a class effect?

Reports of induction or exacerbation of psoriatic palmoplantaris pustulosis (PPPP) after anti-tumor necrosis factor-alpha (TNF-alpha) treatment are few. We describe 2 new cases of PPPP induced by infliximab. In 1999, a total of 442 patients in our department received anti-TNF-alpha treatment for a variety of chronic rheumatic conditions and were regularly followed. Medical records for 166 given infliximab were retrospectively reviewed for disease [rheumatoid arthritis (RA), spondylarthropathies (SpA) including psoriatic arthritis], disease duration, clinical characteristics, skin side-effects, and use of other potentially relevant medications. PPPP was observed in 2 patients treated with infliximab for symmetrical rheumatoid factor-positive RA; the patients had no personal or family history of psoriasis. In both cases, pustulosis appeared after several months of infliximab administration. There was no clinical, biological, or radiological evidence to support a diagnosis of psoriatic SpA. Both patients fulfilled ACR criteria for RA, and there was no reason to suspect previously unidentified psoriasis. Comorbid RA and psoriasis are unusual, and our patients exhibited a clear link between anti-TNF-alpha administration and cutaneous lesions, suggesting a direct effect in both cases. The 28 published cases of PPPP induced by anti-TNF-alpha treatment report lesions that tend towards pustulosis and palmoplantar localization. The mechanisms involved remain elusive. Disappearance of lesions in our second patient when switched to a soluble receptor suggests a molecule-specific side effect, while the literature describing variable reaction to switching anti-TNF agents, and/or their discontinuation and reintroduction, indicates otherwise. Given the rarity of this side effect, its elucidation will require systematic study.

Lumbosacral pain: chordoma--a diagnosis not to forget.

Chordomas are rare tumours (1-4%) whose origin is remnants of the embryonic primitive foetal notochord. Estimated incidence is 0.51 cases per million. They develop at the neuroaxis ends and on vertebral bodies. Clinical manifestations can differ according to different localizations and to insidious and slow evolution. Our case is an illustration of diagnosis and treatment difficulties. Chordomas remain a diagnosis to be reminded.

Safety of infliximab used in combination with leflunomide or azathioprine in daily clinical practice.

OBJECTIVE: To investigate the safety of infliximab (INF) combination therapy with leflunomide (LEF) or azathioprine (AZA) in patients with rheumatoid arthritis (RA). METHOD: A standardized questionnaire on the use of INF in combination with LEF or AZA was mailed to hospital physicians and collected over a 2 month period. Adverse events (AE) and the reasons for withdrawal of combination therapy were analyzed. RESULTS: Data on 225 patients with RA were collected retrospectively. INF was used in combination with LEF in 171 patients and with AZA in 54. The duration of INF exposure was similar in both groups (mean 8.8 mo). AE were reported in 75 patients (33.3%), 60 LEF/INF (35%) and 15 AZA/INF combinations (27.8%) (p=nonsignificant). No unexpected AE were observed. The main AE were infections (6.2%), cytopenia (5.8%), hepatotoxicity (5.8%), reactions to infusion (5.3%), and skin reactions (4%). At the time the questionnaires were sent out, 161 patients were continuing combination therapies. The main reasons for drug withdrawal were AE (53 patients, 23.5%), inefficacy (10 patients, 4%), and one temporary discontinuation for surgery. CONCLUSION: Our study suggests that INF used in combination with LEF or AZA could be an alternative to methotrexate/INF combinations.

A pilot study on the recovery from paresis after lumbar disc herniation.

BACKGROUND: Although the existence of a motor defect in discogenic sciatica is a sign of severity, the literature does not provide evidence for an immediate requirement for surgery. OBJECTIVE: To assess the course of sciatica with discogenic paresis and to determine possible prognostic factors for recovery or improvement. STUDY DESIGN: This open prospective multicenter study included patients with discogenic sciatica with paresis that had been developing for less than 1 month and was rated < or =3 on a 5-grade scale. Pain, the strength of 11 muscles, return to work, and analgesic intake were assessed at 1, 3, and 6 months. Recovery and improvement were defined by pain not exceeding 20 mm or < or =50% of the initial pain score and a score of either 5 (recovery) or 4 (improvement) for the weakest muscle at inclusion. RESULTS: Sixty-seven patients were enrolled; 39 (58%) patients were treated surgically and 28 (42%) medically. Surgically treated patients differed from medically treated patients by a higher rate of extruded herniation, a higher number of paretic muscles (6.3 vs. 5; P = 0.051), and a longer course of sciatica (31.4 vs. 17.3 days; P = 0.034). At 6 months, 7 (10.4%) patients were lost to follow-up; 32 (53.3%) had improved, including 18 (30%) recovered, 33 (85%) back to work and having a professional activity, and 22 (39%) still taking analgesics. The only significant difference between recovered and not recovered patients was mean age at inclusion (43 vs. 51 years, P = 0.034). There were no significant differences between improved and not improved patients. Moreover, the outcome was not different in the two treatment groups: there were 17 (53%) improvements in surgically treated patients, including 8 (25%) recoveries, and 14 (56%) improvements in medically treated patients, including 8 (40%) recoveries. CONCLUSION: This pilot study showed no difference between surgical or medical management for recovery or improvement in patients with discogenic paresis. These results need confirmation by a randomized study.