Evolution of monoclonal gammopathy of undetermined significance in patients treated with JAK inhibitors for rheumatic diseases: data from the MAJIK-SFR registry.

OBJECTIVE: Monoclonal gammopathy of undetermined significance (MGUS) is common, but there are scarce data regarding the effect of DMARDs on this premalignant condition. We aimed to evaluate the impact of JAK inhibitors (JAKis) on MGUS when initiated for an active rheumatic disease. METHODS: Patients with monoclonal abnormality prior to JAKi initiation for an active rheumatic disease were identified through the MAJIK-SFR Registry, a French multicentre prospective study. Clinical and biological data were collected using a standardized case report form. RESULTS: Twenty patients were identified with a mean age of 65 years and a diagnosis of RA (n = 15), PsA (n = 3), and axial SpA (n = 2). The JAKi prescribed was baricitinib (n = 9), tofacitinib (n = 6) or upadacitinib (n = 5), with a mean duration of 15.5 months. Seventeen patients had individualized serum monoclonal protein (IgG kappa n = 9; IgG lambda n = 4; IgM kappa n = 3; IgA lambda n = 1) ranging from 0.16 to 2.3 g/dl, and three patients did not have an initial measurable spike but they had a positive serum immunofixation. With a follow-up of 4-28 months, the serum monoclonal protein level decreased in 8 of 17 patients (47%), remained stable in 8 patients (47%) and increased in 1 patient (6%). The maximal decrease observed was an initial IgG kappa of 2.3 g/dl, decreasing to 0.2 g/dl at month 14. CONCLUSION: This study provides reassuring and promising data on MGUS evolution in patients treated with JAKis for rheumatic diseases, which may guide the choice of treatment in patients with both conditions.

Role of stress in the development of rheumatoid arthritis: a case-control study.

OBJECTIVES: The primary objective of this study was to assess the stressful life events preceding the onset of symptoms in RA. The secondary objectives were to assess how early RA patients perceive stress and cope with stressors. METHODS: A case-control study was performed, comparing patients recently diagnosed with RA to age- and gender-matched control subjects recently hospitalized for an unplanned surgical procedure not known to be influenced by stress. The Social Readjustment Rating Scale assessed the cumulative stress induced by stressful life events in the year preceding the onset of symptoms. Coping strategies, stress and anxiety symptoms were evaluated using validated psychological scales. RESULTS: Seventy-six subjects were included in each group. The mean Social Readjustment Rating Scale score was twice as high in cases compared with controls [respectively, 167.0 (172.5) vs 83.3 (124.4), P < 0.001]. The association between cumulative stress and RA was statistically significant only in women, with a dose-dependent association between stress and RA. While female patients with RA attributed more often the onset of symptoms to a life event than female controls (70.2 vs 24.5%, P < 0.001), no significant difference was found when comparing male RA patients with male controls (26.9 vs 18.5%, respectively, P = 0.46). Increased perceived stress score (P = 0.04) and coping based on emotions (P = 0.001) were found in cases compared with controls. CONCLUSION: Patients with early RA reported more life events in the year preceding the onset of symptoms than controls. Gender specificities were found with a significant association between cumulative stress and RA only in women.

Diagnosis and treatment of Tropheryma whipplei infection in patients with inflammatory rheumatic disease: Data from the French Tw-IRD registry.

OBJECTIVES: Tropheryma whipplei infection can manifest as inflammatory joint symptoms, which can lead to misdiagnosis of inflammatory rheumatic disease and the use of disease-modifying antirheumatic drugs. We investigated the impact of diagnosis and treatment of Tropheryma whipplei infection in patients with inflammatory rheumatic disease. METHODS: We initiated a registry including patients with disease-modifying antirheumatic drugs-treated inflammatory rheumatic disease who were subsequently diagnosed with Tropheryma whipplei infection. We collected clinical, biological, treatment data of the inflammatory rheumatic disease, of Tropheryma whipplei infection, and impact of antibiotics on the evolution of inflammatory rheumatic disease. RESULTS: Among 73 inflammatory rheumatic disease patients, disease-modifying antirheumatic drugs initiation triggered extra-articular manifestations in 27% and resulted in stabilisation (51%), worsening (34%), or improvement (15%) of inflammatory rheumatic disease. At the diagnosis of Tropheryma whipplei infection, all patients had rheumatological symptoms (mean age 58 years, median inflammatory rheumatic disease duration 79 months), 84% had extra-rheumatological manifestations, 93% had elevated C-reactive protein, and 86% had hypoalbuminemia. Treatment of Tropheryma whipplei infection consisted mainly of doxycycline plus hydroxychloroquine, leading to remission of Tropheryma whipplei infection in 79% of cases. Antibiotic treatment of Tropheryma whipplei infection was associated with remission of inflammatory rheumatic disease in 93% of cases and enabled disease-modifying antirheumatic drugs and glucocorticoid discontinuation in most cases. CONCLUSIONS: Tropheryma whipplei infection should be considered in inflammatory rheumatic disease patients with extra-articular manifestations, elevated C-reactive protein, and/or hypoalbuminemia before disease-modifying antirheumatic drugs initiation or in inflammatory rheumatic disease patients with an inadequate response to one or more disease-modifying antirheumatic drugs. Positive results of screening and diagnostic tests for Tropheryma whipplei infection involve antibiotic treatment, which is associated with complete recovery of Tropheryma whipplei infection and rapid remission of inflammatory rheumatic disease, allowing disease-modifying antirheumatic drugs and glucocorticoid discontinuation.

Use of a bDMARD or tsDMARD for the management of inflammatory arthritis under checkpoint inhibitors: an observational study.

OBJECTIVE: There is limited experience regarding the use of biological disease-modifying antirheumatic drug (bDMARD) and JAK inhibitor (JAKi) for the management of immune checkpoint inhibitors (ICI)-induced inflammatory arthritis. We aimed to assess their efficacy and safety in this setting. METHODS: Using the Club Rhumatismes and Inflammation French network, we conducted a multicentre, retrospective, observational study of patients with cancer diagnosed with inflammatory arthritis under ICI(s) and treated with bDMARD or JAKi. Clinical data were collected using a standardised case report form. RESULTS: Twenty patients (60% men, median age 69.5 years) were included, with rheumatoid arthritis (RA)-like (n=16), polymyalgia rheumatica-like (n=2) or psoriatic arthritis-like (n=2) clinical presentation. Two patients had pre-existing RA. 90% were treated with glucocorticoids as first-line therapy and 60% received methotrexate prior to bDMARD or JAKi. Anti-interleukin-6 receptor (IL-6R) therapy was used in 13/20 patients (65%), leading to clinical improvement in 11/13 patients (85%), but one patient experienced intestinal perforation and cancer progression was noticed in 6/13 patients (46%). Tumour necrosis factor inhibitors were used in 5/20 patients (25%), with improvement in 4/5 patients (80%) and cancer progression was observed in 3/5 patients (60%). Two infections (diverticulitis and pneumonitis) were reported. Anakinra, baricitinib and ustekinumab were each used in one patient. Median duration of the bDMARD or JAKi was 17 weeks. CONCLUSION: Anti-IL-6R therapy is currently the most common strategy in patients with ICI-induced inflammatory arthritis and insufficient response to glucocorticoids and methotrexate, leading to improvement in >80%. Overall, cancer progression occurred in about half of patients and whether the bDMARD/JAKi impacted the tumour response remains to be determined.

Use of Biologics to Treat Relapsing and/or Refractory Eosinophilic Granulomatosis With Polyangiitis: Data From a European Collaborative Study.

OBJECTIVE: To describe the efficacy and safety of biologics for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA). METHODS: A retrospective European collaborative study was conducted in patients with EGPA who received treatment with biologics for refractory and/or relapsing disease. RESULTS: Among the 147 patients with EGPA included in the study, 63 received rituximab (RTX), 51 received mepolizumab (MEPO), and 33 received omalizumab (OMA). At the time of inclusion, the median Birmingham Vasculitis Activity Score (BVAS) was 8.5 (interquartile range [IQR] 5-13) in the RTX group, while the median BVAS in the OMA group was 2 (IQR 1-4.5) and the median BVAS in the MEPO group was 2 (IQR 1-5). In patients receiving RTX, the median BVAS declined both at 6 months (median 1, IQR 0-4.5) and at 12 months (median 0, IQR 0-2), and the frequency of remission, partial response, treatment failure, and stopping treatment due to adverse events was 49%, 24%, 24%, and 3%, respectively. For the treatment of glucocorticoid (GC)-dependent asthma, patients who received MEPO had a much better GC-sparing effect and overall response than did patients who received OMA. The frequency of remission, partial response, treatment failure, and stopping treatment due to adverse events was 15%, 33%, 48%, and 4%, respectively, in the OMA group and 78%, 10%, 8%, and 4%, respectively, in the MEPO group. Remission rates at 12 months were 76% and 82% among patients receiving MEPO at a doses of 100 mg and 300 mg, respectively. CONCLUSION: These results suggest that RTX could be effective in treating relapses of EGPA vasculitis. MEPO is highly effective with a good safety profile in patients with GC-dependent asthma. Our data suggest that 100 mg MEPO monthly could be an acceptable dosage for first-line therapy in selected instances of EGPA, recognizing, however, that this has not been compared to the validated dosage of 300 mg monthly.

Acceptance rate and sociological factors involved in the switch from originator to biosimilar etanercept (SB4).

OBJECTIVE: To study acceptance rate and factors influencing acceptance of the switch from originator etanercept (Enbrel©) to biosimilar etanercept (SB4, Bénépali©) in patients with rheumatic disease. METHODS: Patients with a well-controlled rheumatic disease consulting in our rheumatology department were offered the switch for SB4. After oral and written information concerning biosimilar, free choice to accept the switch was left to the patients. The main outcome was primary switch acceptance rate defined by switch acceptance during the initial consult. Real switch adherence, socio-cultural factors and beliefs influencing switch acceptance rate were retrieved during a telephonic interview at distance from the consultation. RESULTS: Fifty-two patients were eligible for the switch: 32 (62%) with spondyloarthritis and 20 (38%) with rheumatoid arthritis. The primary acceptance rate was 92% (48/52). Patients refusing the switch were more likely to report a bad opinion on generic drugs (100% vs 11%, p < 0.001). Other patient characteristics were roughly identical except for a statistical trend in the refusal group toward older age (61.4vs 50.7years, p = 0.08) and longer disease duration (26vs 12.1years, p = 0.05). Despite initial acceptance, two patients did not begin SB4 after receiving negative information by their regular pharmacist. Real SB4 switch rate was 85% (44/52) and 86% (38/44) of patients reported a good experience of the switch. CONCLUSIONS: Acceptance rate of the switch from originator to biosimilar etanercept is high. Patient information, physician and pharmacist knowledge on biosimilars should be taken into account in order to improve their diffusion.

Switching from originator infliximab to biosimilar CT-P13 in real-life: The weight of patient acceptance.

OBJECTIVE: To explore acceptance and retention rate of biosimilar CT-P13 after switching from originator infliximab (OI) in patients with various rheumatic diseases. METHODS: Patients with stable rheumatoid arthritis (RA), ankylosing spondylitis (AS) or psoriatic arthritis (PsA) under OI were proposed to switch to CT-P13 at the same regimen. A prospective cohort of infliximab-naïve patients beginning CT-P13 and a retrospective cohort of patients treated with OI were used as controls. The primary outcome was to evaluate the retention rate of CT-P13. Secondary outcomes were the switch acceptance rate, reasons of failure and safety. RESULTS: Switch was proposed to 100 patients and accepted by 89 of them (63 AS, 12 PsA and 14 RA). After a median follow-up of 33 weeks, 72% of patients were still treated with CT-P13. This retention rate was significantly lower than the one found in our retrospective and prospective control cohorts: 88% and 90% respectively (P-value=0.0002). Within patients who asked to be reswitched to OI, 13/25 (52%) presented clinical disease activity, one developed serum sickness and 11 (44%) presented no objective activity. A subanalysis excluding these 11 patients abrogated difference in retention rates between the 3 cohorts (P-value=0.453). After reswitching to OI, patients without objective disease activity claimed to recover original efficacy. CONCLUSIONS: Retention rate was lower after switching from OI to CT-P13 compared to our control cohorts. However, this difference faded after excluding patients without objective clinical activity, suggesting a reluctance of patients to the switch and a negative perception of the biosimilar.

Automated trapping, assembly, and sorting with holographic optical tweezers.

We combine real-time feature recognition with holographic optical tweezers to automatically trap, assemble, and sort micron-sized colloidal particles. Closed loop control will enable new applications of optical micromanipulation in biology, medicine, materials science, and possibly quantum computation.

Electrostatic interactions of colloidal particles in nonpolar solvents: role of surface chemistry and charge control agents.

We study the electrostatic and hydrodynamic interactions of colloidal particles in nonpolar solvents. Using blinking optical tweezers, we can extract the screening length, kappa-1, the effective surface potential, |ezeta*|, and the hydrodynamic radius, ah, in a single measurement. We apply this technique to suspensions of polystyrene and poly(methyl methacrylate) particles in hexadecane with soluble charge control agents, aerosol sodium di-2-ethylhexylsulfosuccinate (AOT) and polyisobutylene succinimide (OLOA-1200). We find that the electrostatic interactions of these particles depend sensitively on surface composition as well as on the concentration and chemistry of the charge control agent.

Statistics of particle trajectories at short time intervals reveal fN-scale colloidal forces.

We describe and implement a technique for extracting forces from the relaxation of an overdamped thermal system with normal modes. At sufficiently short time intervals, the evolution of a normal mode is well described by a one-dimensional Smoluchowski equation with constant drift velocity v, and diffusion coefficent D. By virtue of fluctuation dissipation, these transport coefficients are simply related to conservative forces, F, acting on the normal mode: F=kBTv/D. This relationship implicitly accounts for hydrodynamic interactions, requires no mechanical calibration, makes no assumptions about the form of conservative forces, and requires no prior knowledge of material properties. We apply this method to measure the electrostatic interactions of polymer microspheres suspended in nonpolar microemulsions.