ToRaRI (Tofacitinib in Rheumatoid Arthritis a Real-Life experience in Italy): Effectiveness, safety profile of tofacitinib and concordance between patient-reported outcomes and physician's global assessment of disease activity in a retrospective study in Central-Italy.

INTRODUCTION: The use of Janus Kinase Inhibitors (JAK-Is) in rheumatoid arthritis (RA) has entered in daily practice. In consideration of ORAL-Surveillance trial and the new EULAR recommendations, real-world data are needed to assess Jak-Is safety and effectiveness. The multicenter study presented here aimed to evaluate effectiveness and safety of tofacitinib in a real-life cohort. METHODS: A retrospective analysis was performed from September 2021 to December 2022. Data were collected when tofacitinib was started (T0) and after 3 (T3), 6 (T6) and 12 (T12) months of treatment. The primary objective was to analyze the efficacy and safety of tofacitinib. Safety was assessed by recording adverse events (AEs) with and without discontinuation. The secondary objective was to assess the difference between Patient-Reported Outcomes (PROs) and Physician's Global Assessment of disease activity (PhGA). RESULTS: 122 patients were included in the study from the following rheumatology Centers: Pisa, Ancona, Florence (two Centers), Siena, and Sardinia. A statistically significant improvement in DAS-28-CRP, CDAI and SDAI score was observed at T3, T6, compared to baseline (p < 0.001). Improvement was confirmed in patients who reach T12. Patients naïve to bDMARDs showed a shorter remission time and higher remission rates. There was also a statistically significant improvement in PROs compared to baseline (p < 0.001). The improvement was rapid and was consistent with PhGA. The 12-month retention rate for tofacitinib was 89.35%. Reasons to stop tofacitinib were: insufficient response (7), gastrointestinal symptoms (2), infection (1), malignancy (1), Zoster (1), pruritus sine materia (1). CONCLUSIONS: Tofacitinib is safe and effective in our RA cohort. It induces higher remission rates in patients naive to bDMARDs, suggesting that there may be a benefit using it as first-line therapy. Additionally, improvement in PROs was consistent with PhGA scores, demonstrating how tofacitinib affects both the objective and subjective components of disease activity. Key Points 1. JAK inhibitors are considered at a similar level as biologic agents in terms of effectiveness. 2. After ORAL-Surveillance results, real-world data are needed to assess the benefit/risk profile of Jaki. 3. Disagreement between patients and physicians has been previously reported with biologic therapy among patients with rheumatoid arthritis, with patients rating disease activity higher than physicians. 4. Jak inhibitors could reduce this discrepancy, due to their mechanism of action.

Efficacy and safety of switching from reference adalimumab to SB5 in a real-life cohort of inflammatory rheumatic joint diseases.

OBJECTIVE: SB5 showed comparable efficacy and safety profile in respect to adalimumab originator (ADA) in randomized clinical trials of rheumatoid arthritis (RA) and psoriasis. We aimed to describe the efficacy and safety of SB5 after switching from ADA in RA, axial spondyloarthritis (axSpA), psoriatic arthritis (PsA) and juvenile idiopathic arthritis (JIA) patients. METHOD: Adult RA, PsA, axSpA, JIA patients treated with ADA for at least 6 months, switched to SB5 in stable clinical conditions, were eligible. Data on safety, activity indexes and patient-reported outcomes were collected at baseline, 3 and 6 months after switching. RESULTS: Eighty-two patients (19 RA, 28 PsA, 32 axSpA and 3 JIA; 45 females, mean age 54 ± 14 years, disease duration 13 ± 7 years, ADA duration 6 ± 3 years) were enrolled. RA patients showed stable conditions, while PsA patients showed an increase in both HAQ, DAS28(CRP) and DAPSA and axSpA patients an increase in VAS pain, VAS patient disease activity and ASDAS, both at 3 months. There were changes in the concomitant medications profile, with regression of activity indexes increases at 6 months. Adverse events were reported by 33.7% patients at 3 months and 16.6% patients at 6 months, mostly disease flares and infectious events. Two patients stopped SB5. CONCLUSIONS: Despite temporary changes in the concomitant medication profile for mild disease flares, our real-life data replicate the safety profile of switching from ADA to SB5 in RA, with additional data for its applicability in PsA and axSpA patients, further supporting switching to biosimilars in treating inflammatory rheumatic conditions. Key Points • Switching from adalimumab originator to SB5 is feasible in real life rheumatic inflammatory joint diseases. • Mild disease flares can present after switching from originator adalimumab to SB5, in particular in axial spondyloarthritis and psoriatic arthritis. • Changes in concomitant medications profile allows the control of minor disease flares presenting after switching from adalimumab originator to SB5.

The switch from etanercept originator to SB4: data from a real-life experience on tolerability and persistence on treatment in joint inflammatory diseases.

AIMS: Switching from originator to biosimilar is part of current practice in inflammatory rheumatic musculoskeletal diseases (iRMDs) such as rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondylarthritis (axSpA), with evidences derived from both etanercept (ETN) to SB4-switching randomized controlled trials and real-life registries. We investigated the safety and treatment persistence of ETN/SB4 in a multi-iRMD cohort derived from two rheumatology departments in our region. METHODS: Adult patients with iRMDs, treated with ETN for at least 6 months and switched to SB4 in stable clinical condition, were eligible for this retrospective evaluation. Retrospective data on adverse events, loss of efficacy and persistence on treatment were collected until latest available follow-up. RESULTS: A total of 220 patients (85 RA, 81 PsA, 33 axSpA, 14 juvenile idiopathic arthritis and seven other conditions; 142 females, mean age 58 ± 7 years, disease duration 12 ± 4 years, ETN duration 7 ± 4 years) were enrolled, with median follow-up of 12.1 (9.7-15.8) months. A total of 50 patients (22.7%) presented with at least one adverse event, with 36 (16.4%) disease flares and 30 (13.6%: 11 for safety and 19 loss of efficacy) SB4 withdrawals. Cumulative SB4 treatment persistence was 99.1%, 88.6% and 64.6% at 6, 12 and 18 months respectively. Back-switch to ETN was performed in 17/30 cases, the remaining cases were managed with change of biologic disease modifying or conventional synthetic anti-rheumatic drug. Age was the only significant predictor of SB4 interruption at 6 months. CONCLUSION: Our real-life data confirm the safety profile of switching from ETN to SB4, with slightly higher treatment persistence rates compared with other real-life registries.

Risk of Malignancy and Biologic Therapy in Rheumatic Inflammatory Diseases: A Single-center Experience.

Objectives: Biologic disease modifying anti-rheumatic drugs (bDMARDs) have significantly improved the care of patients with rheumatic muscle-skeletal disorders (RMDs). Considering their immunosuppressive action, a theoretical increase of malignancy risk has been a major concern in the last few decades. The objective of this study is to analyze the incidence of malignancies in a cohort of patients affected by rheumatoid arthritis (RA), psoriathic arthritis (PsA), and ankylosing spondylitis (AS) treated with bDMARDs. Methods: The charts of bDMARD-treated RMD patients were reviewed, and data about bDMARD exposure and malignant cancers (excluding non-melanoma skin cancer) were collected. Results: 921 patients were included (median age: 50.59 years, 66.67% females); 1374 bDMARD treatments were administered, 87.12% were tumor necrosis factor inhibitors. A total of 21 malignant neoplasms were detected in 21 patients (61.90% females, median age at cancer diagnosis: 64.99 years), 66.67% in RA patients, 19.05% in PsA, and 14.28% in AS. Among them, 10 patients (47.62%) were treated with etanercept, 6 patients (28.57%) with adalimumab, and 1 case each with tocilizumab, certolizumab, golimumab, infliximab, and abatacept. The most common malignancies that we found were lung cancers, ductal mammary carcinomas, melanomas, and lymphomas. The incidence rate (IR) of malignancies in our cohort was 3.47 per 1000 person-years (p-y); the higher IRs were in RA patients (5.13 per 1000 p-y), in males (4.21 per 1000 p-y), and in patients aged >70 years (10.14 per 1000 p-y). Conclusions: The results of our study showed IR of malignancies in RMD patients treated with bDMARDs that is in agreement with literature data.

Sirukumab for the treatment of rheumatoid arthritis: update on sirukumab, 2018.

INTRODUCTION: Interleukin-6 (IL-6) is well-known for its pro-inflammatory properties, has been proven to target a wide range of cells in the joint, and has been implicated in extra-articular and articular manifestations in rheumatoid arthritis (RA). Tocilizumab (TCZ) is now widely used in patients with active RA and a number of additional agents that target the IL-6 pathways are under development, including sirukumab (SRK). Areas covered: SRK is an IgG1κ human anti-IL-6 monoclonal antibody which binds to IL-6 and prevents IL-6-mediated downstream effects. Initial trial results in phase-III studies in patients with RA seemed promising, showing improved results in patients with moderate-to-severe RA. Data derive from the phase-II study and the various SIRROUND studies (phase III). Expert commentary: The available data show that SRK50 mg every 4 weeks or 100 mg every 2 weeks will be effective in treating the RA population, with clinical improvements as early as week 2 and sustained over time. The adverse-event profile seems to be similar to TCZ, except for an increased mortality post open-label studies due to infections and cardiovascular events, our knowledge of which will be deepened with post-marketing surveillance and registry data.

Premedication prevents infusion reactions and improves retention rate during infliximab treatment.

Infliximab (IFX) is an anti-tumor necrosis factor-alpha antibody used to treat inflammatory joint diseases. Infusion reactions (IR) can occur during and after intravenous administration and often require discontinuation of IFX therapy. This retrospective study aimed at evaluating the incidence of IR in patients with joint inflammatory diseases receiving IFX with and without premedication. Clinical charts of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients receiving IFX from January 2002 to December 2014 were reviewed. Patients receiving only one premedication protocol over time were enrolled and clustered based on the type of premedication as follows: group 1 received no premedication; group 2 received paracetamol, esomeprazole, hydrocortisone, and chlorpheniramine maleate; group 3 received paracetamol, hydoxyzine, ranitidine, and 6-methylprednisolone. Adverse events were recorded during the infusion, in the following hours and at control visits. The charts of 105 patients treated with IFX were selected. IR were observed in 23/51 patients of group 1, in 7/35 patients of group 2, and none of 19 patients in group 3. IR incidence was significantly lower in the second (p = 0.021) and third (p < 0.001) compared to the first group. The incidence of IR was significantly lower in group 3 than group 2 (p < 0.043). Moreover, patients in group 1 had a relative risk of developing an IR 2.5 times higher than group 2. In our experience, the use of premedication significantly reduced the number of IR to IFX. In particular, the combination of paracetamol, hydroxyzine, 6-methylprednisolone and ranitidine was more efficacious than paracetamol, esomeprazole, hydrocortisone, and chlorpheniramine maleate combination protocol.

Calcinosis in systemic sclerosis: subsets, distribution and complications.

OBJECTIVE: To retrospectively analyse the features of calcinosis in a cohort of SSc patients. METHODS: Charts of SSc patients attending the Ulcer Unit of the Rheumatology Department, University of Florence and presenting a clinical suspicion of calcinosis were considered in the study. Data on clinical history, including recent skin changes, and clinical examination of all areas with suspected calcinosis, radiological imaging of the calcinotic area, demographics and SSc-related organ involvement and pain measured by a visual analogue scale were recorded. RESULTS: In 52 of 112 SSc patients, a total of 316 calcinoses were recorded and were divided into visible and palpable {154 [47.4%], clustered according to their macroscopic features as mousse [49 (31.8%)] and stone [: 105 (68.2%)]} and non-visible but palpable {: 162 [52.6%]: net [5 (3%)], plate [22 (13.8%)] and stone [135 (83.2%)]}. The X-ray-based classification of all calcinoses, both visible and non-visible, was as follows: stone, 289 (91.4%); net, 12 (3.8%) and plate, 15 (4.8%). Skin ulcers complicated 154 of 316 calcinoses (48.7%). Mousse calcinosis was associated with pulmonary arterial hypertension, the stone subset was suggestive of pulmonary involvement and justified further investigation and the net subset was the slowest to heal. CONCLUSION: Our data indicate that calcinosis may be classified in SSc as mousse, stone, net and plate according to its clinical and X-ray features. This classification awaits validation for a possible use in clinical practice and to support early treatment and prevention of complications.

Assessment, Definition, and Classification of Lower Limb Ulcers in Systemic Sclerosis: A Challenge for the Rheumatologist.

OBJECTIVE: To evaluate pathogenesis and clinical features of lower limb ulcers in systemic sclerosis (SSc) and to propose a classification that could be used in clinical practice. METHODS: Charts of 60 patients with SSc who had lower limb cutaneous lesions were reviewed. All patients had videocapillaroscopy and arterial and venous lower limb color Doppler ultrasonography (US). Arteriography was performed if occlusive peripheral arterial disease was suspected. RESULTS: The 554 lesions were classified as hyperkeratosis, ulcers, and gangrenes. There were 341 (61.6%) hyperkeratoses, 208 (37.5%) ulcers, and 5 (0.9%) gangrenes. Ulcers were divided into pure ulcers, ulcers associated with hyperkeratosis, and ulcers secondary to calcinosis. Involvement of arterial and venous macrocirculation as determined by color Doppler US was observed in 17 (18.3%) and 18 (30%) patients, respectively. Seventeen out of 37 patients with pure ulcers (45.9%) presented neither venous insufficiency nor hemodynamically significant macrovascular arterial disease. In these patients, pure ulcers were most likely caused by isolated SSc-related microvascular involvement (pure microvascular ulcers). The only significant risk factor for development of pure microvascular ulcers in the multivariate analysis was the history of lower limb ulcers (OR 26.67, 95% CI 2.75-259.28; p < 0.001). CONCLUSION: Results of our study indicate that lower limb ulcers in SSc often have a multifactorial pathogenesis that may be difficult to manage. Further studies are needed to validate the proposed classification and to assess the most appropriate management of lower limb ulcers in SSc.