Dario Camellino

Polymyalgia rheumatica (PMR) is a common inflammatory disorder of people aged more than 50 years, usually managed with prolonged glucocorticoid (GC) therapy despite its associated toxicity and frequent relapses. Over the past decade, major advances in understanding innate and adaptive immune mechanisms have reshaped the conceptual framework of PMR, positioning it in an autoinflammation–autoimmunity continuum. Synovial and bursal tissues exhibit macrophage-dominated inflammation driven by interleukin (IL)-6, granulocyte-macrophage colony-stimulating factor and interferon-γ, sustained by T helper (Th) 1 effector responses, senescent T cells, and dysregulated B-cell and dendritic-cell compartments. This expanding immunopathological knowledge has accelerated the development of targeted therapies that challenge traditional management paradigms. Interleukin-6 receptor blockade with tocilizumab and sarilumab has demonstrated reductions in relapse rates and cumulative GC exposure. A recent randomized controlled trial showed a significant effect of the anti-IL-17A inhibitor secukinumab in achieving sustained remission and reducing GC cumulative dose. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway blockade represents another promising approach to treat PMR. Novel therapeutic classes, such as GC receptor modulators and selective 11β-hydroxysteroid dehydrogenase type 1 inhibitors, further aim to optimize anti-inflammatory efficacy while mitigating steroid-associated harm. This review synthetizes current insights into the immunopathophysiology of PMR and critically appraises emerging targeted treatment strategies, highlighting how these advances may redefine the standard of care. As understanding matures and therapeutic options expand, future management of PMR is likely to shift toward more precise, mechanism-driven approaches, rendering GC-free remission an achievable target for many more patients.

Objectives: Guselkumab is a biologic disease-modifying antirheumatic drug (bDMARD) with proven efficacy for psoriatic arthritis (PsA) in randomized controlled trials. Evidence of its effectiveness from clinical practice remains limited. We evaluated the real-world effectiveness of guselkumab for PsA (primary objective) and identified factors influencing clinical outcomes. Methods: This retrospective, observational, multicentre study enrolled consecutive patients with PsA prescribed guselkumab for joint involvement at 26 Italian rheumatology referral centres. Baseline data included patient history, PsA subtype, treatment history and disease activity. Treatment effectiveness was assessed with Kaplan–Meier curves; Cox proportional hazards analysis identified factors associated with treatment persistence. Results: The study included 278 patients (median age: 57 years [interquartile range, IQR: 50–63]; 64.4% female); median observation 10.7 months (IQR: 5.3–15.9; total: 3332.6 patient-months). Retention rates at 6, 12 and 24 months were 90.4%, 80.0% and 67.8%, respectively. Reasons for discontinuation included primary inefficacy (48% of 54 cases), secondary inefficacy (41%) and skin/mucosal intolerance (4%). Statistically significant factors (P < 0.05) influencing treatment persistence included sex, smoking, concurrent conventional synthetic DMARDs (csDMARDs), corticosteroid use, year of prescription and axial or enthesitic involvement. Conclusions: Approximately two-thirds of PsA patients treated with guselkumab remained on therapy after 2 years. Adverse events motivated <10% of discontinuations. Effectiveness was higher in patients with enthesitic or axial PsA and in those without concurrent corticosteroids or csDMARDs, confirming the effectiveness and safety of guselkumab as an optimal choice for monotherapy, particularly in PsA patients with enthesitis, with or without joint impairment, and/or axial involvement.

Objective: A dysregulated immune response is involved in the pathogenesis of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). These diseases have been reported as immune‐related adverse events in patients with cancer treated with immune checkpoints inhibitors. In this cross‐sectional study, the relationship between soluble immune checkpoint molecules (sICMs) and clinical/imaging features of PMR and GCA was investigated.Methods: Consecutive patients with PMR diagnosed according to the criteria by Bird et al were compared with age‐ and sex‐matched healthy controls. Patients with PMR and overlapping GCA had to also satisfy the 1990 ACR classification criteria for GCA. All patients underwent standardized clinical, laboratory examination, and ¹⁸F‐fluorodeoxyglucose positron emission tomography/computed tomography scans. The sICM anticytotoxic T Ly‐4, the programmed cell death protein 1 (PD‐1), and PD‐1 ligands PD‐L1 and PD‐L2 were measured by enzyme‐linked immunosorbent assay.Results: Forty patients (80% women, mean age 76 years, and mean disease duration 88 days) were assessed. Of these, 30 had isolated PMR and 10 had PMR with GCA. Patients showed significantly higher concentrations of all sICMs compared with controls (P < 0.001). Conditional logistic regression revealed the strong discriminative capacity of these molecules between patients and healthy controls, with PD‐1 showing complete separation among groups (effect size = 0.78) and PD‐L1 (odds ratio [OR] 134.33, P < 0.001) and PD‐L2 (OR 63.00, P < 0.001) demonstrating the strongest ability to distinguish patients from controls. Correlations between sICM levels and clinical features were generally weak or absent, with no significant differences based on disease phenotype or glucocorticoid exposure. Results were similar in glucocorticoid‐naive patients.Conclusion: sICMs are significantly elevated in PMR and GCA and strongly differentiate patients from healthy controls. Although they do not correlate with clinical or imaging features, their consistent elevation in active disease might suggest a complex interplay between innate and adaptive immunity. image

Background and Objectives: The treatment landscape for Rheumatoid Arthritis (RA) has evolved significantly with the introduction of Janus kinase inhibitors (JAKi), such as Tofacitinib (TOFA), which offer a new therapeutic option for patients who have failed or are intolerant to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Safety concerns, particularly related to cardiovascular and cancer risks, prompted a need for additional investigation in real-world clinical settings. This study aimed to evaluate the long-term effectiveness and predictors of response to TOFA in two subpopulations of RA patients, categorized by differing cardiovascular risk profiles. Materials and Methods: This was a retrospective, multicenter observational study conducted as part of the BIRRA project, involving 23 Italian rheumatological referral centers. A total of 213 patients diagnosed with RA and treated with TOFA were included, with data collected on baseline demographics, clinical history, disease activity, and comorbidities. Patients were divided into high-risk and low-risk cardiovascular groups based on age (≥65 years) and the presence of at least one cardiovascular risk factor. Disease activity was assessed at baseline, 6 months, and 12 months using DAS28-ESR and DAS28-CRP. Treatment response was evaluated using intention-to-treat (ITT) and per-protocol (PP) approaches. Predictors of low disease activity (LDA) and remission were assessed through logistic regression, and clustering analyses were used to identify subgroups of patients with different therapeutic responses. Results: The study included 213 patients, with 129 classified as high-risk. For the overall cohort, patients achieving LDA and remission at 6 months were 20% and 12%, respectively, for the ITT analysis, and 29% and 14% for the PP analysis. At 12 months, 26% of patients reached LDA, and 17% achieved remission according to ITT, while for the PP analysis, these rates were 30% and 19%, respectively. No significant differences in remission or LDA rates were observed between the high-risk and low-risk groups. In the high-risk subgroup, 17% of patients reached LDA and 9% achieved remission at 6 months (ITT analysis), while these rates increased to 22% and 13%, respectively, in the PP analysis. At 12 months, 22% achieved LDA and 13% achieved remission in the ITT analysis, while 28% and 17% did so in the PP analysis. The reduction in DAS28-ESR and DAS28-CRP scores was significant (p < 0.001) across all time points for both high-risk and low-risk patients. Logistic regression analyses revealed that none of the baseline characteristics—including age, sex, comorbidities, rheumatoid factor, anti-citrullinated protein antibody (ACPA) positivity, initial disease severity, or treatment history—were significant predictors of remission or LDA at 6 or 12 months. The clustering analysis suggested that older patients, particularly those with worse baseline DAS28 scores, tended to show a less favorable response to treatment, potentially indicating impacts of age-related factors such as immunosenescence on therapeutic outcomes. Conclusions: Tofacitinib demonstrated similar effectiveness in both high- and low-risk cardiovascular subgroups of RA patients, with significant reductions in disease activity observed at both 6 and 12 months. Despite safety concerns related to cardiovascular risk, TOFA remained an effective treatment option across patient subgroups, with no significant differences in remission or LDA rates based on cardiovascular risk profiles. Age appeared to negatively impact treatment response, highlighting the role of immunosenescence in RA management. These findings support the use of TOFA as a personalized therapeutic option for RA, emphasizing the need for careful evaluation of cardiovascular and age-related risks in clinical decision-making.

Objective: Polymyalgia rheumatica (PMR) is an inflammatory disorder of the elderly characterized by girdle pain and stiffness. Obesity has an influence on disease activity and outcome in rheumatic diseases like osteoarthritis and rheumatoid arthritis. We aimed to investigate the relationship between high BMI and the severity and outcome of PMR, which is incompletely understood.Methods: In a post hoc analysis, 83 patients with recent-onset PMR were studied over 6 months using clinical examination, laboratory evaluation, and girdle ultrasound (US). The modified Health Assessment Questionnaire (mHAQ), 36-item Short Form Health Survey (SF-36), and PMR visual analog scale (VAS) scores, as well as prednisone therapy data, were recorded. Patients were grouped according to their BMI.Results: At baseline, the 12 patients with obesity had significantly more shoulder pain (P= 0.03), global pain (P= 0.03), PMR VAS (P< 0.01), and fatigue (P= 0.03); higher mHAQ (P= 0.01); and lower SF-36 physical component summary (P= 0.048) and SF-36 pain index (P< 0.001). The mean initial prednisone dose was similar among groups, but patients with obesity received a lower dose/kg (1.9 [SD 0.7] mg vs 2.2 [SD 0.7] mg;P< 0.01). At 6 months, patients with obesity were being treated with higher mean daily prednisone doses (8.5 [SD 3.2] mg/d vs 6.2 [SD 5.2] mg/d;P= 0.02), and 40% of them were receiving higher daily prednisone doses than the standard protocol compared with 14% patients without obesity (P= 0.048). Clinical features, laboratory results, and US results were similar between patients with and without obesity.Conclusion: Obesity affects both symptom severity and prednisone utilization in patients with PMR. The reason for this may relate to different subjective pain perception rather than increased inflammation in patients with obesity. BMI should be considered when interpreting symptoms in patients with PMR and deciding their prednisone doses.

The objective of this case series is to describe the efficacy and safety of baricitinib (BARI) in a group of patients with polymyalgia rheumatica (PMR) and/or giant cell arteritis (GCA). These patients were treated with BARI due to either a refractory disease course or the unavailability of tocilizumab because of the pandemic. A total of six patients (five females and one male, median age 64 years, range 50-83) were treated with BARI. Two of them had isolated PMR, two had PMR with associated large vessel (LV)-GCA, one had LV-GCA presenting as fever of unknown origin, and one had cranial-GCA. All patients reported improvement with BARI. At the time of starting BARI, patients were taking a median prednisone dose of 8.75 mg/day (range 0-25), and the four patients with PMR had a median PMR-activity score of 23.3 (indicating high disease activity), which decreased to 1.58 after 6 months of treatment with BARI. Two of them could stop glucocorticoids (GC) and continue BARI monotherapy. One patient suffered from pneumonia, and BARI was therefore stopped. No other adverse events attributable to BARI were detected. Our case series supports previous reports suggesting the efficacy of Janus kinase inhibitors as a GC-sparing strategy in PMR and GCA.

Dario Camellino, Elvis Hysa, Christian Dejaco; From polymyalgia arteritica to arteritis polymyalgica: redefining the GCA-PMR spectrum through advanced MRI

Background/Objectives: The Janus kinase inhibitors (JAKi) tofacitinib (TOFA), baricitinib (BARI), upadacitinib (UPA), and filgotinib (FILGO) are effective drugs for the treatment of rheumatoid arthritis. However, the US Food and Drug Administration (FDA) raised concerns about the safety of TOFA after its approval. This prompted the European Medicines Agency (EMA) to issue two safety warnings for limiting TOFA use, then extended a third warning to all JAKi in patients at high risk of developing serious adverse effects (SAE). These include thrombosis, major adverse cardiac events (MACE), and cancer. The purpose of this work was to analyze how the first two safety warnings from the EMA affected the prescribing of JAKi by rheumatologists in Italy. Methods: All patients with rheumatoid arthritis who had been prescribed JAKi for the first time in a 36-month period from 1 July 2019, to 30 June 2022 were considered. Data were obtained from the medical records of 29 Italian tertiary referral rheumatology centers. Patients were divided into three groups of 4 months each, depending on whether the JAKi prescription had occurred before the EMA’s first safety alert (1 July–31 October 2019, Group 1), between the first and second alerts (1 November 2019–29 February 2020, Group 2), or between the second and third alerts (1 March 2021–30 June 2021, Group 3). The percentages and absolute changes in the patients prescribed the individual JAKi were analyzed. Differences among the three groups of patients regarding demographic and clinical characteristics were also assessed. Results: A total of 864 patients were prescribed a JAKi during the entire period considered. Of these, 343 were identified in Group 1, 233 in Group 2, and 288 in Group 3. An absolute reduction of 32% was observed in the number of patients prescribed a JAKi between Group 1 and Group 2 and 16% between Group 1 and Group 3. In contrast, there was a 19% increase in the prescription of a JAKi in patients between Group 2 and Group 3. In the first group, BARI was the most prescribed drug (227 prescriptions, 66.2% of the total), followed by TOFA (115, 33.5%) and UPA (1, 0.3%). In the second group, the most prescribed JAKi was BARI (147, 63.1%), followed by TOFA (65, 27.9%) and UPA (33, 11.5%). In the third group, BARI was still the most prescribed JAKi (104 prescriptions, 36.1%), followed by UPA (89, 30.9%), FILGO (89, 21.5%), and TOFA (33, 11.5%). The number of patients prescribed TOFA decreased significantly between Group 1 and Group 2 and between Group 2 and Group 3 (p ˂ 0.01). The number of patients who were prescribed BARI decreased significantly between Group 1 and Group 2 and between Group 2 and Group 3 (p ˂ 0.01). In contrast, the number of patients prescribed UPA increased between Group 2 and Group 3 (p ˂ 0.01). Conclusions: These data suggest that the warnings issued for TOFA were followed by a reduction in total JAKi prescriptions. However, the more selective JAKi (UPA and FILGO) were perceived by prescribers as favorable in terms of the risk/benefit ratio, and their use gradually increased at the expense of the other molecules.