Israel Medical Association Journal

Over the last decade the use of artificial intelligence (AI) has reformed academic research. While clinical diagnosis of psoriasis and psoriatic arthritis is largely straightforward, the determining factors of a clinical response to therapy, and specifically to biologic agents, have not yet been found. AI may meaningfully impact attempts to unravel the prognostic factors that affect response to therapy, assist experimental techniques being used to investigate immune cell populations, examine whether these populations are associated with treatment responses, and incorporate immunophenotype data in prediction models. The aim of this mini review was to present the current state of the AI-mediated attempts in the field. We executed a Medline search in October 2023. Selection and presentation of studies were conducted following the principles of a narrative–review design. We present data regarding the impact AI can have on the management of psoriatic disease by predicting responses utilizing clinical or biological parameters. We also reviewed the ways AI has been implemented to assist development of models that revolutionize the investigation of peripheral immune cell subsets that can be used as biomarkers of response to biologic treatment. Last, we discussed future perspectives and ethical considerations regarding the use of machine learning models in the management of immune-mediated diseases.

Psoriatic arthritis can present with significant hand and wrist deformity and dysfunction [1]. The development of newer biological therapies has resulted in higher rates of remission [2]. However, surgical intervention is still indicated in pain, disability, and severe deformation cases. The management of patients with rheumatic diseases has a controversial history, characterized by rheumatologists and hand surgeons debating the efficacy of surgical interventions. Some surgeons attribute the controversial results to “too little and too late” referral of patients from rheumatologists [3]. While the availability of new and more effective medication has changed the indications and postponed surgical intervention, it is important to remember that surgery is often more effective when used preventively in the early stages than when forced to salvage. In the following case, we present a patient with psoriatic arthritis who presented with advanced-stage debilitating hand deformity and was treated surgically.

Background: The parasympathetic system and its main neurotransmitter, acetylcholine, contributes to homeostasis of inflammation. Cholinergic dysregulation is thought to contribute to the pathogenesis of inflammatory rheumatic diseases. Cholinesterase activity in patients with psoriatic arthritis (PsA) has not been investigated.

Objectives: To compare the cholinesterase activity in patients with PsA and immunocompetent controls and to explore the correlation between cholinergic status (CS) and PsA disease activity.

Methods: Serum acetylcholinesterase (AChE) and total cholinesterase activity were measured in patients with PsA (n=88) and matched controls (n=84). Cholinergic activity before and 3–6 months after the initiation of a biologic treatment was evaluated in seven patients with PsA.

Results: The levels of AChE and CS were similar in both PsA patients and controls. PsA patients treated with biologics had significantly lower levels of AChE and CS compared to patients treated with non-biologics: 447.4 vs. 526 substrate hydrolyzed/min/ml, P = 0.005, and 1360.9 vs. 1536, P = 0.029, respectively. We found an association between C-reactive protein levels, AChE activity (r = 0.291, P = 0.008), and cholinergic status (r = 0.247, P = 0.026) in patients with PsA but not in controls. No correlation between AChE activity, cholinergic status, and the indices of PsA disease activity was found. After initiating or switching biologic treatment in 7 patients, AChE levels remained stable.

Conclusions: We demonstrated similar cholinesterase activity in patients with psoriatic arthritis and controls, highlighting a potential effect of biologic treatment on cholinergic activity in patients with PsA.

Background: Psoriatic arthritis (PsA) is an inflammatory rheumatic disease characterized by different phenotypes in terms of joint involvement. The so-called oligoarticular pattern involves fewer than five active joints at a different time points. The evaluation of disease activity in this subset of patients is an unmet need due to the lack of specific indices able to capture modifications over time.

Objectives: To evaluate the ability of musculoskeletal ultrasound to monitor the response to apremilast treatment in oligoarticular PsA patients.

Methods: We evaluated 24 oligoarticular patients (19 women, 5 men; median age 56 years, interquartile range (IQR) 19; median disease duration 5 years, IQR 5.75). All patients were assessed at baseline (T0), and after 6 (T1), 12 (T2), and 24 (T3) weeks. Clinical assessment included evaluation of 66 swollen joints and patient global health assessment. All the patients underwent ultrasound assessment of the clinically involved joints. Synovial effusion/hypertrophy and power Doppler were scored with a semi-quantitative scale (0–3). The total inflammatory score was the sum of the scores.

Results: We found a reduction in the ultrasound inflammatory score at all time points, with a significant improvement at 6 and 12 weeks of treatment compared with baseline: T0 median 8.5 (IQR 5.0); T1 3.5 (3.0); T2 2.0 (3.5); P  = 0.01. We observed a significant reduction of patient global health assessment after 24 weeks (T0 median 50 (32.5); T3 40 (57.5); P = 0.01).

Conclusions: Musculoskeletal ultrasound could be useful in the assessment of treatment response in PsA patients with oligoarticular subset

We describe the features of nocebo, and its impact in studies of transition from the originator to the respective biosimilar in inflammatory rheumatic diseases. Investigations in healthy volunteers as well as in the neurology and anesthesiology fields demonstrated the involved cerebral areas and the neurotransmitter pathways responsible for the nocebo response. Whether these findings are applicable to patients with inflammatory rheumatic diseases remains to be demonstrated. Nocebo may account for part of the after-switching biosimilar failures. However, in the absence of validated classification or diagnostic criteria, specific neurochemical and neuroimaging studies, the lack of data on serum tumor necrosis factor and drug levels, and the disease improvement after the switching back to the originator biologic observed in some patients, the nocebo diagnosis remains the role of the individual clinician. Investigations on nocebo pathophysiology and diagnosis are required to address its impact in after-transition biosimilar studies in rheumatology.

Enthesitis is a term that refers to inflammation at tendon, ligament, or joint capsule insertions. The entheses are increasinlgly considered to be the primary site of joint inflammation in the spondyloarthropathies including psoriatic arthritis (PsA). Great advances have occurred in the understanding of enthesopathy, which has resulted in a better understanding of the etiopathogenesis of PsA. Enthesitis is difficult to assess on both clinical examination and on imaging because of the overlap in features between mechanical, degenerative, and inflammatory pathologies. Ultrasonography frequently detects entheseal abnormalities in patients with psoriasis, despite the absence of clinical symptoms of arthropathy and the longitudinal value of such lesions for PsA prediction remains unknown. The role of magnetic resonance imaging (MRI) in the assessment and monitoring of enthesitis is not fully agreed on but it is clearly superior for the assessment of spinal polyenthesitis and for diffuse peri-enthseal osteitis that can occur anywhere in the skeleton. Nuclear medicine, including conventional positron-emission tomography (PET) and high-resolution PET scan (hrPET), is more of a research tool for enthesitis and can, for example, help distinguish between PsA and osteoarthritis. Entheseal abnormalities are common in osteoarthritis, which creates diagnostic difficulty from PsA. Entheseal changes, especially on imaging, may also occur in rheumatoid arthritis (RA) and likely reflect the extension of the inflammatory process from the adjacent synovium. The nail is anatomically anchored to the skeleton via a mini-enthesis network. An association between ultrasonography determined distal interphalageal joint (DIP) extensor tendon enthesopathy and clinical nail disease was found, which highlights the pivotal role of the enthesis in this PsA risk factor. This review summarizes the relevant insights and implication of imaging for enthesitis, primarily in PsA but also in other arthropathies.

Background: Tumor necrosis factor-alpha (TNFα) inhibitors are indicated for patients with psoriatic arthritis (PsA) in whom conventional disease-modifying anti-rheumatic drugs (DMARDs) are insufficient to achieve disease remission. 

Objectives: To determine the value of acute-phase reactant levels at diagnosis of psoriatic arthritis in predicting the need for biologic treatment with TNFα inhibitors.

Methods: We conducted a longitudinal observational study of an inception cohort of 71 consecutive patients diagnosed with psoriatic arthritis. C-reactive protein (CRP) was assayed for all patients at their first visit.

Results: All patients were treated with one or more DMARDs, mainly methotrexate (81.6%). Thirty-seven patients (52.11%) had an inadequate response and received at least one TNF inhibitor. CRP level at diagnosis was positively correlated with need for a TNF inhibitor (P = 0.009, HR 1.8, 95%CI 1.27–1.85). Patients with CRP > 0.9 mg/dl at diagnosis started biologic treatment significantly earlier than patients with a lower level (P = 0.003, HR 2.62, 95%CI 0.393–2.5).

Conclusions: In patients with psoriatic arthritis, CRP ≥ 0.9 mg/dl at diagnosis significantly predicts an earlier need for a TNF inhibitor to achieve disease control.

 

Lung involvement is a well-recognized extra-articular manifestation of ankylosing spondylitis (AS). Anecdotal reports suggest that the use of anti-TNF drugs may be related to lung disease and pulmonary fibrosis. To examine the association between anti-TNF drugs and the development of lung disease in patients with AS or  psoriatic arthritis (PsA) we conducted a systematic review. Of the 670 papers identified by means of key word and hand search, only one full-text paper was considered potentially relevant but had to be discarded as it did not meet the eligibility criteria. Although no conclusion was reached, this is the first systematic review to examine this problem which is becoming increasingly important as these drugs are widely prescribed in patients with spondyloarthritis.

Psoriatic arthritis (PsA) is a chronic inflammatory condition associated with skin psoriasis and manifests a wide clinical phenotype, with proposed differences between sexes. Current treatments are based on traditional disease-modifying anti-rheumatic drugs (DMARD), and biologic agents and studies have reported different clinical response patterns depending on sex factors. We aimed to identify sex differences in drug retention rate in patients with PsA and performed a systematic research on MEDLINE, EMBASE and Cochrane databases (1979 to June 2015) for studies regarding effectiveness (measured as drug retention rate) in PsA in both traditional DMARDs and biologics. Demographic data as well as retention rates between sexes were extracted. From a total 709 retrieved references, we included 9 articles for the final analysis. Only one study reported data regarding DMARDs, while eight studies reported retention rate for anti-tumor necrosis factor (TNF) biologics, mainly infliximab, adalimumab and etanercept. No differences were reported in retention rates between sexes for methotrexate, while women manifested lower retention rates compared to men with regard to anti-TNF. We highlight the need to include sex differences in the management flow chart of patients with PsA.

Background: Infliximab and etanercept have been included in the Israeli national list of health services since 2002 for rheumatoid arthritis and juvenile idiopathic arthritis, and since 2005 for psoriatic arthritis and ankylosing spondylitis. The regulator (Ministry of Health and health funds) mandates using fixed doses of infliximab as the first drug of choice and increased dosage is not allowed. For other indications (e.g., vasculitis), anti-tumor necrosis factor therapy is given on a "compassionate" basis in severe refractory disease.

Objectives: To describe our experience with anti-TNF[1] therapy in a single tertiary referral center in northern Israel and to analyze the impact of the national health policy on the results.

Methods: We reviewed the medical records of patients who received anti-TNF therapy in our institution, and analyzed demographic data, diagnosis, clinical and laboratory features, previous and current therapies, and anti-TNF treatment duration and side effects.

Results: Between 2001 and 2006, 200 patients received anti-TNF therapy for rheumatoid arthritis (n=108), juvenile idiopathic arthritis (n=11), psoriatic arthritis (n=37), ankylosing spondylitis (n=29), adult Still's disease (n=4), overlap disease (RA[2] and scleroderma or polymyositis, n=6), temporal arteritis (n=1), polyarteritis nodosa (n=1), dermatomyositis (n=1), amyloidosis secondary to RA (n=1) and Wegener's granulomatosis (n=1). Forty percent of RA patients discontinued the first anti-TNF agent due to side effects or insufficient response. Higher sedimentation rate and lower or negative rheumatoid factor predicted better response to therapy among RA patients. AS[3] and PS[4] patients had a better safety and efficacy profile. Severe infections occurred in 2% of patients. All eight patients who presented lung involvement as part of their primary rheumatic disease remained stable or improved. A significant improvement was achieved in all six patients with overlap disease.

Conclusion: Our daily practice data are generally in agreement with worldwide experience. The ‘deviations’ might be explained by the local health policy at that time. The impact of health policy and economic and administrative constraints should be taken into account when analyzing cohort daily practice data.