An MRI study of immune checkpoint inhibitor-induced musculoskeletal manifestations myofasciitis is the prominent imaging finding.

OBJECTIVE: To assess: (i) the prevalence, and clinical and imaging characteristics of immune checkpoint inhibitor (ICI)-induced musculoskeletal immune-related adverse events (ir-AEs) in a prospective manner and (ii) whether serum levels of cytokines associated with the Th1/Th2/Th17 response are differentially expressed in patients with and without musculoskeletal Ir-AEs. METHODS: All patients treated with ICI who developed musculoskeletal manifestations were referred to the Rheumatology Department, and an MRI of the involved area(s) was performed. RESULTS: During the study period, a total of 130 patients were treated with ICIs. Of these, 10 (7.7%) developed ICI-induced Ir-AEs. The median time from ICI treatment since development of symptoms was 2.5 months. Three different patterns of musculoskeletal manifestations were found: (i) prominent joint involvement (n = 3); (ii) prominent 'periarticular' involvement (n = 4). These patients had diffuse swelling of the hands, feet or knees. MRI depicted mild synovitis with more prominent myositis and/or fasciitis in the surrounding tissues in all cases; (iii) myofasciitis (n = 3). Clinically, these patients presented with pain in the knee(s)/thigh(s), whereas MRI depicted myofasciitis of the surrounding muscles. Patients with musculoskeletal ir-AEs had significantly higher oncologic response rates compared with patients not exhibiting musculoskeletal ir-AEs (50% vs 12.5%, respectively, P = 0.0016). Cytokine levels associated with a Th1/Th2/Th17 response were similar between patients with and without musculoskeletal ir-AEs. Overall, symptoms were mild/moderate and responded well to treatment, with no need for ICI discontinuation. CONCLUSION: In our cohort, ICI-induced musculoskeletal manifestations developed in 7.7% of patients. Imaging evidence of myofasciitis was found in most patients, indicating that the muscle/fascia is more frequently involved than the synovium.

Rheumatic Manifestations in Patients Treated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that activate the immune system, aiming at enhancing antitumor immunity. Their clinical efficacy is well-documented, but the side effects associated with their use are still under investigation. These drugs cause several immune-related adverse events (ir-AEs), some of which stand within the field of rheumatology. Herein, we present a literature review performed in an effort to evaluate all publicly available clinical data regarding rheumatic manifestations associated with ICIs. The most common musculoskeletal ir-AEs are inflammatory arthritis, polymyalgia rheumatica and myositis. Non-musculoskeletal rheumatic manifestations are less frequent, with the most prominent being sicca, vasculitides and sarcoidosis. Cases of systemic lupus erythematosus or scleroderma are extremely rare. The majority of musculoskeletal ir-AEs are of mild/moderate severity and can be managed with steroids with no need for ICI discontinuation. In severe cases, more intense immunosuppressive therapy and permanent ICI discontinuation may be employed. Oncologists should periodically screen patients receiving ICIs for new-onset inflammatory musculoskeletal complaints and seek a rheumatology consultation in cases of persisting symptoms.

Clopidogrel treatment may associate with worsening of endothelial function and development of new digital ulcers in patients with systemic sclerosis: results from an open label, proof of concept study.

BACKGROUND: Activated platelets release serotonin that binds 5-HT2B receptor on fibroblasts leading to fibroblast activation. Clopidogrel, an inhibitor of ADP-dependent platelet activation prevents fibrosis in animal models of systemic sclerosis (SSc). We aimed at assessing whether i) ADP-dependent platelet activation is increased in patients with SSc compared to healthy subjects and patients with rheumatoid arthritis (RA) and ii) whether clopidogrel can effectively suppress ADP-dependent activation, reduce circulating serotonin levels and hence, favorably affect fibrosis or vasculopathy in patients with systemic sclerosis. METHODS: Thirteen patients with SSc were recruited. Platelet activation was assessed by aggregometry prior to and following 14 days of clopidogrel treatment. At the same time points serotonin and soluble vascular cell adhesion molecule 1 (s-VCAM1), a marker of endothelial dysfunction, were measured. RESULTS: ADP-dependent platelet activation was similar between patients with SSc (n = 13), patients with RA (n = 28) and healthy subjects (n = 22) (mean ± SEM AU*min: 392.1 ± 58.4, 535.5 ± 61.33 and 570.9 ± 42.9 in patients with SSc, patients with RA and healthy subjects respectively, p = 0.14). Clopidogrel treatment significantly reduced platelet activation in patients with SSc (mean ± SEM AU*min: 392.1 ± 58.4 vs 163.8 ± 51.7, p = 0.014). Clopidogrel treatment did not affect serotonin levels but led to a significant increase in s-VCAM1 (p = 0.03). Three patients developed new digital ulcers during the study. The potential association of the study drug with the development of new digital ulcers led to early termination of the study. CONCLUSION: Clopidogrel may worsen markers of endothelial function and associate with development of new digital ulcers in patients with SSc. CLINICAL TRIAL REGISTRATION: ISRCTN63206606 . Registered 02/Dec/2014.

Real-world data show high efficacy of IL23 inhibitors guselkumab and risankizumab in psoriatic arthritis and difficult-to-treat areas.

BACKGROUND: Psoriasis and psoriatic arthritis are chronic inflammatory skin and joint diseases requiring effective therapies. Although clinical studies have shown the efficacy of IL-23 inhibitors, real-world data are limited. METHODS: We conducted a single-center retrospective Greek study enrolling patients with psoriatic arthritis and moderate-to-severe plaque psoriasis being treated at our multidisciplinary psoriasis outpatient clinic. Our aim was to investigate the efficacy and safety of IL-23 inhibitors guselkumab and risankizumab. Additionally, we sought to determine the clinical characteristics affecting treatment response. Primary endpoints were the evaluation of absolute Psoriasis Area and Severity Index (aPASI) and Disease Activity Index for Psoriatic Arthritis (DAPSA) at week 24. RESULTS: Fifty-nine patients (55.9% male, 69.5% early onset) with a mean age of 51.7 years were included. Twenty-four patients (40.7%) had a concomitant psoriatic arthritis. Obesity was the main comorbidity (49.2%) with a mean body mass index (BMI) of 31.3 kg/m2 . Additional comorbidities were hypertension (44.1%), dyslipidemia (32.2%), and diabetes (18.6%). Only eight patients (13.6%) were naïve to previous systemic treatments, whereas 40 patients (67.8%) were bio-experienced. A statistically significant improvement of aPASI and DAPSA was demonstrated after 4, 16, and 24 weeks of treatment (P < 0.05). IL23 blockers were also efficacious in difficult-to-treat areas. Clinical outcome was affected from previous treatment with biologics. Treatment response was the same between guselkumab and risankizumab (P > 0.05). CONCLUSION: This real-world study confirms the efficacy and safety of guselkumab and risankizumab in psoriatic arthritis and psoriasis reported from clinical trials.

Should we be Afraid of Immune Check Point Inhibitors in Cancer Patients with Pre-Existing Rheumatic Diseases? Immunotherapy in Pre-Existing Rheumatic Diseases.

BACKGROUND: Cancer immunotherapy is rapidly expanding but its clinical efficacy is hampered by immune related adverse events (ir-AE). There is a concern regarding patients with pre-existing auto-immune diseases (PAD) undergoing immunotherapy. METHODS: An electronic search was performed (Medline) to identify cases of patients with PAD treated with immune checkpoint inhibitors (ICI). RESULTS: Published data are rather limited but continue to emerge. Patients with PAD exhibit a high risk of PAD flare and/or de novo ir-AE. In most cases PAD flares and de novo irAEs were not severe and could be managed effectively with standard treatment. CONCLUSIONS: This risk in patients with PAD appears acceptable, and therefore, these patients could receive immunotherapy under close monitoring. Collaboration of oncologists and rheumatologists for the management of these patients is crucial.

B cell depletion therapy upregulates Dkk-1 skin expression in patients with systemic sclerosis: association with enhanced resolution of skin fibrosis.

BACKGROUND: Rituximab (RTX) may favorably affect skin and lung fibrosis in patients with systemic sclerosis (SSc); however, the underlying molecular mechanisms remain unknown. We aimed to explore the hypothesis that RTX may mediate its antifibrotic effects by regulating the expression of Dickkopf-1 (Dkk-1), an inhibitor of the Wnt pathway. METHODS: Fourteen patients with SSc and five healthy subjects were recruited. Dkk-1 expression was immunohistochemically assessed in skin biopsies obtained from 11 patients with SSc (8 treated with RTX and 3 with standard treatment), whereas DKK1 gene expression was assessed in 3 patients prior to and following RTX administration. RESULTS: In baseline biopsies obtained from all patients with SSc but not in healthy subjects, Dkk-1 was undetectable in skin fibroblasts. Following RTX treatment, four out of eight patients had obvious upregulation of Dkk-1 skin expression. Similarly, RTX treatment correlated with a significant 4.8-fold upregulation of DKK1 gene expression (p = 0.030). In contrast, TGFß expression in the upper dermis was significantly attenuated following treatment. Moreover, this decreased expression of TGFß in the skin was significantly more pronounced in the subgroup of patients with Dkk-1 upregulation. In this subgroup TGFß was downregulated by 50.88 % in contrast to only 15.98 % in patients who did not have Dkk-1 upregulation (p = 0.022). CONCLUSIONS: This is the first study demonstrating a link between B cell depletion and skin Dkk-1 upregulation in patients with SSc. RTX-mediated B cell depletion may mechanistically function via the recently established TGFß-Dkk-1 axis in improving skin fibrosis.

Decreased Serotonin Levels and Serotonin-Mediated Osteoblastic Inhibitory Signaling in Patients With Ankylosing Spondylitis.

Evidence suggests that serotonin is an inhibitor of bone formation. We aimed to assess: 1) serum serotonin levels in patients with ankylosing spondylitis (AS), a prototype bone-forming disease, compared with patients with rheumatoid arthritis (RA) and healthy subjects; 2) the effect(s) of TNFα blockers on serum serotonin levels in patients with AS and RA; and 3) the effect(s) of serum of AS patients on serotonin signaling. Serum serotonin levels were measured in 47 patients with AS, 28 patients with RA, and 40 healthy subjects by radioimmunoassay; t test was used to assess differences between groups. The effect of serum on serotonin signaling was assessed using the human osteoblastic cell line Saos2, evaluating levels of phospho-CREB by Western immunoblots. Serotonin serum levels were significantly lower in patients with AS compared with healthy subjects (mean ± SEM ng/mL 122.9 ± 11.6 versus 177.4 ± 24.58, p = 0.038) and patients with RA (mean ± SEM ng/mL 244.8 ± 37.5, p = 0.0004). Patients with AS receiving TNFα blockers had significantly lower serotonin levels compared with patients with AS not on such treatment (mean ± SEM ng/mL 95.8 ± 14.9 versus 149.2 ± 16.0, p = 0.019). Serotonin serum levels were inversely correlated with pCREB induction in osteoblast-like Saos-2 cells. Serotonin levels are low in patients with AS and decrease even further during anti-TNFα treatment. Differences in serotonin levels are shown to have a functional impact on osteoblast-like Saos-2 cells. Therefore, serotonin may be involved in new bone formation in AS.

Anti-TNFα treatment decreases the previously increased serum Indian Hedgehog levels in patients with ankylosing spondylitis and affects the expression of functional Hedgehog pathway target genes.

OBJECTIVE: Indian Hedgehog (Ihh) is the ligand that activates the Hedgehog pathway (HH) in the skeleton-the main controller of endochondral ossification. We aimed at assessing serum levels of Ihh in patients with ankylosing spondylitis (AS) and the effect of serum from patients with AS on HH pathway activation. METHODS: Serum Ihh levels were measured in 59 patients with AS, 70 patients with rheumatoid arthritis (RA), and 53 healthy subjects. The effect of serum from patients with AS on HH pathway activation was evaluated using an osteoblast-like cell line model. RESULTS: Patients with AS not on anti-TNFα treatment had significantly higher Ihh levels compared to patients with RA not on anti-TNFα treatment (mean ± SEM of OD: 0.370 ± 0.025 vs. 0.279 ± 0.026 for patients with AS and RA, respectively, p = 0.027) and healthy subjects (p = 0.031). Patients with AS on anti-TNFα treatment had significantly lower Ihh levels compared to patients with AS not on such treatment (p = 0.028). Patients with RA on anti-TNF treatment had higher levels of Ihh compared to patients not on such treatment (p = 0.013). PTHrP levels were similar in patients with RA, AS, and healthy subjects and were not affected by anti-TNFα treatment. We next assessed HH pathway activation in Saos2 cells following incubation with serum from AS patients prior to and following anti-TNF treatment. The HH pathway was downregulated following treatment. CONCLUSIONS: Ihh levels are increased in patients with AS and decrease following anti-TNFα treatment; this finding may have pathogenic and clinical implications.