Reliability assessment of the definition of ultrasound enthesitis in SpA: results of a large, multicentre, international, web-based study.

OBJECTIVES: To investigate the reliability of the OMERACT US Task Force definition of US enthesitis in SpA. METHODS: In this web exercise, based on the evaluation of 101 images and 39 clips of the main entheses of the lower limbs, the elementary components included in the OMERACT definition of US enthesitis in SpA (hypoechoic areas, entheseal thickening, power Doppler signal at the enthesis, enthesophytes/calcifications, bone erosions) were assessed by 47 rheumatologists from 37 rheumatology centres in 15 countries. Inter- and intra-observer reliability of the US components of enthesitis was calculated using Light's kappa, Cohen's kappa, Prevalence And Bias Adjusted Kappa (PABAK) and their 95% CIs. RESULTS: Bone erosions and power Doppler signal at the enthesis showed the highest overall inter-reliability [Light's kappa: 0.77 (0.76-0.78), 0.72 (0.71-0.73), respectively; PABAK: 0.86 (0.86-0.87), 0.73 (0.73-0.74), respectively], followed by enthesophytes/calcifications [Light's kappa: 0.65 (0.64-0.65), PABAK: 0.67 (0.67-0.68)]. This was moderate for entheseal thickening [Light's kappa: 0.41 (0.41-0.42), PABAK: 0.41 (0.40-0.42)], and fair for hypoechoic areas [Light's kappa: 0.37 (0.36-0.38); PABAK: 0.37 (0.37-0.38)]. A similar trend was observed in the intra-reliability exercise, although this was characterized by an overall higher degree of reliability for all US elementary components compared with the inter-observer evaluation. CONCLUSIONS: The results of this multicentre, international, web-based study show a good reliability of the OMERACT US definition of bone erosions, power Doppler signal at the enthesis and enthesophytes/calcifications. The low reliability of entheseal thickening and hypoechoic areas raises questions about the opportunity to revise the definition of these two major components for the US diagnosis of enthesitis.

Composite Measures for Clinical Trials in Psoriatic Arthritis: Testing Pain and Fatigue Modifications in a UK Multicenter Study.

OBJECTIVE: To test the addition of pain and fatigue to the Composite Psoriatic Arthritis Disease Activity (CPDAI) and the Group for Research and Assessment of Psoriasis and PsA (GRAPPA) Composite Exercise (GRACE) composite measures of psoriatic arthritis (PsA). METHODS: Clinical and patient-reported outcome measures were assessed in patients with PsA at 3 consecutive follow-up visits over 6 months in a UK multicenter observational study. A pain visual analog scale and Functional Assessment of Chronic Illness Therapy Fatigue scale were added as modifications to the CPDAI and GRACE composite measures. Original and modified versions were tested against the PsA Disease Activity Score (PASDAS) and the Disease Activity Index for PsA (DAPSA). Discrimination between disease states and responsiveness were tested with t-scores, standardized response means (SRMs), and effect sizes. Data were presented to members at the 2020 annual meeting who then voted on the GRAPPA-recommended composite and treatment targets for clinical trials. RESULTS: One hundred forty-one patients were recruited with a mean PsA disease duration of 6.1 years (range 0-41 yrs). The SRMs for the GRACE and modified GRACE (mGRACE) were 0.67 and 0.64, respectively, and 0.54 and 0.46, respectively, for the CPDAI and modified CPDAI (mCPDAI). The t-scores for the GRACE and mGRACE were unchanged at 7.8 for both, and 6.8 and 7.0 for the CPDAI and mCPDAI, respectively. The PASDAS demonstrated the best responsiveness (SRM 0.84) and discrimination (t-scores 8.3). Most members (82%) agreed the composites should not be modified and 77% voted for the PASDAS as the GRAPPA-recommended composite for clinical trials, with 90% minimal disease activity (MDA) as the target. CONCLUSION: Modifying the CPDAI and GRACE with the addition of pain and fatigue does not enhance responsiveness nor the measures' ability to detect disease status in terms of requiring treatment escalation. GRAPPA members voted for the PASDAS as the composite measure in clinical trials and MDA as the target.

Composite Measures for Routine Clinical Practice in Psoriatic Arthritis: Testing of Shortened Versions in a UK Multicenter Study.

OBJECTIVE: To test shortened versions of the psoriatic arthritis (PsA) composite measures for use in routine clinical practice. METHODS: Clinical and patient-reported outcome measures (PROMs) were assessed in patients with PsA at 3 consecutive follow-up visits in a UK multicenter observational study. Shortened versions of the Composite Psoriatic Arthritis Disease Activity Index (CPDAI) and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) Composite Exercise (GRACE) measures were developed using PROMs and tested against the Disease Activity Score in 28 joints (DAS28), composite Disease Activity in Psoriatic Arthritis, and Routine Assessment of Patient Index Data (RAPID3). Discrimination between disease states and responsiveness were tested with the t-score, standardized response mean (SRM), and effect size (ES). Data were presented to members at the GRAPPA 2020 annual meeting and members voted on the recommended composite routine practice. RESULTS: The SRM for the GRACE, 3 visual analog scale (VAS), and 4VAS were 0.67, 0.77, and 0.63, respectively, and for CPDAI and shortened CPDAI (sCPDAI) were 0.54 and 0.55, respectively. Shortened versions of the GRACE increased the t-score from 7.8 to 8.7 (3VAS) and 9.0 (4VAS), but reduced the t-score in the CPDAI/sCPDAI from 6.8 and 6.1. The 3VAS and 4VAS had superior performance characteristics to the sCPDAI, DAS28, Disease Activity in Psoriatic Arthritis, and RAPID3 in all tests. Of the members, 60% agreed that the VAS scales contained enough information to assess disease and response to treatment, 53% recommended the 4VAS for use in routine care, and 26% the 3VAS, while leaving 21% undecided. Conclusion. Shortening the GRACE to VAS scores alone enhances the ability to detect status and responsiveness and has the best performance characteristics of the tested composite measures. GRAPPA members recommend further testing of the 3VAS and 4VAS in observational and trial datasets.

Composite Measures for Clinical Trials in Psoriatic Arthritis: Testing Pain and Fatigue Modifications in a UK Multicenter Study.

OBJECTIVE: To test the addition of pain and fatigue to the Composite Psoriatic Arthritis Disease Activity (CPDAI) and the Group for Research and Assessment of Psoriasis and PsA (GRAPPA) Composite Exercise (GRACE) composite measures of psoriatic arthritis (PsA). METHODS: Clinical and patient-reported outcome measures were assessed in patients with PsA at 3 consecutive follow-up visits over 6 months in a UK multicenter observational study. A pain visual analog scale and Functional Assessment of Chronic Illness Therapy Fatigue scale were added as modifications to the CPDAI and GRACE composite measures. Original and modified versions were tested against the PsA Disease Activity Score (PASDAS) and the Disease Activity Index for PsA (DAPSA). Discrimination between disease states and responsiveness were tested with t-scores, standardized response means (SRMs), and effect sizes. Data were presented to members at the 2020 annual meeting who then voted on the GRAPPArecommended composite and treatment targets for clinical trials. RESULTS: One hundred forty-one patients were recruited with a mean PsA disease duration of 6.1 years (range 0-41 yrs). The SRMs for the GRACE and modified GRACE (mGRACE) were 0.67 and 0.64, respectively, and 0.54 and 0.46, respectively, for the CPDAI and modified CPDAI (mCPDAI). The t-scores for the GRACE and mGRACE were unchanged at 7.8 for both, and 6.8 and 7.0 for the CPDAI and mCPDAI, respectively. The PASDAS demonstrated the best responsiveness (SRM 0.84) and discrimination (t-scores 8.3). Most members (82%) agreed the composites should not be modified and 77% voted for the PASDAS as the GRAPPA-recommended composite for clinical trials, with 90% minimal disease activity (MDA) as the target. CONCLUSION: Modifying the CPDAI and GRACE with the addition of pain and fatigue does not enhance responsiveness nor the measures' ability to detect disease status in terms of requiring treatment escalation. GRAPPA members voted for the PASDAS as the composite measure in clinical trials and MDA as the target.

Composite Measures for Routine Clinical Practice in Psoriatic Arthritis: Testing of Shortened Versions in a UK Multicenter Study.

OBJECTIVE: To test shortened versions of the psoriatic arthritis (PsA) composite measures for use in routine clinical practice. METHODS: Clinical and patient-reported outcome measures (PROMs) were assessed in patients with PsA at 3 consecutive follow-up visits in a UK multicenter observational study. Shortened versions of the Composite Psoriatic Arthritis Disease Activity Index (CPDAI) and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) Composite Exercise (GRACE) measures were developed using PROMs and tested against the Disease Activity Score in 28 joints (DAS28), composite Disease Activity in Psoriatic Arthritis, and Routine Assessment of Patient Index Data (RAPID3). Discrimination between disease states and responsiveness were tested with the t-score, standardized response mean (SRM), and effect size (ES). Data were presented to members at the GRAPPA 2020 annual meeting and members voted on the recommended composite routine practice. RESULTS: The SRM for the GRACE, 3 visual analog scale (VAS), and 4VAS were 0.67, 0.77, and 0.63, respectively, and for CPDAI and shortened CPDAI (sCPDAI) were 0.54 and 0.55, respectively. Shortened versions of the GRACE increased the t-score from 7.8 to 8.7 (3VAS) and 9.0 (4VAS), but reduced the t-score in the CPDAI/sCPDAI from 6.8 and 6.1. The 3VAS and 4VAS had superior performance characteristics to the sCPDAI, DAS28, Disease Activity in Psoriatic Arthritis, and RAPID3 in all tests. Of the members, 60% agreed that the VAS scales contained enough information to assess disease and response to treatment, 53% recommended the 4VAS for use in routine care, and 26% the 3VAS, while leaving 21% undecided. CONCLUSION: Shortening the GRACE to VAS scores alone enhances the ability to detect status and responsiveness and has the best performance characteristics of the tested composite measures. GRAPPA members recommend further testing of the 3VAS and 4VAS in observational and trial datasets.

DRESS syndrome in response to Denosumab: First documented case report.

Denosumab is an antiresorptive drug targeting RANK ligand, currently licensed for postmenopausal and male osteoporosis, bone loss associated with hormone ablation in men with prostate cancer and with systemic glucocorticoid treatment, and also used in oncology for the treatment of bone metastases and unresectable giant cell tumour of bone. When used for the treatment of osteoporosis or bone loss the drug is usually well-tolerated with non-specific musculoskeletal pain being the most common side effect. However denosumab has been associated with some dermatological manifestations including dermatitis, eczema, pruritus and, less commonly, cellulitis. All these side effects are generally mild and self-limiting. We hereby report the first documented case of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome following denosumab administration. DRESS syndrome is an extremely rare but potentially life-threatening hypersensitivity reaction. The syndrome should be considered in patients who present with new rash, eosinophilia and systemic organ dysfunction, especially when associated with new medications. Notably it has been previously reported in patients with osteoporosis treated with strontium ranelate but it has never been linked to any other antiosteoporotic drugs. Since the clinical manifestations of DRESS syndrome can span over a period of several months the diagnosis can frequently be quite difficult and it can become even more challenging in people taking denosumab and other drugs given in period doses, as both clinicians and patients are less likely to link the symptoms to the medication. Better recognition of DRESS syndrome is therefore needed, as well as awareness of the possibility of this reaction to occur in patients taking denosumab.

Primary bone lymphoma of the talus: a challenging diagnosis.

PURPOSE: Diagnostic challenges are common in clinical practice and diagnostic or classification criteria for musculoskeletal conditions cannot overshadow clinical skills. METHODS: We present the case of a young man who complained of prolonged articular pain and mild swelling of the right ankle in the absence of other remarkable data. Apparently fulfilling the Budapest diagnostic criteria for complex regional pain syndrome, the patient was treated accordingly, but the pain increased over time. Then the patient underwent an additional diagnostic workup including synovial and bone biopsies in 2 separate occasions with the second one demonstrating diffuse lymphoid infiltrate compatible with lymphoma. RESULTS: The conclusive diagnosis of primary diffuse large B-cell lymphoma of the talus was made and adequate treatment initiated. CONCLUSIONS: The diagnostic difficulties as well as the importance of a multidisciplinary approach for complex cases are highlighted in this report.

Myeloid suppressor cells in cancer and autoimmunity.

A bottleneck for immunotherapy of cancer is the immunosuppressive microenvironment in which the tumor cells proliferate. Cancers harness the immune regulatory mechanism that prevents autoimmunity from evading immunosurveillance and promoting immune destruction. Regulatory T cells, myeloid suppressor cells, inhibitory cytokines and immune checkpoint receptors are the major components of the immune system acting in concert with cancer cells and causing the subversion of anti-tumor immunity. This redundant immunosuppressive network poses an impediment to efficacious immunotherapy by facilitating tumor progression. Tumor-associated myeloid cells comprise heterogeneous populations acting systemically (myeloid-derived suppressor cells/MDSCs) and/or locally in the tumor microenvironment (MDSCs and tumor-associated macrophages/TAMs). Both populations promote cancer cell proliferation and survival, angiogenesis and lymphangiogenesis and elicit immunosuppression through different pathways, including the expression of immunosuppressive cytokines and checkpoint inhibitors. Several evidences have demonstrated that myeloid cells can express different functional programs in response to different microenvironmental signals, a property defined as functional plasticity. The opposed extremes of this functional flexibility are generally represented by the classical macrophage activation, which identifies inflammatory and cytotoxic M1 polarized macrophages, and the alternative state of macrophage activation, which identifies M2 polarized anti-inflammatory and immunosuppressive macrophages. Functional skewing of myeloid cells occurs in vivo under physiological and pathological conditions, including cancer and autoimmunity. Here we discuss how myeloid suppressor cells can on one hand support tumor growth and, on the other, limit autoimmune responses, indicating that their therapeutic reprogramming can generate opportunities in relieving immunosuppression in the tumor microenvironment or reinstating tolerance in autoimmune conditions.

Eight-Year Retention Rate of First-Line Tumor Necrosis Factor Inhibitors in Spondyloarthritis: A Multicenter Retrospective Analysis.

OBJECTIVE: To evaluate the 8-year survival of the first tumor necrosis factor inhibitor (TNFi) in patients with axial spondyloarthritis (SpA) or psoriatic arthritis (PsA), identify the predictive factors for withdrawal, and compare the discontinuation rates for infliximab, etanercept, and adalimumab. METHODS: We evaluated PsA and axial SpA patients treated with a first-line TNFi between 2005 and 2015 at 4 Italian tertiary centers. Eight-year drug survival was calculated by the Kaplan-Meier method, and risk for discontinuation among treatment groups compared by stratified log-rank test. Univariate and multivariate Cox proportional hazard models were developed to examine predictors of withdrawal. RESULTS: Of 614 patients (316 axial with SpA, 298 with PsA), 203 received adalimumab, 131 etanercept, and 280 infliximab, with similar frequencies in axial SpA and PsA subgroups. The cumulative 8-year retention rate in the whole population was 55.1% (57.2% and 51.9% for axial SpA and PsA, respectively; P = not significant). No significant differences were observed in drug persistence among individual TNFi in either group. Male sex (hazard ratio [HR] 0.595 [95% confidence interval (95% CI) 0.405-0.875]; P = 0.008) and concomitant methotrexate use (HR 0.648 [95% CI 0.426-0.985]; P = 0.042) were associated with a lower risk of withdrawal in PsA. High baseline Bath Ankylosing Spondylitis Disease Activity Index (HR 0.9842 [95% CI 0.9708-0.9980]; P = 0.028) was associated with a lower risk of withdrawal in axial SpA. No difference was found in the comparative analysis of reasons for discontinuation between PsA and axial SpA. CONCLUSION: We reported that the real-life 8-year retention rate of the first TNFi in axial SpA and PsA is greater than 50%, with no significant differences between axial SpA and PsA, irrespective of the individual TNFi.

Serum antinuclear and extractable nuclear antigen antibody prevalence and associated morbidity and mortality in the general population over 15 years.

The prevalence of ANA and anti-ENA in the general population is not well established, especially their clinical significance in healthy subjects. We herein determined the prevalence and predictive value of serum ANA and anti-ENA for connective tissue diseases (CTD), cancer, and mortality. We took advantage of a randomly selected sample of the 1998 general population (Isola I) consisting of 2828 subjects (53% women, age 43±13 years) from a well-defined Northern Italian area. Serum ANA and anti-ENA were tested on the 2690 samples available in 2012 (Isola II, 50% women, age 58±13 years). Administrative databases were searched for CTD, cancer diagnosis, and death cases occurring between enrollment and December 31, 2013. The hazard ratio (HR) was calculated for incident cases. Serum ANA is positive in 18.1% for any titer and 6.1% for titers ≥1:160, 23% in subjects over 50 years and 13.1% and 6.1% for any titer and titers ≥1:160, respectively, in women. The HR for CTD development was significantly high for all ANA titers, with the highest for ANA ≥1:160 (HR 14.19, 95% CI 3.07-65.68). ANA positivity was not associated with cancer (HR 1.03; 95% CI 0.75-1.43), or with mortality (HR adjusted for age and sex 1.40; 95% CI 0.94-2.09). Serum anti-ENA is positive in a minority of subjects with highest figures for anti-nucleosome (1.9%), -histone (1.6%) and -PM/Scl (1.5%). In conclusion, serum ANA prevalence in the general population is highest in senior subjects and in women, while the female predominance is significantly lower compared to overt CTD. Serum ANA is associated with an increased probability of CTD development over time, but does not influence survival or cancer risk.

Seronegative reactive spondyloarthritis and the skin.

Spondyloarthritidies represent a group of conditions affecting the axial and peripheral muscoloskeletal apparatus and are often associated with psoriasis, infections, and inflammatory bowel diseases. Other diseases included in this category are psoriatic arthritis, ankylosing spondylitis, and enteropathic arthritis. Reactive arthritis is an elusive spondyloarthritis, commonly occurring 1 to 3 weeks after a digestive or a genitourinary tract infection, in which microorganisms do not infect the joint directly. Reactive arthritis is classically characterized by large-joint arthritis, urethritis in men and cervicitis in women, and eye inflammation (usually conjunctivitis or uveitis) but encompasses numerous other symptoms and signs, including manifestations of dermatologic interest such as keratoderma blenorrhagicum and circinate balanitis. The diagnosis of reactive arthritis is clinical, and the infectious agent cannot always be identified due to disease latency after the infection. Most cases are self-limiting, but reactive arthritis may become chronic in 30% of cases. Treatment options include anti-inflammatory drugs, steroids, and sulfasalazine; biologic agents, such as tumor necrosis factor α (TNF-α) blockers, have been recently used, but there are only a few randomized clinical trials on the treatment of reactive arthritis. The effectiveness of antimicrobials needs further evaluation.

Hypophosphatemic Osteomalacia Associated with Tenofovir: a Multidisciplinary Approach is Required.

Tenofovir is widely used as first-line treatment of HIV infection, although its use is sometimes complicated by a reversible proximal renal tubulopathy.We report the case of a 45-year-old woman with chronic HIV infection and personality disorder, who after 12 months of tenofovir, complained of fatigue, diffuse bone pain and gait disturbances. The elevated level of alkaline phosphatase, hypophosphatemia and inappropriate phosphaturia suggested the diagnosis of hypophosphatemic osteomalacia secondary to proximal renal tubulopathy. A dual-energy x-ray absorptiometry showed a bone mineral density below the expected range for age (lumbar spine Z-score -3.3, femoral neck Z-score -2.1). A whole body (99m)Tc-methylene diphosphonate bone scan showed multiple areas of increased focal activity in the lumbar and thoracic spine and in sacroiliac and hip joints consistent with pseudofractures. Two months after tenofovir discontinuation and administration of vitamin D and phosphate, osteomalacia-related symptoms disappeared. Eleven months later, bone and mineral metabolism data were normal and bone scintigraphy did not show any pathological findings.This report highlights the importance of considering the diagnosis of osteomalacia in patients treated with tenofovir and emphasizes the need for monitoring alkaline phosphatase, blood and urinary phosphate and creatinine, especially in patients with risk factors for bone disease.

Metastatic melanoma in a young woman treated with TNF-α inhibitor for psoriatic arthritis: a case report.

INTRODUCTION: The risk of cancer with the use of biologic agents in rheumatic diseases is still a matter of debate. Published data suggest that the extent of cancer risk might differ according to the type of cancer, and there is recent clinical evidence for a significant increased risk for skin cancer, including melanoma. In contrast with the extensive literature on cancer risk in rheumatoid arthritis, little has been reported on the development of malignancies in spondyloarthroparthies. CASE PRESENTATION: We report the case of an otherwise healthy 31-year-old Italian woman with psoriasic arthritis who developed a melanoma of left third toe with metastatic involvement of regional lymphnodes after a 3-year treatment with the TNF-alpha inhibitor adalimumab. CONCLUSION: This case illustrates the possibility of a causal relationship between TNF-alpha inhibitors and melanoma. We believe that vigilance should continue in patients treated with TNF-alpha blocking agents, until the question on the increased incidence of cancers, including skin cancers, associated with these drugs will be defined.

Metastatic gastric cancer presenting with shoulder-hand syndrome: a case report.

INTRODUCTION: Shoulder-hand syndrome is a relatively rare clinical entity classified as a complex regional pain syndrome type 1 and consisting essentially of a painful 'frozen shoulder' with disability, swelling, vasomotor or dystrophic changes in the homolateral hand. The pathophysiology is not completely clear but a predominant 'sympathetic' factor affecting the neural and vascular supply to the affected parts seems to be involved. Shoulder-hand syndrome has been related to many surgical, orthopedic, neurological and medical conditions; it is more often seen after myocardial infarction, hemiplegia and painful conditions of neck and shoulder, such as trauma, tumors, cervical discogenic or intraforaminal diseases and shoulder calcific tendinopathy, but has also been associated with herpetic infections, brain and lung tumors, thoracoplasty and drugs including phenobarbitone and isoniazid. The diagnosis of shoulder-hand syndrome is primarily clinical, but imaging studies, particularly bone scintigraphy, may be useful to exclude other disorders. CASE PRESENTATION: We report the case of a 67-year-old woman who presented with shoulder-hand syndrome as the initial manifestation of gastric cancer which had metastasized to bone. CONCLUSION: Wider investigations are advisable in patients with atypical shoulder-hand syndrome. To the best of the authors' knowledge this is the first case of shoulder-hand syndrome associated with metastatic gastric cancer.

A case of atypical giant cell arteritis diagnosed by positron emission tomography (PET).

The authors describe an atypical case of a patient having giant cell arteritis presenting only with fever, diagnosed by positron emission tomography and subsequently confirmed by temporal artery biopsy.