The role of PET/CT in connective tissue disorders: systemic sclerosis, Sjögren's syndrome and systemic lupus erythematosus.

Advanced imaging techniques are needed to help clinicians in the diagnosis, in the choice of the right time for therapeutic interventions or for modifications and monitoring of treatment response in patients with autoimmune connective tissue diseases. Nuclear medicine imaging, especially PET/CT and PET/MRI, may play an important role in detecting disease activity, assessing early treatment response as well as in clarifying the complex mechanisms underlying systemic sclerosis, Sjögren's syndrome or systemic lupus erythematosus. In addition, [18F]FDG PET/CT may help in excluding or detecting coexisting malignancies. Other more specific radiopharmaceuticals are being developed and investigated, targeting specific cells and molecules involved in connective tissue diseases. Further larger studies with standardized imaging protocol and image interpretation are strongly required before including PET/CT in the diagnostic work-up of subsets of patients with autoimmune connective tissue diseases.

Tumour-associated antigens in systemic sclerosis patients with interstitial lung disease: association with lung involvement and cancer risk.

OBJECTIVE: To evaluate the serum levels of tumour-associated antigens (TAAs) in patients with SSc and interstitial lung disease (ILD) and to define whether their levels mirror the severity and the progression of lung damage. METHODS: Data from 80 SSc patients with ILD were collected at baseline and after 2 years as well as from 40 SSc controls without ILD. The occurrence of any malignancy was recorded. RESULTS: At baseline, an increase of at least one TAA was present in 35 SSc patients with ILD compared with 6 SSc patients without ILD (P < 0.0001); this was associated with lower forced vital capacity (FVC) and higher interstitial and alveolar scores. Levels of carbohydrate antigen 15-3 and carcinoembryonic antigen inversely correlated with FVC and directly correlated with alveolar and interstitial scores and their levels were higher in patients who presented a progression of lung damage after 2 years. During 4 years of follow-up, a malignancy was detected in seven patients who already had an increase of at least one TAA. Values of TAAs increased over time in patients who developed cancer, while their trend remained stable in the others. At multivariate analysis, to have three or more TAAs emerged as a strong independent predictor of the development of malignancies [relative risk 24.1 (95% CI 1.8, 315.0), P = 0.02]. CONCLUSION: TAAs can be elevated in the sera of SSc patients and correlate with the degree of lung damage, suggesting a role as severity biomarkers. Close follow-up is necessary in SSc patients because of the increased cancer risk overall in patients with increased TAAs.

ß-Thymosins and interstitial lung disease: study of a scleroderma cohort with a one-year follow-up.

BACKGROUND: ß-thymosins play roles in cytoskeleton rearrangement, angiogenesis, fibrosis and reparative process, thus suggesting a possible involvement in the pathogenesis of systemic sclerosis. The aim of the study was to investigate the presence of thymosins ß4, ß4 sulfoxide, and ß10 in bronchoalveolar lavage fluid of scleroderma patients with interstitial lung disease and the relation of these factors with pulmonary functional and radiological parameters. METHODS: ß-thymosins concentrations were determined by reverse phase-high performance liquid chromatography-electrospray-mass spectrometry in the bronchoalveolar lavage fluid of 46 scleroderma patients with lung involvement and of 15 controls. RESULTS: Thymosin ß4, ß4 sulfoxide, and ß10 were detectable in bronchoalveolar lavage fluid of patients and controls. Thymosin ß4 levels were significantly higher in scleroderma patients than in controls. In addition, analyzing the progression of scleroderma lung disease at one-year follow-up, we have found that higher thymosin ß4 levels seem to have a protective role against lung tissue damage. Thymosin ß4 sulfoxide levels were higher in the smokers and in the scleroderma patients with alveolitis. CONCLUSIONS: We describe for the first time ß-thymosins in bronchoalveolar lavage fluid and their possible involvement in the pathogenesis of scleroderma lung disease. Thymosin ß4 seems to have a protective role against lung tissue damage, while its oxidation product mirrors an alveolar inflammatory status.

COVID-19 and RA share an SPP1 myeloid pathway that drives PD-L1+ neutrophils and CD14+ monocytes.

We explored the potential link between chronic inflammatory arthritis and COVID-19 pathogenic and resolving macrophage pathways and their role in COVID-19 pathogenesis. We found that bronchoalveolar lavage fluid (BALF) macrophage clusters FCN1+ and FCN1+SPP1+ predominant in severe COVID-19 were transcriptionally related to synovial tissue macrophage (STM) clusters CD48hiS100A12+ and CD48+SPP1+ that drive rheumatoid arthritis (RA) synovitis. BALF macrophage cluster FABP4+ predominant in healthy lung was transcriptionally related to STM cluster TREM2+ that governs resolution of synovitis in RA remission. Plasma concentrations of SPP1 and S100A12 (key products of macrophage clusters shared with active RA) were high in severe COVID-19 and predicted the need for Intensive Care Unit transfer, and they remained high in the post-COVID-19 stage. High plasma levels of SPP1 were unique to severe COVID-19 when compared with other causes of severe pneumonia, and IHC localized SPP1+ macrophages in the alveoli of COVID-19 lung. Investigation into SPP1 mechanisms of action revealed that it drives proinflammatory activation of CD14+ monocytes and development of PD-L1+ neutrophils, both hallmarks of severe COVID-19. In summary, COVID-19 pneumonitis appears driven by similar pathogenic myeloid cell pathways as those in RA, and their mediators such as SPP1 might be an upstream activator of the aberrant innate response in severe COVID-19 and predictive of disease trajectory including post-COVID-19 pathology.

Residual minimal disease activity in rheumatoid arthritis: a simple definition through an in-depth statistical analysis of the major outcome.

OBJECTIVE: To obtain the simplest definition of minimal disease activity (MDA) and to compare it with published proposed definitions of MDA in patients with RA. METHODS: Two hundred and fourteen patients with long-standing RA (LSRA) were evaluated for clinical and laboratory parameters. Factor analysis was performed to remove redundant variables included in the core set measure for MDA definition stated by the OMERACT. Receiver operating characteristic (ROC) curves analysis allowed to obtain optimal cut-off predictors of a 28-joint disease activity score (DAS28) < or =2.85. These were tested in 112 LSRA and 95 early-onset RA (ERA) patients. RESULTS: Factor and ROC curve analysis showed that the best predictors of a DAS28 < or = 2.85 in LSRA cohort were: (i) ESR <20 mm/h (sensitivity: 80%, specificity: 54%); (ii) swollen joint count (out of 28) < or =2 (sensitivity: 95%, specificity: 74%); (iii) patient global assessment (0-100) < or =15 (sensitivity: 78%, specificity: 78%); and (iv) HAQ (0-3) < or =0.5 (sensitivity: 91%, specificity: 61%). To each of these four criteria we assigned a value of 1 when it was satisfied (score ranging: 0-4). The cut-off with the highest overall accuracy for identifying RA patients with DAS28 < or = 2.85 was a score > or =3. We adopted these four parameters in order to define the residual MDA (RMDA). Comparing RMDA criteria, in distinct 112 LSRA and 95 ERA patients, with OMERACT, Simplified Disease Activity Index and Clinical Disease Activity Index definitions of MDA, we found a good agreement in the LSRA cohort and moderate agreement in the ERA cohort. CONCLUSIONS: HAQ, PaGA, SJC28 and ESR allow identification of RA patients with an RMDA. The RMDA criteria behaves similarly to OMERACT definitions, but appears more simple and feasible.

Long-term efficacy of B cell depletion therapy on lung and skin involvement in diffuse systemic sclerosis.

OBJECTIVES: To assess the long-term efficacy and safety of single and multiple courses of rituximab therapy in systemic sclerosis (SSc) patients with and without lung disease. METHODS: A total of 20 SSc patients with a diffuse disease were treated with rituximab. At baseline and during follow-up the lung involvement was evaluated with pulmonary function tests (FVC and DLCO) and with lung high-resolution computed tomography (HRCT). RESULTS: The skin score, activity, and severity indices improved significantly after 12 months and at final follow-up compared to baseline. After 12 months, there was a significant increase of FVC and TLC compared to baseline (p = 0.024 and p = 0.005, respectively), while the mean DLCO value remained stable. Considering the last available follow-up in six patients with restrictive lung disease at baseline, two patients (33.3%) experienced an increase of more than 10% of FVC, one patient had a decrease of FVC >10%, while in three patients FVC remained stable (50%). After the mean follow-up of 48.5 ± 20.4 months, among the patients with normal lung parameters at baseline, FVC remained stable in 12 (85.7%) and in one patient (14.3%) it increased by more than 10%. At the final follow-up, the alveolar and interstitial HRCT scores remained stable in more than 80% of patients, both in patients with and without restrictive lung disease at baseline. CONCLUSIONS: Anti-CD20 B cell depletion therapy is effective on skin involvement but seems also to preserve the pulmonary function, as supported by a stable or improved FVC and stable interstitial score, suggesting a possible role of rituximab as a modifying therapy overall in early diffuse SSc.