Glucocorticoids prescribing practices in systemic sclerosis: an analysis of the EUSTAR database.

OBJECTIVES: To estimate the prevalence of long-term exposure to glucocorticoids (GCs) and to identify factors associated with, and variations in prescribing practices over time and across recruiting countries. METHODS: We included patients with SSc having a visit recorded in the EUSTAR database from January 2013 onward. We analysed the prevalence and the main features of GCs users, their exposure to GCs over time, and their GCs dosages. Multivariable linear regression was used to analyse the factors identified as associated with GCs intake duration. Time trends, and variations in GCs utilization across recruiting countries were explored. Missing data were imputed using multiple imputation with chained equations. RESULTS: The 9819 patients included were mostly females (85%), the majority had lcSSc (73%), and the median age was 58 years. At baseline, 34% of patients (n = 2769/8109) (48% dcSSc vs 29% lcSSc) were on GCs, and the median dose was 7.5 mg/day. GCs users were more frequently males and anti-Scl70 positive, and more commonly had dcSSc and more severe disease. On average, GCs users spent 25% of their follow-up time (median 33.2 months) on GCs, with no significant between-subsets difference. Notably, 33% (n = 971/2959) and 22% (n = 647/2959) of patients followed up for >1 year had received GCs for >6 and >12 months, respectively. Multivariable analysis showed that patient and disease characteristics poorly explained the variability in GCs exposure (adjusted-R2 = 0.06, P < 0.001). GCs utilization varied within and across countries, and gradually decreased over time (36% in 2013 vs 23% in 2018). CONCLUSIONS: GCs are widely and long-term prescribed in SSc, with significant between-countries and within-country differences. A gradual decrease in their utilization has been observed.

Influence of contextual factors and reliability of ultrasound skin measures in persons with systemic sclerosis and healthy controls.

OBJECTIVES: To examine the influence of contextual factors upon the evaluation of skin thickness and stiffness by ultrasound and to assess the reliability of these parameters. METHODS: Ultrasound dermal thickness (by B-mode, 18MHz) and skin stiffness (by shear-wave elastography, 9MHz) were assessed in persons with systemic sclerosis (SSc) and in healthy controls. The influence of contextual factors upon repeated measures was evaluated: (i) room temperature (16-17ºC vs. 22-24ºC); (ii) time of day (morning vs. afternoon), and (iii) menstrual cycle phase (menstrual vs. ovulatory). Differences were analysed using the related-samples Wilcoxon signed-rank test. Inter- and intra-rater reliability of ultrasound skin thickness and stiffness were evaluated in the 17 skin Rodnan sites of 20 persons with SSc and 20 healthy controls, under stable contextual conditions. RESULTS: A significant increase in ultrasound dermal thickness was observed at the leg in the afternoon vs morning, in both patients and controls. Similar observations were made for skin stiffness at the leg (in SSc) and at the foot (in SSc and controls) in the afternoon. No significant changes were observed in association with room temperature and menstrual cycle. Intra- and inter-rater-reliability was good to excellent for ultrasound dermal thickness and stiffness, both in SSc and healthy controls. CONCLUSIONS: The timing of the ultrasound procedure within each day seems to influence the ultrasound measures at the legs and feet. Our study corroborates that ultrasound dermal thickness and skin stiffness are reliable domains to quantify skin involvement in SSc.

Happiness, quality of life and their determinants among people with systemic sclerosis: a structural equation modelling approach.

BACKGROUND: Patients' objectives and experiences must be core to the study and management of chronic diseases, such as SSc. Although patient-reported outcomes are attracting increasing attention, evaluation of the impact of disease on the overall subjective well-being, equivalent to 'happiness', is remarkably lacking. OBJECTIVES: To examine the determinants of happiness and quality of life in patients with SSc, with emphasis on disease features and personality traits. METHODS: Observational, cross-sectional multicentre study, including 142 patients, with complete data regarding disease activity, disease impact, personality, health-related quality of life (HR-QoL) and happiness. Structural equation modelling was used to evaluate the association between the variables. RESULTS: The results indicated an acceptable fit of the model to the data. Perceived disease impact had a significant negative direct relation with HR-QoL (ß = -0.79, P < 0.001) and with happiness (ß = -0.52, P < 0.001). Positive personality traits had a positive relation with happiness (ß = 0.36, P = 0.002) and an important indirect association upon QoL (ß = 0.43) and happiness (ß = 0.23). Perceived disease impact is influenced by body image, fatigue and SSc-related disability to a higher degree (ß = 0.6-0.7) than by disease activity (ß = 0.28) or form (ß = 0.17). Impact of disease had a much stronger relation with HR-QoL than with happiness. CONCLUSIONS: The results suggest that treatment strategies targeting not only disease control but also the mitigation of relevant domains of disease impact (body image, fatigue, global disability) may be important to improve patients' experience of the disease. The reinforcement of resilience factors, such as positive psychological traits, may also play a contributory role towards better patient outcomes.

The many faces of IgG4-related disease: report of a case with inaugural recurrent aortic aneurism ruptures and literature review.

Vascular involvement in IgG4-related disease (IgG4-RD), is a well-recognized feature and large vessel commitment, especially the aorta, can be the only manifestation of the disease. Being a newly recognized disease, its diagnosis and workup still represents a challenge in clinical practice. A 47-year-old-man with two aortic aneurysms ruptures, one at abdominal and the other at thoracic level, was referred to our rheumatology department. The initial analysis of the surgical specimen obtained 3 years earlier revealed a nonspecific aortitis. Re-evaluation of the biopsy with immunohistology now demonstrated the presence of IgG4 deposits. Evidence-based recommendations regarding diagnosis, treatment and follow-up of IgG4-related large-vessel involvement are lacking. In this particular case, histopathology were crucial. The authors review and discuss vascular involvement in IgG4-RD and respective treatment options.

Psoriasiform Graft-Versus-Host Disease: Report and Brief Review of the Literature.

Graft-versus-host disease (GVHD) is the primary cause of morbidity and non-relapse-related mortality after hematopoietic stem cell transplantation. GVHD is classically divided into acute and chronic forms; acute cutaneous GVHD presents as a morbilliform eruption, whereas chronic cutaneous GVHD presents with lichen planus-like or sclerodermoid morphology. Psoriasiform GVHD is a rarely described subtype that is challenging to distinguish clinically from psoriasis. In addition to classic psoriasiform histologic findings, demonstration of an often subtle vacuolar interface dermatitis and lymphocyte satellitosis are helpful for discrimination. Herein, the authors describe psoriasiform GVHD and review the clinicopathologic findings of this unusual variant. With the appropriate clinical findings, psoriasiform GVHD should be considered in the histologic differential diagnosis of a mixed tissue reaction pattern with both psoriasiform and interface changes.

Generalized Discoid Lupus Erythematosus as the Presenting Sign of Small Cell Lung Carcinoma.

A 46-year-old woman with a 30 pack-year smoking history presented with a worsening eruption on the left cheek that failed to improve with metronidazole gel. The cutaneous eruption spread to most of her face and did not respond to a brief tapering course of prednisone. During the initial evaluation at our institution, approximately 6 weeks after the onset of the cutaneous eruption, the patient had erythematous, crusted plaques on her face and scalp (Figure 1A); they were also present on the V-area of the anterior aspect of the neck and upper region of the chest, the shoulders, and the arms, with isolated lesions on the trunk and legs. Her oral mucosa had erythematous erosions on the hard palate and gingivae. A review of systems revealed pain and burning of her skin lesions, but no muscle weakness or other systemic clinical manifestations. The differential diagnosis included autoimmune connective tissue disease, pemphigus foliaceous, sarcoidosis, lichen planus, phototoxic drug eruption, and eczema herpeticum.

A preliminary study using virtual touch imaging and quantification for the assessment of skin stiffness in systemic sclerosis.

OBJECTIVES: To evaluate ultrasound Virtual Touch Imaging and Quantification (VTIQ) as a method for determining absolute skin stiffness in patients with systemic sclerosis (SSc). METHODS: Skin thickness, assessed by the modified Rodnan Skin Score (mRSS) and absolute skin stiffness, using VTIQ, were measured at all mRSS anatomical sites to quantify the shear wave velocity (in m/s) in 26 SSc patients and in 17 age- and gender-matched controls. Correlations between mRSS and absolute skin stiffness, and comparisons between patients and controls were analysed statistically using Mann-Whitney U tests and correlations between variables using Pearson's. P values <0.05 were considered significant. RESULTS: Shear wave velocity as a measure of skin stiffness was significantly higher in SSc than in controls in 11 out of 16 mRSS sites investigated. Shear-wave velocity was strongly correlated with the local mRSS in the following anatomical sites: forearm, hand, phalanx, and thigh. In the patient group, clinically unaffected skin could also be differentiated from healthy skin using shear-wave velocity. CONCLUSIONS: VTIQ represents an innovative and promising technique that provides, for the first time, a non-invasive, absolute quantification of skin stiffness. Further studies of VTIQ are required, but this early study supports the clinical and scientific potential of this new measure of skin involvement in SSc.

Frequency of cutis laxa-like clinical features and elastolysis in scleromyxedema: a retrospective clinicopathologic study of 19 patients with scleromyxedema.

BACKGROUND: Cutis laxa-like features were observed in a subset of patients with scleromyxedema. Given this observation, clinical and histopathologic features of scleromyxedema were reviewed in correlation with elastic tissue staining. METHODS: We retrospectively reviewed clinical records and histopathologic features from patients with scleromyxedema seen at our institution from 1992 through 2013. We also evaluated available skin biopsies with an elastin stain and assessed whether dermal elastin fibers were diminished in density or were fragmented (or both). RESULTS: Nineteen patients with scleromyxedema and 34 skin biopsies were identified. Alcian blue (mucin) stain was used to grade mucin deposition as weakly positive (24%), positive (44%) and markedly positive (32%). Eight patients (42%) had clinical findings of cutis laxa, which were often observed in conjunction with areas of papular eruption or induration. Elastic tissue fibers were normal in 9 of 34 skin specimens (26%), 18 of 34 specimens (53%) had diminished elastic fiber density and 7 of 34 (21%) had markedly decreased density. The elastic tissue was fragmented in 25 specimens (74%). CONCLUSIONS: A cutis laxa-like clinical presentation and decreased elastic tissue density on skin biopsy were consistent findings. Dermatologists and dermatopathologists should be aware of these previously unreported clinical and histopathologic findings.

Safety of glucocorticoids in rheumatoid arthritis: evidence from recent clinical trials.

Glucocorticoids are one of the most effective treatments for rheumatoid arthritis, with well-established efficacy in controlling the disease symptoms and structural progression. Fears regarding their toxicity are reflected in common recommendations for the use of the lowest possible dose for the shortest possible time. We herein review toxicity data obtained in randomized clinical trials of low-dose glucocorticoid in rheumatoid arthritis, given that observational studies cannot guarantee the avoidance of bias by indication. Seven eligible randomized controlled trials were identified. These publications do not identify any strong signal of relevant toxicity of glucocorticoid in doses of up to 10 mg of prednisone equivalent/day for up to 2 years. However, the quantity (1,100 patient years of exposure) and especially the quality of evidence are too limited to establish conclusions. A large prospective trial dedicated to the toxicity of low-dose glucocorticoid is dearly needed. Meanwhile, adherence to recommendations on standardized methodologies for the registration and report of glucocorticoid adverse events is essential to improve our knowledge and competence in the best management of these important medications.

Macrophagic myofasciitis and vaccination: consequence or coincidence?

Macrophagic myofasciitis (MMF) characterized by specific muscle lesions assessing long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization has been reported with increasing frequency in the past 10 years. We describe clinical and laboratory findings in patients with MMF. We did a retrospective analysis of 16 cases observed in our Neuropathology Laboratory, between January 2000 and July 2013. The mean age of the 16 patients was 48.8 ± 18.0 years; 80.0 % were female. Chronic fatigue syndrome was found in 8 of 16 patients. Half of the patients had elevated creatinine kinase levels, and 25.0 % had a myopathic electromyogram. Thirteen patients received intramuscular administration of aluminum-containing vaccine prior to the onset of symptoms. MMF may mirror a distinctive pattern of an inflammatory myopathy. The vaccines containing this adjuvant may trigger MMF in some patients.

Diagnosis of deep cutaneous fungal infections: correlation between skin tissue culture and histopathology.

BACKGROUND: Deep cutaneous fungal infections (DCFIs) are responsible for significant morbidity and mortality, particularly in immunocompromised patients. Although a direct correlation between histopathologic examination and culture is expected, discordant findings may be seen, presenting a unique diagnostic and therapeutic challenge. OBJECTIVES: We sought to determine the correlation between skin tissue cultures and histopathologic examination in patients with DCFI. METHODS: This is a 10-year retrospective review (2003-2012) of patients with a diagnosis of DCFI seen at a single tertiary care institution. Tissue cultures and histopathologic findings were reviewed. RESULTS: In 8 of 33 cases, fungal elements were seen on routine histopathologic sections but skin cultures were negative. Three of 8 of the discordant cases had concurrent positive non-skin tissue cultures that correlated with the pathology interpretation, and 3 of 8 patients in the discordant group died of systemic fungal infection. LIMITATIONS: This was a retrospective study design and a single tertiary care institution experience. CONCLUSIONS: The histopathologic interpretation of skin tissue specimens is critical for rapid and accurate diagnosis of DCFI. Despite the identification of fungal organisms on histopathologic assessment of skin tissue specimens, skin tissue culture may fail to show fungal growth. A diagnosis of a DCFI and initiation of appropriate treatment should always be considered in spite of discordant results.

Lessons learnt from the recent recommendations for the non-pharmacological management of systemic sclerosis.

In inflammatory rheumatic diseases, including, systemic sclerosis (SSc) there is growing evidence that treatment strategies should not only target disease control in terms of clinical features and laboratory tests but consider distinct interventions to mitigate all domains of perceived disease impact. The results of a multicentric work based on data from the Rheumatic Diseases Portuguese Registry (Reuma.pt)/Scleroderma indicated that the optimization of outcomes for patients with SSc would in all probability require assessment of the needs of individual patients and consider adjunctive interventions in clinical practice to mitigate all significantly affected domains of disease impact. Recently, in June 2023, a task force under the auspices of EULAR, comprising rheumatologists, health professionals and patient advocates published four overarching principles and twelve recommendations for the non-pharmacological management of people living with SSc and systemic lupus erythematosus (SLE).

10-year experience of early arthritis clinic at a tertiary rheumatology center: achievements and challenges.

OBJECTIVES: To characterize patients evaluated in our Early Arthritis Clinic (EAC) in the first ten years; to assess diagnostic delay and its underlying causes; and to evaluate the level of agreement between the referring physician and the rheumatologist regarding the presence of referral criteria. METHODS: Cross-sectional study including patients attending EAC between 2012 and 2021. Demographic data, provenience, final diagnosis, referral criteria and time related to diagnosis delay were retrieved from clinical files and the Portuguese Registry of Rheumatic Patients (reuma.pt). Characteristics of the patients and the time variables were analysed with descriptive statistical analysis. The agreement between the referring physician and rheumatologist regarding the referral criteria was evaluated using Cohen's Kappa. RESULTS: A total of 440 patients (68.9% females, mean age of 54±16.7 years) were referred, mostly from primary care (71.6%). Inflammatory Rheumatic Disease was diagnosed in 65.7% of the patients, with 58.9% classified as early arthritis. The median time from onset of symptoms to referral for EAC was 76 days (IQR 33.5-144.0); the median time from referral to the first EAC was 34 (IQR 19.0-46.0) days, and the median time from onset of symptoms to first EAC was 114.5 (IQR 66.8-190.3) days (16.3 weeks). Only about 10% were observed by a Rheumatologist before six weeks after symptom onset. The level of agreement between the referring physician and the rheumatologist was slight to fair to clinical criteria and moderate to substantial to laboratory criteria. CONCLUSIONS: A significant delay still is observed in patients with early arthritis suspicion, being the time from onset of symptoms to referral is the most relevant. A low agreement between referral and Rheumatologists suggests that non-rheumatologists education/training is needed. Identifying the barriers that prevent the adequate referral of patients is necessary to define strategies to improve it.

Systematic literature review to inform the Portuguese recommendations for the management of Raynaud's phenomenon and digital ulcers in systemic sclerosis and other connective tissue diseases.

OBJECTIVE: To perform a systematic literature review (SLR) aimed at evaluating the efficacy and safety of pharmacological and non-pharmacological treatments for Raynaud's phenomenon (RP) and digital ulcers (DU) in patients with systemic sclerosis (SSc) and other connective tissue diseases (CTD), in order to inform the Portuguese recommendations for managing RP and DU in these patients. METHODS: A SLR was conducted until May 2022 to identify studies assessing the efficacy and safety of pharmacological and non-pharmacological interventions for RP and DU in SSc and other CTD. Eligible study designs included randomized controlled trials (RCTs), controlled clinical trials, and their extensions for assessing efficacy and safety of interventions. Observational studies with a comparator were included for evaluating the efficacy and safety of non-pharmacological interventions and safety of pharmacological interventions. The risk of bias of each study was assessed using standard tools. RESULTS: Out of 71 publications meeting the inclusion criteria, 59 evaluated pharmacological and 12 non-pharmacological interventions. We found moderate quality evidence supporting the efficacy of calcium channel blockers, phosphodiesterase-5 inhibitors, and intravenous prostacyclin analogues in reducing RP frequency, severity, and duration. Intravenous iloprost had a small to moderate effect size in improving DU healing. Phosphodiesterase-5 inhibitors were effective in reducing total DU count, new DU occurrence, and enhancing DU healing. Bosentan effectively prevented new DU in SSc patients. No new safety concerns were associated with these treatments. The studies on non-pharmacological interventions were, in general, of low quality, and had a small sample size. Warming measures decreased frequency and duration of RP attacks; laser therapy improved RP-related outcomes; local oxygen-ozone therapy improved RP outcomes as an add-on therapy; bone marrow mononuclear cell implantation improved DU-associated pain; periarterial sympathectomy and vascular bypass reduced DU number and finger amputation risk. CONCLUSION: The available evidence supports the efficacy and safety of pharmacological interventions, namely nifedipine, sildenafil, iloprost, and bosentan in treating RP and DU in patients with SSc and other CTD. Scarce and low-quality evidence does support the use of some non-pharmacological interventions but with only a modest effect size. This SLR underscores the limited availability of high-quality evidence for determining the optimal treatment.

West Nile Virus Seroprevalence in Wild Birds and Equines in Madrid Province, Spain.

West Nile virus (WNV) is a re-emerging flavivirus, primarily circulating among avian hosts and mosquito vectors, causing periodic outbreaks in humans and horses, often leading to neuroinvasive disease and mortality. Spain has reported several outbreaks, most notably in 2020 with seventy-seven human cases and eight fatalities. WNV has been serologically detected in horses in the Community of Madrid, but to our knowledge, it has never been reported from wild birds in this region. To estimate the seroprevalence of WNV in wild birds and horses in the Community of Madrid, 159 wild birds at a wildlife rescue center and 25 privately owned equines were sampled. Serum from thirteen birds (8.2%) and one equine (4.0%) tested positive with a WNV competitive enzyme-linked immunosorbent assay (cELISA) designed for WNV antibody detection but sensitive to cross-reacting antibodies to other flaviviruses. Virus-neutralization test (VNT) confirmed WNV antibodies in four bird samples (2.5%), and antibodies to undetermined flavivirus in four additional samples. One equine sample (4.0%) tested positive for WNV by VNT, although this horse previously resided in a WN-endemic area. ELISA-positive birds included both migratory and resident species, juveniles and adults. Two seropositive juvenile birds suggest local flavivirus transmission within the Community of Madrid, while WNV seropositive adult birds may have been infected outside Madrid. The potential circulation of flaviviruses, including WNV, in birds in the Madrid Community raises concerns, although further surveillance of mosquitoes, wild birds, and horses in Madrid is necessary to establish the extent of transmission and the principal species involved.

Portuguese Recommendations for the management of Raynaud's phenomenon and digital ulcers in systemic sclerosis and other connective tissue diseases.

OBJECTIVE: To develop evidence-based recommendations for the non-pharmacological and pharmacological management of Raynaud's phenomenon (RP) and digital ulcers (DUs) in patients with systemic sclerosis and other immune-mediated connective tissue diseases (CTDs). METHODS: A task force comprising 21 rheumatologists, two surgeons (vascular and plastic), two nurses, and one patient representative was established. Following a systematic literature review performed to inform the recommendations, statements were formulated and discussed during two meetings (one online and one in-person). Levels of evidence, grades of recommendation (GoR), and level of agreement (LoA) were determined. RESULTS: Five overarching principles and 13 recommendations were developed. GoR ranged from A to D. The mean ± standard difference (SD) LoA with the overarching principles and recommendations ranged from 7.8±2.1 to 9.8±0.4. Briefly, the management of RP and DUs in patients with CTDs should be coordinated by a multidisciplinary team and based on shared decisions with patients. Nifedipine should be used as first-line therapy for RP and/or DUs. Sildenafil, tadalafil, and/or iloprost IV are second-line options for severe and/or refractory patients with RP and/or DUs. Sildenafil, tadalafil and/or Iloprost IV, should be prescribed for healing and prevention (also including bosentan) of DUs. In patients with RP and/or DUs, non-pharmacological interventions might be considered as add-ons, but there is limited quality and quantity of scientific evidence supporting their use. CONCLUSIONS: These recommendations will inform rheumatologists, specialist nurses, other healthcare professionals, and patients about a comprehensive and personalized management of RP and DUs. A research agenda was developed to address unmet needs, particularly for non-pharmacologic interventions.

Cutaneous extramedullary plasmacytoma: clinical, prognostic, and interphase cytogenetic analysis.

Extramedullary plasmacytoma (EMP) of the skin is a rare indolent neoplasm that shares morphological and immunophenotypic features with plasma cell myeloma (PCM), but the molecular features that distinguish these two entities have not been defined. We reviewed the clinical characteristics, course, and molecular abnormalities in 7 cases of cutaneous EMP (cEMP); 2 patients had primary cEMP and 5 had secondary cEMP. Two patients died of progressive extramedullary plasmacytoma, 1 without PCM; 1 patient who had only a hyperdiploid clone, died within 17 months of the diagnosis of cEMP; and 3 died of PCM. One patient, who had cEMP with a hyperdiploid clone and a 13q deletion, was alive 28 months after diagnosis. Our findings raise questions about the relative prognostic value of molecular aberrations observed in cEMP and PCM. The role of fluorescence in situ hybridization testing in predicting disease progression of cEMP remains to be defined.