Identification and characteristics of patients with potential difficult-to-treat Psoriatic Arthritis: exploratory analyses of the Greek PsA registry.

OBJECTIVE: To present the characteristics of patients with potential difficult-to-treat (D2T) psoriatic arthritis (PsA). METHODS: We used data from the Greek multicentre registry of PsA patients. D2T-PsA was defined as follows: patients with at least 6-months disease duration, who have failed to at least 1 csDMARD and at least 2 bDMARDs/tsDMARDs with a different mechanism of action and have either at least moderate disease activity (MODA) defined as DAPSA > 14, and/or are not at minimal disease activity (MDA). Demographic and clinical characteristics were compared between D2T and non-D2T PsA patients. In two sensitivity analyses, patients classified as D2T solely according to the MODA or MDA criterion were examined separately. RESULTS: Among 467 patients included, 77 (16.5%) were considered D2T and 390 non-D2T PsA. Compared with non-D2T, patients with D2T PsA presented more commonly with extensive psoriasis (p< 0.0001) and were more likely to have higher BMI (p= 0.023) and a history of inflammatory bowel disease (p= 0.026). In the MODA and MDA sensitivity analyses, 7.5% and 12.5% of patients were considered D2T, respectively. In both sensitivity analyses, extensive psoriasis was again identified as an independent variable for D2T PsA (p= 0.001 and p= 0.008, respectively). Moreover, female gender (p= 0.034) in the MODA analysis and axial disease (p= 0.040) in the MDA analysis were independent variables for D2T PsA. CONCLUSION: Despite the availability of therapies, D2T PsA is common in real-life cohorts of patients with PsA and extensive psoriasis. High BMI, female gender, axial-disease, and history of IBD were also associated with D2T PsA.

Anti-TNF-α induced paradoxical psoriasis in patients with ankylosing spondylitis: a systematic review.

OBJECTIVES: The approval of TNF-a inhibitors (TNFi) was a breakthrough in the treatment of ankylosing spondylitis (AS). Although also effective in psoriasis, drug-related adverse events of onset of psoriasiform skin lesions - paradoxical psoriasis (PP) under TNFi have been reported. METHODS: We performed an electronic data search in MEDLINE via Pubmed and Cochrane library scientific databases from inception to January 2023, following the PRISMA guidelines. We assessed the distinct characteristics and frequency of risks for PP appearance in AS patients treated with different TNFi. RESULTS: PP was found in 0.5-1% of TNFi-treated AS patients and the latency period was 2-11 months. The safest TNFi in terms of PP induction was certolizumab, whereas the one most commonly associated with PP was infliximab. CONCLUSIONS: PP is an uncommon adverse reaction to TNFi treatment in AS patients and responds well to drug withdrawal. More large data studies need to be conducted though, to shed light on PP nature and management.

The role of anti-eosinophilic therapies in eosinophilic granulomatosis with polyangiitis: a systematic review.

Eosinophilic granulomatosis with polyangiitis (EGPA) is an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, mostly affecting small-sized arteries and usually occurring in patients with an allergic background. Eosinophils seem to play a significant role in the pathogenesis of the disease and, therefore, biologics targeting interleukin 5 (IL5), a cytokine tightly linked to eosinophils, have emerged as a promising therapeutic tool. A systematic review of Medline was conducted from 2007 to 2022 to search for data regarding the use of anti-IL5 therapies in patients with EGPA. Ongoing or unpublished trials were also searched in ClinicalTrials.gov and the World Health Organization trials portal. The efficacy and safety of mepolizumab, an anti-IL5 monoclonal antibody (mAb), was confirmed by a randomized controlled trial (RCT), although a significant proportion of patients did not respond to this treatment. Other studies showed that both doses of 100 mg and 300 mg of mepolizumab are almost equally effective in EGPA. Benralizumab, an anti-IL5 receptor mAb has preliminary promising results and an RCT is planned to be conducted. Apart from their clinical efficacy in EGPA, anti-IL5 therapies may have steroid-sparing properties. Anti-IL5 therapies seem to be effective and safe in patients with refractory/relapsing EGPA and can be used as a steroid-sparing treatment. Nevertheless, more research is needed to clarify the pathophysiology of the disease; this may potentially lead to the identification of biomarkers to pinpoint patients most likely to respond to anti-IL5-blockade.

Identification of outcome domains in immune checkpoint inhibitor-induced inflammatory arthritis and polymyalgia rheumatica: A scoping review by the OMERACT irAE working group.

INTRODUCTION: Immune checkpoint inhibitors (ICI), increasingly used cancer therapeutics, can cause off-target inflammatory effects called immune-related adverse events (irAEs), including ICI-induced inflammatory arthritis (ICI-induced IA) and polymyalgia rheumatica (ICI-induced PMR). There are no validated classification criteria or outcome measures for these conditions, and adaptation of treatment recommendations from corresponding rheumatic diseases may not be appropriate. We summarized clinical descriptors of ICI-induced IA and ICI-induced PMR and aggregated domains used for these conditions in order to inform the development of a core set of outcome domains. METHODS: As the initial step of the core domain set generation process, we systemically searched Medline (Pubmed), EMBASE, Cochrane, and CINHL through March 2021 to identify all studies that provide both clinical descriptions and domains relevant to ICI-induced IA and ICI-induced PMR. Domains were mapped to core areas, such as pathophysiological manifestations, life impact, resource use, and longevity/survival, as suggested by the OMERACT 2.1 Filter. RESULTS: We identified 69 publications, over a third of which utilized non-specific diagnoses of "arthritis," "arthralgia," and/or "PMR". Other publications provided the number, the distribution and/or names of specific joints affected, while others labeled the irAE as the corresponding rheumatic disease, such as rheumatoid arthritis or spondyloarthritis. Most distinct domains mapped to the pathophysiology/manifestations core area (24 domains), such as signs/symptoms (13 domains), labs (6 domains), and imaging (5 domains), with harm domains of adverse effects from irAE treatment and fear of irAE treatment decreasing ICI efficacy. Forty-three publications also referenced irAE treatment and 35 subsequent response, as well as 32 tumor response. CONCLUSION: There is considerable heterogeneity in the domains used to clinically characterize ICI-induced IA and ICI-induced PMR. There were several domains mapped to the pathophysiologic manifestations core area, although several publications highlighted domains evenly distributed among the other core areas of life impact, longevity/survival and resource use.

Disease Profile and Achievement of Therapeutic Goals in a Modern, Nationwide Cohort of 923 Patients with Psoriatic Arthritis.

Background: Psoriatic arthritis (PsA) is a heterogenous chronic inflammatory disease affecting skin, joints, entheses, and spine with various extra-musculoskeletal manifestations and comorbidities. The reported patient, disease and treatment characteristics in the modern therapeutic era are limited. Methods: In this cross-sectional, multi-centre, nationwide study, we recorded the demographic, clinical, and therapeutic characteristics as well as the comorbidities of patients with PsA seen for 1 year (1/1/2022-31/12/2022). Results: 923 patients (55% females) with a median (IQR) age of 57 (48-65) years and a mean disease duration of 9.5 years were enrolled. Family history of psoriasis and PsA was noted in 28.3% and 6.3%, respectively. Most patients had limited psoriasis (BSA<3: 83%) while enthesitis, dactylitis, nail and axial involvement reported in 48.3%, 33.2%, 43% and 25.9% of patients, respectively. Regarding comorbidities, approximately half of patients had dyslipidaemia (42%) or hypertension (45.4%), 36.8% were obese and 17% had diabetes while 22.7% had a depressive disorder. Overall, 60.1% received biologics and among them more patients treated with anti-IL-17 or -12/23 agents were on monotherapy (64.2%) compared to those on TNFi monotherapy (49.4%, p=0.0001). The median PsA activity as assessed by the DAPSA score was 6 (IQR: 2.3 - 13.1) with 46% of patients reaching minimal disease activity status (MDA). Conclusion: In this large, real life, modern cohort of patients with PsA with frequent comorbidities who were treated mainly with biologics, almost half achieved minimal disease activity. These results show the value of existing therapeutic approaches while at the same time highlight the existing unmet needs.

Pathogenetic Aspects of Systemic Sclerosis: A View Through the Prism of B Cells.

Systemic sclerosis (SSc) is a rare fibrotic rheumatic disease, associated with psychological distress and increased morbidity and mortality due to skin involvement and internal organ damage. The current understanding of the complex pathogenesis is yet incomplete and disease therapeutic algorithms are far from optimal. Immunologic aberrations are considered key factors for the disease, along with vascular involvement and excess fibrosis. Adaptive immunity and its specialized responses are an attractive research target and both T and B cells have been extensively studied in recent years. In the present review, the focus is placed on B cells in SSc. B cell homeostasis is deranged and B cell subsets exhibit an activated phenotype and abnormal receptor signaling. Autoantibodies are a hallmark of the disease and the current perception of their diagnostic and pathogenetic role is analyzed. In addition, B cell cytokine release and its effect on immunity and fibrosis are examined, together with B cell tissue infiltration of the skin and lung. These data support the concept of targeting B cells as part of the therapeutic plan for SSc through well designed clinical trials.

DKK-1 Is Underexpressed in Mesenchymal Stem Cells from Patients with Ankylosing Spondylitis and Further Downregulated by IL-17.

Dickkopf-1 (Dkk-1) is a key regulator of bone remodeling in spondyloarthropathies. Nevertheless, data regarding its expression in cells of pathophysiologic relevance, such as mesenchymal stem cells (MSCs), are lacking. Herein, we aimed to address DKK1 gene expression and Wnt pathway activation in MSCs from patients with ankylosing spondylitis (AS) and explore the effect of IL-17 on MSCs with respect to DKK-1 expression and Wnt pathway activation. Primary MSCs were isolated from the bone marrow of the femoral head of two patients with AS and two healthy controls undergoing orthopedic surgery. MSCs were cultured for 7 days in expansion medium and for 21 days in osteogenic medium in the presence or absence of IL-17A. Gene expression of DKK-1 and osteoblastic markers was determined by RT-PCR. Alkaline phosphatase activity, alizarin red and Van Kossa staining were used to assess osteoblastic function and mineralization capacity. DKK-1 was significantly downregulated in MSCs and osteoblasts from patients with AS compared to controls. Moreover, MSCs and osteoblasts from AS patients displayed increased Wnt pathway activation and enhanced osteoblastic activity, as indicated by increased expression of osteoblast marker genes and alkaline phosphatase activity. IL-17 downregulated DKK-1 expression and increased osteoblastic activity and mineralization capacity. DKK-1 is underexpressed in MSCs from AS patients compared to controls, whereas IL-17 has an inhibitory effect on DKK-1 expression and stimulates osteoblastic function. These data may have pathogenetic and clinical implications in AS.

Vision loss in giant cell arteritis: case-based review.

Prompt initiation of pulse glucocorticoid treatment is recommended in case of visual symptoms and suspected or proven giant cell arteritis (GCA). Pulse treatment in most cases prevents involvement of an initially unaffected fellow eye. We present the case of a biopsy-proven GCA in a 79-year-old man, complicated by sequential bilateral blindness. Initial unilateral vision loss was treated by 1 g methylprednisolone intravenously for 3 days, followed by 1 g/kg prednisone daily. Despite treatment, the second eye went completely blind 11 days after the initial vision loss. We performed a systematic search on Medline and Scopus aiming at identifying all cases of GCA complicated with loss of vision in a previously unaffected eye under pulse treatment for initially monocular vision loss. We identified 11 articles reporting 21 patients that met our inclusion criteria. Contralateral vision loss occurred 1-12 days following treatment initiation, with a median of 2 days. Treatment initiation was delayed up to 8 days since the initial vision loss, with a median delay of 2 days. Anterior ischemic optic neuropathy was the dominant mechanism of vision loss. Sequential involvement of the fellow eye in case of unilateral vision loss in GCA is rare. With 12-day interval being the longest reported, we conclude that even though the first 2 days are the most critical for the visual outcome, blindness in the initially unaffected eye may rarely occur later. Nonetheless, immediate initiation of pulse treatment remains of vital importance to preserve vision in the contralateral eye.

Real-world safety and efficacy data of immunotherapy in patients with cancer and autoimmune disease: the experience of the Hellenic Cooperative Oncology Group.

BACKGROUND: Data on the safety and efficacy of immune checkpoint inhibitors (ICI) in patients with concurrent autoimmune diseases (AID) are limited. METHODS: We performed a retrospective multicenter review of medical records of patients with cancer and underlying AID who received ICI. The primary endpoint was progression-free survival (PFS). RESULTS: Among 123 patients with pre-existing AID who received ICI, the majority had been diagnosed with non-small cell lung cancer (NSCLC, 68.3%) and melanoma (14.6%). Most patients had a rheumatologic (43.9%), or an endocrine disorder (21.1%). Overall, 74 (60.2%) patients experienced an immune-related adverse event (irAE) after ICI initiation, AID flare (25.2%), or new irAE (35%). Frequent irAEs included thyroiditis, dermatitis and colitis. ICI was permanently discontinued due to unacceptable (8.1%) or fatal (0.8%) toxicity. In patients with NSCLC, corticosteroid treatment at the initiation of immunotherapy was associated with poor PFS (HR = 2.78, 95% CI 1.40-5.50, p = 0.003). The occurrence of irAE was associated with increased PFS (HR = 0.48, 95% CI 0.25-0.92, p = 0.026). Both parameters maintained their independent prognostic significance. CONCLUSIONS: ICI in patients with cancer and pre-existing AID is associated with manageable toxicity that infrequently requires treatment discontinuation. However, since severe AID flare might occur, expected ICI efficacy and toxicity must be balanced. CLINICAL TRIAL IDENTIFIER: NCT04805099.

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.

Renal dysfunction in systemic sclerosis beyond scleroderma renal crisis.

Research regarding renal involvement in SSc has almost exclusively focused on scleroderma renal crisis (SRC). There are relatively limited data regarding renal impairment in SSc beyond SRC. We performed an electronic search using the key words systemic sclerosis or scleroderma combined with each of the following: renal dysfunction, kidney, glomerular filtration rate (GFR), proteinuria and hematuria. We searched for reports relevant to renal dysfunction in SSc beyond SRC. In 796 SSc patients recruited in five studies. 251 (31.5%) had GFR < 90 ml/min whereas 155(19.5%) patients had GFR < 60 ml/min. Most data indicate that the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula should be considered as the most suitable tool for assessing renal function in SSc pts, since it provides similar results to measured GFR. These data indicate that renal dysfunction in SSc in not uncommon and therefore patients with SSc should have their renal function assessed by GFR estimation on a regular basis.

B cells in systemic sclerosis: from pathophysiology to treatment.

Systemic sclerosis is a debilitating autoimmune disease with unknown pathogenesis. The clinical phenotype of fibrosis is preceded by vascular and immunologic aberrations. Adaptive immunity has been extensively studied in patients with the disease and B cells appear to be dysregulated. This is evident in peripheral blood B cell subsets, with activated effector B cells and impaired B regulatory function. In addition, B cells infiltrate target organs and tissues of patients with the disease, such as the skin and the lung, indicating a probable role in the pathogenesis. Impaired B cell homeostasis explains the rationale behind B cell therapeutic targeting. Indeed, several studies in recent years have shown that depletion of B cells appears to be a promising treatment alongside current established therapeutic choices, such as mycophenolate. In this review, B cell aberrations in animal models and human patients with systemic sclerosis will be presented. Moreover, we will also summarize current existing data regarding therapeutic targeting of the B cells in systemic sclerosis.

Immune checkpoint inhibitor-induced musculoskeletal manifestations.

Immune checkpoint inhibitors (ICI) associate with a wide range of immune-related adverse events (Ir-AE), including musculoskeletal manifestations. We aimed at identifying all studies reporting musculoskeletal Ir-AE. An electronic (Medline, Scopus and Web of Science) search was performed using two sets of key words. The first set consisted of: arthritis, musculoskeletal, polymyalgia rheumatica and myositis. The second set consisted of: anti-PD-1, anti-PD-L1, anti-CTLA-4, ipilimumab, tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab. We identified 3 prospective studies, 17 retrospective studies and 4 case series reporting 363 patients in total. Combined data from all three prospective studies provide a prevalence rate of 6.13%. Most patients were males (59.68%) and the vast majority (73%) were on programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors. Most studies report a median time of ≤ 12 weeks from first ICI administration to symptom onset. The main clinical phenotypes reported were: (a) inflammatory arthritis (57.57%), (b) myositis (14.04%) and (c) polymyalgia rheumatica (PMR) (12.12%). A total of 256 patients required steroids (70.52%) and 67 patients (18.45%) were treated with DMARDs. Positive auto-antibodies and family history of any autoimmune disease were present in 18.48% and 19.04% of cases, respectively. Only a few patients (19%) had to discontinue treatment due to musculoskeletal Ir-AE. Two prospective studies show that significantly more patients with musculoskeletal Ir-AE exhibit a favorable oncologic response compared to patients not exhibiting such manifestations whereas retrospective studies show that 77.22% of patients with musculoskeletal Ir-AE have a good tumor response. One out of 15 patients treated with ICI will develop musculoskeletal Ir-AE; in most cases the severity of these manifestations is mild/moderate and usually ICI may be continued. Rheumatologists should familiarize with this new clinical entity and develop relevant therapeutic algorithms.

Adrenocorticotropic hormone: an effective "natural" biologic therapy for acute gout?

Treatment of acute gout consists of non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and steroids. However, the typical patient with gout has multiple comorbidities such as cardiovascular disease, hypertension, renal dysfunction or diabetes/metabolic syndrome that represent contraindications to these therapeutic options. The aim of this study is to review the available evidence regarding the use of ACTH as an alternative therapeutic option for acute gout and explore potential mechanisms of action. We performed an electronic search (MEDLINE, Scopus and Web of Science) using the keywords ACTH or adrenocorticotropic hormone combined with gout or crystal-induced arthritis. ACTH appears suitable for patients with many comorbidities due to its good safety profile. Clinical evidence shows that ACTH is at least as effective as classic agents. The mechanism of action of ACTH in gout is not entirely known. Robust experimental evidence points to the direction that ACTH does not act solely by triggering the release of endogenous steroids but also appears to downregulate inflammatory responses by activating melanocortin receptors on innate immune cells, such as macrophages. Moreover, indirect evidence indicates that ACTH may have an IL-1 antagonistic effect. We propose that ACTH may be an alternative therapeutic option for gout in patients with multiple comorbidities. Large-scale studies assessing the efficacy and safety of ACTH compared to classic therapeutic options are needed.

Immune checkpoint inhibitor-induced musculoskeletal manifestations. A multicentre prospective study.

BACKGROUND: Immune checkpoint inhibitors (ICI) are anti-cancer drugs that act by enhancing anti-tumour immunity. Due to their mechanism of action, they have been associated with immune related adverse events (Ir-AE), including musculoskeletal manifestations. AIM: To assess a) the prevalence, clinical and imaging (MRI) characteristics of ICI-induced musculoskeletal immune related adverse events (ir-AE) in a prospective manner, b) the potential association of musculoskeletal ir-AE with oncologic response and changes in the immune system at the level of soluble molecules (cytokines) as well as T/B cell subpopulations. METHODS: This a multicentre prospective study. We plan to recruit all patients who are going to start treatment with ICI from October 2019 until October 2020 in all collaborating Oncology Departments. This study is consisted of a clinical and a laboratory arm. RESULTS: The study is currently recruiting patients. CONCLUSIONS: We anticipate that this study will provide useful data regarding the clinical characteristics of ICI-induced musculoskeletal manifestations as well as potential predictive biomarkers.

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.

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.

Comorbidity burden in systemic sclerosis: beyond disease-specific complications.

Systemic sclerosis (SSc) is a chronic, systemic disease characterized by fibrosis of the skin and internal organs, vasculopathy, and auto-immune activation. On the top of severe organ involvement such as interstitial lung and myocardial fibrosis, pulmonary hypertension, and renal crisis, individuals diagnosed with SSc may suffer from a number of comorbidities. This is a narrative review according to published recommendations and we searched the online databases MEDLINE and EMBASE using as key words the following terms: systemic sclerosis, scleroderma, myocardial fibrosis in combination with micro- and macro-vascular disease, cardiac involvement, atherosclerosis, cardiovascular disease and coronary arteries, infections, cancer, depression, osteoporosis, and dyslipidemia. Although data are usually inconclusive it appears that comorbidities with significant impact on life expectancy, namely cardiovascular disease, infections, and cancer as well as phycological disorders affecting emotional and mental health are highly prevalent in SSc population. Thereafter, the aim of this review is to summarize the occurrence and the clinical significance of such comorbidities in SSc population and to discuss how rheumatologists can incorporate the management of these conditions in daily clinical practice.