Pan American League of Associations for Rheumatology Recommendations for the Treatment of Psoriatic Arthritis.

OBJECTIVE: Psoriatic arthritis (PsA) is chronic disease that compromises multiple domains and might be associated with progressive joint damage, increased mortality, functional limitation, and considerably impaired quality of life. Our objective was to generate evidence-based recommendations on the management of PsA in Pan American League of Associations for Rheumatology (PANLAR) countries. METHODS: We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE)-ADOLOPMENT approach to adapt the 2019 recommendations of the European Alliance of Associations for Rheumatology. A working group consisting of rheumatologists from various countries in Latin America identified relevant topics for the treatment of PsA in the region. The methodology team updated the evidence and synthesized the information used to generate the final recommendations. These were then discussed and defined by a panel of 31 rheumatologists from 15 countries. RESULTS: Theses guidelines report 15 recommendations addressing therapeutic targets, use of antiinflammatory agents and corticosteroids, treatment with disease-modifying antirheumatic drugs (conventional synthetic, biologic, and targeted synthetic), therapeutic failure, optimization of biologic therapy, nonpharmacological interventions, assessment tools, and follow-up of patients with PsA. CONCLUSION: Here we present a set of recommendations to guide decision making in the treatment of PsA in Latin America, based on the best evidence available, considering resources, medical expertise, and the patient's values and preferences. The successful implementation of these recommendations should be based on clinical practice conditions, healthcare settings in each country, and a tailored evaluation of patients.

Pan American League of Associations for Rheumatology recommendations for the management of axial spondyloarthritis.

Axial spondyloarthritis (axSpA) comprises a spectrum of chronic inflammatory manifestations affecting the axial skeleton and represents a challenge for diagnosis and treatment. Our objective was to generate a set of evidence-based recommendations for the management of axSpA for physicians, health professionals, rheumatologists and policy decision makers in Pan American League of Associations for Rheumatology (PANLAR) countries. Grading of Recommendations, Assessment, Development and Evaluation-ADOLOPMENT methodology was used to adapt existing recommendations after performing an independent systematic search and synthesis of the literature to update the evidence. A working group consisting of rheumatologists, epidemiologists and patient representatives from countries within the Americas prioritized 13 topics relevant to the context of these countries for the management of axSpA. This Evidence-Based Guideline article reports 13 recommendations addressing therapeutic targets, the use of NSAIDs and glucocorticoids, treatment with DMARDs (including conventional synthetic, biologic and targeted synthetic DMARDs), therapeutic failure, optimization of the use of biologic DMARDs, the use of drugs for extra-musculoskeletal manifestations of axSpA, non-pharmacological interventions and the follow-up of patients with axSpA.

Symptomatic fractures in systemic sclerosis: A case-control study.

This case-control study analyzed risk factors for symptomatic fractures in a group of 52 patients with systemic sclerosis compared with a group of 104 patients without fractures, matched for sex and age, who were attended at a single systemic sclerosis outpatient clinic from 2010 to 2020. Fractures affected predominantly vertebral (65.4%), rib (13.5%), and hip (7.7%) joints, while the mean age of fracture was 55.3 ± 9.5 years. Age at disease onset, age at diagnosis, disease duration, age at menarche, and age at menopause were similar in both groups, and 58.9% of the patients were menopausal at the time of the fracture. The presence of fractures had a significant association with densitometric osteoporosis (p < 0.001), lower weight (p = 0.032), and bone mineral index (p = 0.044), anti-RNA polymerase III (p = 0.040), use of corticosteroids (p = 0.019), and bisphosphonates (p < 0.001), as well as with densitometric T-scores of lumbar spine (p < 0.001), femoral neck (p = 0.025), and total hip (p = 0.013). Multivariate analysis showed that the variables significantly associated with fractures were high doses of corticosteroids (odds ratio = 4.10; 95% confidence interval = 1.290-13.090; p = 0.017), bisphosphonates (odds ratio = 3.91; 95% confidence interval = 1.699-8.984; p = 0.001), negative anti-Scl70 (OR = 0.34; 95% confidence interval = 0.124-0.943; p = 0.038), and lumbar T-score (odds ratio = 0.39; 95% confidence interval = 0.034-0.460; p = 0.010). In conclusion, symptomatic fractures were associated predominantly with lower bone mineral density of lumbar spine and use of high doses of corticosteroids and bisphosphonates in this cohort.

Immunogenicity decay and case incidence six months post Sinovac-CoronaVac vaccine in autoimmune rheumatic diseases patients.

The determination of durability and vaccine-associated protection is essential for booster doses strategies, however data on the stability of SARS-CoV-2 immunity are scarce. Here we assess anti-SARS-CoV-2 immunogenicity decay and incident cases six months after the 2nd dose of Sinovac-CoronaVac inactivated vaccine (D210) in 828 autoimmune rheumatic diseases patients compared with 207 age/sex-balanced control individuals. The primary outcome is the presence of anti-S1/S2 SARS-CoV-2 IgG at 6 months compared to 6 weeks after 2nd vaccine dose for decay evaluation. Secondary outcomes are presence of neutralizing antibodies, percent inhibition by neutralizing, geometric mean titers and cumulative incident cases at 6 months after 2nd dose. Anti-S1/S2 IgG positivity and titers reduce to 23.8% and 38% in patients (p < 0.001) during the six-month follow up and 20% and 51% in controls (p < 0.001), respectively. Neutralizing antibodies positivity and percent inhibition declines 41% and 54% in patients (p < 0.001) and 39.7% and 47% in controls (p < 0.001). Multivariate logistic regression analysis show males (OR = 0.56;95% CI0.40-0.79), prednisone (OR = 0.56; 95% CI0.41-0.76), anti-TNF (OR = 0.66;95% CI0.45-0.96), abatacept (OR = 0.29; 95% CI0.15-0.56) and rituximab (OR = 0.32;95% CI0.11-0.90) associate with a substantial reduction in IgG response at day 210 in patients. Although cellular immunity was not assessed, a decrease of COVID-19 cases (from 27.5 to 8.1/100 person-years; p < 0.001) is observed despite the concomitant emergence and spread of the Delta variant. Altogether we show a reduction in immunity 6-months of Sinovac-CoronaVac 2nd dose, particularly in males and those under immunosuppressives therapies, without a concomitant rise in COVID-19 cases. (CoronavRheum clinicaltrials.gov:NCT04754698).

Collagen V α1 Chain Decrease in Papillary Dermis from Early Systemic Sclerosis: A New Proposal in Cutaneous Fibrosis Molecular Structure.

Cutaneous fibrosis is one of the main features of systemic sclerosis (SSc). Recent findings correlated abnormal collagen V (Col V) deposition in dermis with skin thickening and disease activity in SSc. Considering that Col V is an important regulator of collagen fibrillogenesis, understanding the role of Col V in the first two years of the skin fibrosis in SSc (early SSc) can help to determine new targets for future treatments. In this study, we analyzed the morphological, ultrastructural and molecular features of α1(V) and α2(V) chains and the expression of their coding genes COL5A1 and COL5A2 in collagen fibrillogenesis in early-SSc. Skin biopsies were obtained from seven consecutive treatment-naïve patients with SSc-related fibrosis and four healthy controls. Our data showed increased α1(V) and α2(V) chain expression in the reticular dermis of early-SSc patients; however, immunofluorescence and ultrastructural immunogold staining determined a significant decreased expression of the α1(V) chain along the dermoepidermal junction in the papillary dermis from early-SSc-patients in relation to the control (12.77 ± 1.34 vs. 66.84 ± 3.36; p < 0.0001). The immunoblot confirmed the decreased expression of the α1(V) chain by the cutaneous fibroblasts of early-SSc, despite the increased COL5A1 and COL5A2 gene expression. In contrast, the α2(V) chain was overexpressed in the small vessels (63.18 ± 3.56 vs. 12.16 ± 0.81; p < 0.0001) and capillaries (60.88 ± 5.82 vs. 15.11 ± 3.80; p < 0.0001) in the reticular dermis of early-SSc patients. Furthermore, COLVA2 siRNA in SSc cutaneous fibroblasts resulted in a decreased α1(V) chain expression. These results highlight an intense decrease in the α1(V) chain along the dermoepidermal junction, suggesting an altered molecular histoarchitecture in the SSc papillary dermis, with a possible decrease in the expression of the α1(V)3 homotrimeric isoform, which could interfere with the thickening and cutaneous fibrosis related to SSc.

Strong response after fourth dose of mRNA COVID-19 vaccine in autoimmune rheumatic diseases patients with poor response to inactivated vaccine.

OBJECTIVES: To assess immunogenicity of a heterologous fourth dose of an mRNA (BNT162b2) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in autoimmune rheumatic diseases (ARD) patients with poor/non-response to inactivated vaccine (Sinovac-CoronaVac). METHODS: A total of 164 ARD patients who were coronavirus disease 2019 (COVID-19) poor/non-responders (negative anti-SARS-CoV-2 S1/S2 IgG and/or neutralizing antibodies-NAb) to the third dose of Sinovac-CoronaVac received an additional heterologous dose of mRNA (BNT162b2) 3 months after last dose. IgG and NAb were evaluated before and after the fourth dose. RESULTS: Significant increases were observed after the fourth dose in IgG (66.4 vs 95.1%, P < 0.001), NAb positivity (5.5 vs 83.5%, P < 0.001) and geometric mean titre (29.5 vs 215.8 AU/ml, P < 0.001), and 28 (17.1%) remained poor/non-responders. Patients with negative IgG after a fourth dose were more frequently under rituximab (P = 0.001). Negative NAb was associated with older age (P = 0.015), RA (P = 0.002), SSc (P = 0.026), LEF (P = 0.016) and rituximab use (P = 0.007). In multiple logistic regression analysis, prednisone dose ≥7.5 mg/day (OR = 0.34; P = 0.047), LEF (OR = 0.32, P = 0.036) and rituximab use (OR = 0.19, P = 0.022) were independently associated with negative NAb after the fourth vaccine dose. CONCLUSIONS: This is the largest study to provide evidence of a remarkable humoral response after the fourth dose of heterologous mRNA SARS-CoV-2 vaccination in ARD patients with poor/non-response to the third dose of an inactivated vaccine. We further identified that treatment, particularly rituximab and prednisone, impaired antibody response to this additional dose. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, CoronavRheum #NCT04754698.

Effect of an exercise bout before the booster dose of an inactivated SARS-CoV-2 vaccine on immunogenicity in immunocompromised patients.

This randomized controlled study aimed to investigate whether a single bout of exercise before the homologous booster dose of a SARS-CoV-2 inactivated vaccine could enhance immunogenicity in patients with spondyloarthritis. We selected 60 consecutive patients with spondyloarthritis (SpA). Patients assigned to the intervention group performed an exercise bout comprising three exercises. Then, they remained at rest for 1 h before vaccination. The control group remained at rest before vaccination. Immunogenicity was assessed before (Pre) and 1 mo after (Post) the booster using seropositivity rates of total anti-SARS-CoV-2 S1/S2 IgG, geometric mean titers of anti-S1/S2 IgG (GMT), frequency of neutralizing antibodies (NAb) positivity, and NAb activity. At Pre, 16 patients from the exercise group and 16 patients from the control group exhibited seropositivity for IgG (59% vs. 57.1%), and 1 mo after the booster dose, seropositivity occurred in 96% versus 100% of the cases. Only 10 patients from the exercise group and 12 patients from the control group showed positive NAb serology at Pre (37% vs. 42.8%). One month following the booster, NAb positivity was 96% versus 93%. GMT was comparable between groups at Pre. At Post, GMT increased similarly in both groups. Likewise, NAb activity was similar between groups at Pre and increased similarly in both of them as a result of the booster (47.5% vs. 39.9%). In conclusion, a single bout of exercise did not enhance immunogenicity to a homologous booster dose of an inactivated SARS-CoV-2 vaccine among patients with spondyloarthritis.NEW & NOTEWORTHY We tested the role of exercise as an adjuvant to a booster of a COVID-19 vaccine. Immunocompromised patients were immunized after an acute bout of exercise or not. Patients exhibited an excellent immunogenicity in response to the booster dose. Exercise did not add to the vaccine effects on IgG or neutralizing antibodies.

Predictors of progression to systemic sclerosis: analysis of very early diagnosis of systemic sclerosis in a large single-centre cohort.

OBJECTIVE: This study analysed the very early disease of SSc (VEDOSS) characteristics in a group of 217 patients with RP and at least one manifestation of SSc in search of predictors for the progression to SSc. METHODS: This was a cross-sectional single-centre analysis of patients presenting with RP with a specific SSc clinical manifestation or SSc autoantibody or SD pattern at nailfold capillaroscopy (SD-NFC), without skin involvement, who attended a scleroderma outpatient clinic between 2010 and 2019. The performance of VEDOSS and the importance of the combination of VEDOSS characteristics to predict the progression to SSc were evaluated. RESULTS: Among 217 patients, 153 (70.5%) were classified as SSc, including 65 (30%) in the first investigation; 69.3% of the SSc patients met VEDOSS criteria compared with 6.3% of patients who did not progress to SSc. The combinations most associated with progression to SSc were RP + puffy fingers (PF) + positive ANA + SD-NFC and/or SSc-specific antibody (VEDOSS level 2), with an odds ratio (OR) of 19.52 (95% CI 4.48, 85.06; P < 0.001) and RP + PF + positive ANA (VEDOSS level 1; 'red flags') (OR 15.45; P < 0.001), while combinations without non-RP clinical symptoms, as RP + SD-NFC (OR 0.03; P < 0.001) and RP + anticentromere + SD-NFC (OR 0.06; P = 0.006) were associated with non-progression to SSc. CONCLUSION: Among patients with RP with at least one manifestation of SSc, without skin involvement, combinations of VEDOSS characteristics were the strongest predictors of progression to SSc at a median follow-up of 4 years.

Immunogenicity and safety of two doses of the CoronaVac SARS-CoV-2 vaccine in SARS-CoV-2 seropositive and seronegative patients with autoimmune rheumatic diseases in Brazil: a subgroup analysis of a phase 4 prospective study.

BACKGROUND: We aimed to examine the immunogenicity pattern induced by the inactivated SARS-CoV-2 vaccine CoronaVac (Sinovac Life Sciences, Beijing, China) in SARS-CoV-2 seropositive patients with autoimmune rheumatic diseases compared with seropositive controls, seronegative patients with autoimmune rheumatic diseases, and seronegative controls. METHODS: CoronavRheum is an ongoing, prospective, controlled, phase 4 study, in which patients aged 18 years or older with autoimmune rheumatic diseases, and healthy controls were recruited from a single site (Rheumatology Division of Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo) in São Paulo, Brazil Participants were vaccinated with two doses of CoronaVac (intramuscular injection, 3 µg in 0·5 mL of ß-propiolactone inactivated SARS-CoV-2) on day 0 and on day 28. Blood samples were taken pre-vaccination on day 0, day 28, and also on day 69. For this subgroup analysis, participants were defined as being SARS-CoV-2 seropositive or seronegative prevaccination via anti-SARS-CoV-2 spike (S)1 or S2 IgG (cutoff of 15·0 arbitrary units [AU] per mL) or neutralising antibody titres (cutoff of ≥30%) and were matched for age and sex, via convenience sampling, in a 1:3:1:1 ratio (seropositive patients to seronegative patients to seropositive controls to seronegative controls). The primary outcomes were rates of anti-SARS-CoV-2 S1 and S2 IgG seropositivity and SARS-CoV-2 neutralising antibody positivity at day 28 and day 69 and immunogenicity dynamics assessed by geometric mean titres (GMTs) of IgG and median neutralising activity in seropositive patients with autoimmune rheumatic diseases compared with seronegative patients and seropositive and seronegative controls. We assessed safety in all participants randomly selected for this subgroup analysis. This study is registered with ClinicalTrials.gov, NCT04754698, and is ongoing for long-term immunogenicity evaluation. FINDINGS: Between Feb 4 and Feb 8, 2021, 1418 patients and 542 controls were recruited, of whom 1685 received two vaccinations (1193 patients and 492 controls). After random sampling, our immunogenicity analysis population comprised 942 participants, of whom 157 were SARS-CoV-2 seropositive patients with autoimmune rheumatic diseases, 157 were seropositive controls, 471 were seronegative patients, and 157 were seronegative controls; the median age was 48 years (IQR 38-56) and 594 (63%) were female and 348 (37%) were male. For seropositive patients and controls, an increase in anti-SARS-CoV-2 S1 and S2 IgG titres (seropositive patients GMT 52·3 [95% CI 42·9-63·9] at day 0 vs 128·9 [105·6-157·4] at day 28; seropositive controls 53·3 [45·4-62·5] at day 0 vs 202·0 [174·8-233·4] at day 28) and neutralising antibody activity (seropositive patients 59% [IQR 39-83] at day 0 vs 82% [54-96] at day 28; seropositive controls 58% [41-79] at day 0 vs 92% [79-96] at day 28), was observed from day 0 to day 28, without further increases from day 28 to day 69 (at day 69 seropositive patients' GMT was 137·1 [116·2-161·9] and neutralising antibody activity was 79% [57-94]); and seropositive controls' GMT was 188·6 [167·4-212·6] and neutralising antibody activity was 92% [75-96]). By contrast, for seronegative patients and controls, the second dose was required for maximum response at day 69, which was lower in seronegative patients than in seronegative controls. GMTs in seronegative patients were 2·3 (95% CI 2·2-2·3) at day 0, 5·7 (5·1-6·4) at day 28, and 29·6 (26·4-33·3) at day 69, and in seronegative controls were 2·3 (2·1-2·5) at day 0, 10·6 (8·7-13·1) at day 28, and 71·7 (63·5-81·0) at day 69; neutralising antibody activity in seronegative patients was 15% (IQR 15-15) on day 0, 15% (15-15) at day 28, and 39% (15-65) at day 69, and in seronegative controls was 15% (15-15) at day 0, 24% (15-37) at day 28, and 61% (37-79) at day 69. Neither seronegative patients nor seronegative controls reached the GMT or antibody activity levels of seropositive patients at day 69. INTERPRETATION: By contrast with seronegative patients with autoimmune rheumatic diseases, seropositive patients have a robust response after a single dose of CoronaVac. Our findings raise the possibility that the reduced immunogenicity observed in seronegative patients might not be the optimum response potential to SARS-CoV-2 vaccination, and therefore emphasise the importance of at least a single booster vaccination in these patients. FUNDING: Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, and B3-Bolsa de Valores do Brasil. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

Acometimento da função ventricular direita em pacientes com esclerose sistêmica e doença pulmonar intersticial: avaliação pelo doppler tecidual / Impairment of right ventricular function in patients with systemic sclerosis and interstitial lung disease: tissue doppler evaluation

Introdução: A esclerose sistêmica (ES) é uma doença autoimune do tecido conjuntivo que cursa com fibrose e disfunção microvascular. O envolvimento dos órgãos viscerais, incluindo os pulmões e o coração, é a principal causa de óbito na ES. Nesse contexto, analisamos a relação entre os parâmetros ventriculares direitos (VD) pela ecocardiografia com Doppler tecidual e o acometimento pulmonar em pacientes com ES. Métodos: Os pacientes que preencheram os Critérios de Classificação da ES de 2013 foram submetidos à ecocardiografia com Doppler tecidual para avaliação da função sistólica (fração de ejeção) ventricular esquerda (VE), enquanto a função sistólica do VD foi avaliada por meio da fração de variação de área do VD (fractional area change ­ FAC), velocidade (sistólica) do Doppler tecidual, índice de desempenho miocárdico (IDM) e excursão sistólica do plano anular tricúspide (TAPSE). A pressão sistólica pulmonar foi estimada por insuficiência tricúspide. A tomografia computadorizada de alta resolução (TCAR) de tórax avaliou a presença de fibrose pulmonar. De acordo com os resultados da TCAR, os pacientes foram divididos em 2 subgrupos: Grupo I, incluindo pacientes com fibrose pulmonar (n=26), e Grupo II sem fibrose (n=17). Resultados: Entre os 43 pacientes com ES, a maioria era do sexo feminino (86%) com idade de 51±12 anos. Todos os pacientes apresentavam função ventricular sistólica normal, avaliada pela FEVE>55% e FAC VD>35%. Não houve diferença significativa em termos de idade ou duração da doença para os grupos. Exceto pela diminuição das velocidades do Doppler tecidual em pacientes com fibrose pulmonar, todos os índices de desempenho do VD foram semelhantes. Conclusão: Em pacientes com ES e fibrose pulmonar, o Doppler tecidual identifica acometimento miocárdico longitudinal precoce do VD, apesar do desempenho sistólico radial preservado do VD.(AU)

Introduction: Systemic sclerosis (SSc) is an autoimmune tissue connective disease that courses with fibrosis and microvascular dysfunction. Involvement of the visceral organs, including the lungs and heart, is the main cause of death among patients with SSc. In this context, here we analyzed the relationship between right ventricle (RV) parameters assessed by tissue Doppler echocardiography and lung involvement in patients with SSc. Methods: Patients fulfilling the 2013 SSc Classification Criteria underwent tissue Doppler echocardiography for the assessment of left ventricular (LV) systolic function (ejection fraction) and RV fractional area change (FAC), tissue Doppler s' (systolic) velocity, myocardial performance index, and tricuspid annular plane systolic excursion for the assessment of RV systolic function. Pulmonary systolic pressure was estimated using tricuspid regurgitation. Chest high-resolution computed tomography was used to evaluate the presence of pulmonary fibrosis. The patients were divided into two subgroups accordingly: Group I, patients with pulmonary fibrosis (n=26); and Group II, those without fibrosis (n=17). Results: Among the 43 patients with SSc, most were female (86%), and the mean age was 51 ± 12 years. All patients had normal systolic ventricular function as evidenced by an LV ejection fraction > 55% and an RV FAC > 35%. No significant intergroup difference was noted in age or disease duration. Except for a decreased tissue Doppler s' velocity in patients with lung fibrosis, all indexes of RV performance were similar. Conclusion: In patients with SSc and pulmonary fibrosis, tissue Doppler identified early RV longitudinal myocardial involvement despite preserved RV radial systolic performance.(AU)

Immunogenicity and safety of the CoronaVac inactivated vaccine in patients with autoimmune rheumatic diseases: a phase 4 trial.

CoronaVac, an inactivated SARS-CoV-2 vaccine, has been approved for emergency use in several countries. However, its immunogenicity in immunocompromised individuals has not been well established. We initiated a prospective phase 4 controlled trial (no. NCT04754698, CoronavRheum) in 910 adults with autoimmune rheumatic diseases (ARD) and 182 age- and sex-frequency-matched healthy adults (control group, CG), who received two doses of CoronaVac. The primary outcomes were reduction of ≥15% in both anti-SARS-CoV-2 IgG seroconversion (SC) and neutralizing antibody (NAb) positivity 6 weeks (day 69 (D69)) after the second dose in the ARD group compared with that in the CG. Secondary outcomes were IgG SC and NAb positivity at D28, IgG titers and neutralizing activity at D28 and D69 and vaccine safety. Prespecified endpoints were met, with lower anti-SARS-Cov-2 IgG SC (70.4 versus 95.5%, P < 0.001) and NAb positivity (56.3 versus 79.3%, P < 0.001) at D69 in the ARD group than in the CG. Moreover, IgG titers (12.1 versus 29.7, P < 0.001) and median neutralization activity (58.7 versus 64.5%, P = 0.013) were also lower at D69 in patients with ARD. At D28, patients with ARD presented with lower IgG frequency (18.7 versus 34.6%, P < 0.001) and NAb positivity (20.6 versus 36.3%, P < 0.001) than that of the CG. There were no moderate/severe adverse events. These data support the use of CoronaVac in patients with ARD, suggesting reduced but acceptable short-term immunogenicity. The trial is still ongoing to evaluate the long-term effectiveness/immunogenicity.

Is exposure to environmental factors associated with a characteristic clinical and laboratory profile in systemic sclerosis? A retrospective analysis.

To identify environmental factors (EF) in a large cohort of patients with systemic sclerosis (SSc) analyzing their clinical and laboratory presentation. A cohort of consecutive patients attended at a single Brazilian SSc outpatient clinic was analyzed regarding EF. Data were analyzed according to clinical, demographic and laboratory characteristics, as well as SSc subtype. In a cohort of 662 patients, 70 (10.6%) had known previous exposure to EF, predominantly organic solvents (51.4%), silica (20%), silicone (12.9%) and pesticides (11.4%). In the SSc cohort, patients with EF had a significantly higher frequency of male gender (p < 0.01), African-Brazilian ethnicity (p = 0.01), myopathy (p = 0.02), and pigmentary disorders (p = 0.04), with shorter disease duration (p = 0.01). When SSc subtypes were analyzed separately, there was positive association with male gender in limited (p < 0.01) and diffuse (p < 0.01) SSc, as well as African-Brazilian ethnicity (p = 0.04), severe interstitial lung disease (p < 0.01), myopathy (p = 0.02) and SD pattern at nailfold capillaroscopy (p = 0.01) in limited SSc, and negative association with esophageal hypomotility (p < 0.01) and ANA positivity (p = 0.02) in diffuse SSc. Multiple regression analyses showed that myopathy was independently associated with previous exposure to EF (OR = 2.09; 95% CI 1.15-3.82), especially silica exposure (OR = 3.09; 95% CI 1.67-5.73). This study showed that SSc patients with previous exposure to EF may have some specific clinical characteristics, mainly a higher frequency of myopathy, also showing more severe ILD, preferably in male and African-Brazilian patients, associated with a lower frequency of ANA positivity.

Clinical and laboratory features of African-Brazilian patients with systemic sclerosis.

OBJECTIVE: African-Brazilians comprise a group of blacks and "pardos." As racial differences can be associated with distinct presentations, we evaluated the clinical and serological associations of African-Brazilians with systemic sclerosis (SSc). METHODS: Sera from 260 adult SSc patients (203 whites and 57 African-Brazilians) were evaluated. Patients with overlap syndromes were excluded. Clinical and demographic data were obtained from an electronic register database. Laboratory analysis included the following: anti-CENP-A/CENP-B, Scl70, RNA polymerase III, Ku, fibrillarin, Th/To, PM-Scl75, and PM-Scl100 by line immunoassay and anti-nuclear antibodies (ANA) by indirect immunofluorescence (IIF) on HEp-2 cells. RESULTS: African-Brazilian SSc patients presented shorter disease duration (12.8 ± 6.5 vs. 15.9 ± 8.1 years, p = 0.009), higher frequency of nucleolar ANA pattern (28% vs. 13%, p = 0.008), and lower frequencies of centromeric ANA pattern (14% vs. 29%, p = 0.026) and CENP-B (18% vs. 34%, p = 0.017), as well as an association with severe interstitial lung disease (58% vs. 43%; p = 0.044). Further comparison of ethnic groups according to subsets revealed that diffuse SSc African-Brazilian patients presented higher frequency of pulmonary hypertension (p = 0.017), heart involvement (p = 0.037), nucleolar ANA pattern (p = 0.036), anti-fibrillarin antibodies (p = 0.037), and higher mortality (48% vs. 19%; p = 0.009). A different pattern was observed for the limited subset with solely a lower frequency of esophageal involvement (p = 0.050) and centromeric ANA pattern (p = 0.049). Survival analysis showed that African-Brazilians had a higher mortality, when adjusted for age, gender, and clinical subset (RR 2.06, CI 95% 1.10-3.83, p = 0.023). CONCLUSION: African-Brazilians have distinct characteristics according to clinical subset and an overall more severe SSc than whites, similar to the blacks from other countries.Key Points • African-Brazilian SSc patients were associated with severe interstitial lung disease and nucleolar ANA pattern when compared to white SSc patients. • When disease subsets were considered, African-Brazilian patients with diffuse SSc presented association with pulmonary hypertension, heart involvement, nucleolar ANA pattern, and anti-fibrillarin antibodies. • White SSc patients were associated with centromeric ANA pattern. • Survival analysis at 5, 10, 15, and 20 years, adjusted for age, gender, and disease subset, was significantly worse in African-Brazilian SSc patients.

Proposition of a novel animal model of systemic sclerosis induced by type V collagen in C57BL/6 mice that reproduces fibrosis, vasculopathy and autoimmunity.

BACKGROUND: Type V collagen (Col V) has the potential to become an autoantigen and has been associated with the pathogenesis of systemic sclerosis (SSc). We characterized serological, functional, and histopathological features of the skin and lung in a novel SSc murine model induced by Col V immunization. METHODS: Female C57BL/6 mice (n = 19, IMU-COLV) were subcutaneously immunized with two doses of Col V (125 µg) emulsified in complete Freund adjuvant, followed by two intramuscular boosters. The control group (n = 19) did not receive Col V. After 120 days, we examined the respiratory mechanics, serum autoantibodies, and vascular manifestations of the mice. The skin and lung inflammatory processes and the collagen gene/protein expressions were analyzed. RESULTS: Vascular manifestations were characterized by endothelial cell activity and apoptosis, as shown by the increased expression of VEGF, endothelin-1, and caspase-3 in endothelial cells. The IMU-COLV mice presented with increased tissue elastance and a nonspecific interstitial pneumonia (NSIP) histologic pattern in the lung, combined with the thickening of the small and medium intrapulmonary arteries, increased Col V fibers, and increased COL1A1, COL1A2, COL3A1, COL5A1, and COL5A2 gene expression. The skin of the IMU-COLV mice showed thickness, epidermal rectification, decreased papillary dermis, atrophied appendages, and increased collagen, COL5A1, and COL5A2 gene expression. Anti-collagen III and IV and ANA antibodies were detected in the sera of the IMU-COLV mice. CONCLUSION: We demonstrated that cutaneous, vascular, and pulmonary remodeling are mimicked in the Col V-induced SSc mouse model, which thus represents a suitable preclinical model to study the mechanisms and therapeutic approaches for SSc.

Acroosteolysis and bone metabolism parameters distinguish female patients with limited systemic sclerosis with and without calcinosis: a case control study.

Calcinosis usually represents a late manifestation of systemic sclerosis (SSc), inducing tissue damage and chronic calcifications. To analyze clinical and bone metabolism parameters associated with calcinosis in limited systemic sclerosis (lSSc), thirty-six female lSSc patients with calcinosis were compared with 36 female lSSc patients without calcinosis, matched by age, disease duration, and body mass index. Organ involvement, autoantibodies, bone density, and laboratory parameters were analyzed. Statistical significance was considered if p < 0.05. Calcinosis was significantly associated with acroosteolysis (69% vs. 22%, p < 0.001), higher modified Rodnan skin score (mRSS 4.28 ± 4.66 vs. 1.17 ± 2.50, p < 0.001), and higher 25-hydroxyvitamin D (25OHD) (24.46 ± 8.15 vs. 20.80 ± 6.60 ng/ml, p = 0.040) and phosphorus serum levels (3.81 ± 0.41 vs. 3.43 ± 0.45 mg/dl, p < 0.001). 25OHD levels > 30 ng/ml were also significantly more frequent in patients with calcinosis (p = 0.041). Regarding treatment, current use of corticosteroids was lower in patients with calcinosis compared with patients without calcinosis (8% vs. 28%, p = 0.032). On logistic regression analysis, acroosteolysis (OR = 12.04; 95% CI, 2.73-53.04; p = 0.001), mRSS (OR = 1.37; 95% CI, 1.11-1.69; p = 0.003), phosphorus serum levels (OR = 5.07; 95% CI, 1.06-24.23; p = 0.042), and lower glucocorticoid use (OR = 0.07; 95% CI, 0.007-0.66; p = 0.021) are independent risk factors for calcinosis. This study showed that limited SSc patients with calcinosis present a distinct clinic and biochemical profile when compared with a matched group without calcinosis, paired by disease duration, age and BMI. KEY POINTS: • Calcinosis in patients with limited SSc was associated with acroosteolysis, higher mRSS and higher serum levels of phosphorus.

Systemic sclerosis induced by the use of cocaine: is there an association?

The association between cocaine abuse and systemic sclerosis (SSc) is rarely described. Two new cases of this association are presented: two young adults, after using inhaled cocaine for a few years, were diagnosed with SSc. While a 24 year-old white female patient presented with diffuse SSc with multiple digital ulcers and scleroderma renal crisis (SRC), a 27 year-old male patient presented limited SSc with skin ulcers and digital gangrene, rapidly evolving to death due to massive intestinal hemorrhage. The authors performed a literature search and found only eight previously published cases. The clinical picture of these patients shows a predominance of vascular involvement, including multiple ulcers and SRC. There is no association with specific SSc autoantibodies. The concomitance of alcohol and other drugs abuse, as well as the presence of drug adulterers, complicates a clear understanding of the role of cocaine in SSc patients.

Clinical and laboratory profile of juvenile-onset systemic sclerosis in a Brazilian cohort.

Objective: To characterize the clinical and laboratory profile of juvenile-onset compared to adult-onset systemic sclerosis in a large Brazilian cohort. Methods: Retrospective analysis of a cohort of 1016 systemic sclerosis patients followed at the Scleroderma Outpatient Clinic from two referral university centers in Brazil. Patients were classified as systemic sclerosis according to the 1980 American College of Rhaumatology (ACR) criteria. Juvenile-onset systemic sclerosis was defined if age at onset was <16 years. Results: Thirty-one (3.1%) patients were classified as juvenile-onset systemic sclerosis. These patients were predominantly females (90.3%), Caucasians (71.0%), and presented diffuse systemic sclerosis (51.6%), with mean age at onset of 12.71 years. Compared to the adult-onset patients, juvenile onset was associated with diffuse systemic sclerosis (p < 0.001), calcinosis (p < 0.001), myositis (p = 0.050), and lower frequency of interstitial lung disease (p = 0.050), pulmonary hypertension (p = 0.035), and esophageal (p = 0.005) involvement. Conclusion: Juvenile-onset systemic sclerosis characterized a distinct clinical pattern in this large series of systemic sclerosis patients, since it was predominantly associated with diffuse systemic sclerosis without significant organ involvement.

Factors associated with ASDAS remission in a long-term study of ankylosing spondylitis patients under tumor necrosis factor inhibitors.

OBJECTIVE: To determine the clinical and demographic factors associated with disease remission and drug survival in patients with ankylosing spondylitis (AS) on TNF inhibitors. METHODS: Data from a longitudinal electronic database of AS patients under anti-TNF therapy between June/2004 and August/2013. Demographic, clinical parameters, disease activity by ASDAS remission (< 1.3) and inactive/low (< 2.1) were analyzed to characterize reasons for drug survival and switching of anti-TNF. RESULTS: Among 117 AS patients, 69 (59%) were prescribed only one anti-TNF, 48 (41%) switched to a second anti-TNF and 13 (11%) to a third anti-TNF. Considering ASDAS-CRP < 1.3, 31 (39%) patients were inactive at the end of the study. Non-switchers (P = 0.04), younger age (P = 0.004), non-smoking (P = 0.016), shorter disease duration (P = 0.047), more frequent use of SSZ (P = 0.037) and lower BASDAI (P = 0.027), BASMI (P = 0.034) and BASFI (P = 0.003) at baseline were associated with remission. In the multivariate analysis younger age (P = 0.016) and lower BASDAI (P = 0.032) remained as remission predictors. CONCLUSION: This study supports that ASDAS-CRP remission is an achievable goal not only for non-switchers but also for second anti-TNF, particularly in patients with younger age and lower BASDAI at baseline. Co-medication and non-smoker status seems to have a beneficial effect in anti-TNF response in this population.

Pandemic non-adjuvanted influenza A H1N1 vaccine in a cohort of patients with systemic sclerosis.

Objective: To assess the possible effect of therapy, disease subtype and severity on H1N1 immunogenicity in patients with SSc. Methods: Ninety-two patients and 92 age- and gender-matched healthy controls received adjuvant-free influenza A/California/7/2009 (pH1N1) vaccine. Blood samples were collected immediately before and 3 weeks after vaccination to evaluate antibody responses to the H1N1 virus. Efficacy was assessed by seroprotection (SP) and seroconversion (SC) rates and the factor increase in geometric mean antibody titre. Participants received a 21-day symptom diary card and were instructed to report local and systemic adverse events. Results: SSc patients were predominantly females (91%) and 61% had limited SSc, 12% had severe skin involvement and 57.6% were on immunosuppressive (IS) therapy. SSc patients and controls presented comparable overall SP (P = 0.20) and SC (P = 0.61) rates. Further evaluation of the possible effect of disease and therapy revealed similar rates of SP and SC in patients with dcSSc vs lcSSc (SP P = 0.62 and SC P = 0.66), severe vs mild/moderate skin involvement (SP P = 1 and SC P = 0.45) and with vs without IS (SP P = 0.26 and SC P = 0.10). The frequency of mild local and minor systemic reactions was similar in patients with dcSSC vs lcSSc (P = 0.70 vs 0.32) and in those with and without severe skin involvement (P = 0.59 vs 0.28). Conclusion: The non-adjuvanted influenza H1N1 virus vaccine proved to be safe and effective, independent of SSc clinical subtype, disease severity or therapy. These latter factors do not seem to contribute to mild adverse events observed in SSc. Our data support the annual influenza vaccination recommendation for these patients. Trial registration: ClinicalTrials.gov (http://clinicaltrials.gov), NCT01151644.