Can subcutaneous treprostinil be an alternative for treating pulmonary hypertension in patients with systemic sclerosis-related interstitial lung disease?

Pulmonary hypertension (PH) is one of the most feared complications of systemic sclerosis (SSc). There are currently specific drugs approved for PH group I (pulmonary arterial hypertension - PAH), but for PH related to lung disease (group III) the use of vasodilators is still controversial and not routinely recommended in patients with non-severe PH. However, SSc-PH-interstitial lung disease (ILD) has a poorer survival compared with SSc-PAH, making the management of these patients a challenge, ideally carried out in a reference centre. Herein we report the case of a a 45-year-old female with systemic sclerosis-myositis overlap syndrome, with documented lung involvement (ILD with fibrotic nonspecific interstitial/organizing pneumonia pattern), who was diagnosed with pre-capillary PH. She started sequential combination vasodilator therapy including parenteric prostanoid, with clinical benefit and without evidence of ILD worsening.

Effectiveness of switching between TNF inhibitors in patients with axial spondyloarthritis: is the reason to switch relevant?

BACKGROUND: To investigate whether the reason to discontinue the first TNF inhibitor (TNFi) affects the response to the second TNFi in axial spondyloarthritis (axSpA). METHODS: Patients with axSpA from the Rheumatic Diseases Portuguese Register (ReumaPt), who discontinued their first TNFi and started the second TNFi between June 2008 and May 2018, were included. Response was assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS) clinically important improvement (ASDAS-CII), major important improvement (ASDAS-MI), low disease activity (ASDAS-LDA), and inactive disease (ASDAS-ID). The reason for discontinuation of the first TNFi was defined, according to ASDAS-CII as primary failure (no response ≤ 6 months), secondary failure (response ≤ 6 months but lost thereafter), adverse events, and others. The association between the reason for discontinuation of the first TNFi and response to the second TNFi over time was assessed in multivariable generalized equation (GEE) models. RESULTS: In total, 193 patients were included. The reason for discontinuation of the first TNFi did not influence the response to the second TNFi, according to the ASDAS-CII. However, a difference was found with more stringent outcomes, e.g., there was a higher likelihood to achieve ASDAS-ID with the second TNFi for patients discontinuing the first TNFi due to secondary failure (OR 7.3 [95%CI 1.9; 27.7]), adverse events (OR 9.1 [2.5; 33.3]), or other reasons (OR 7.7 [1.6; 37.9]) compared to primary failure. CONCLUSION: Patients with axSpA with secondary failure to their first TNFi, compared to those with primary failure, have a better response to the second TNFi according to stringent outcomes.

Eligibility criteria for biologic disease-modifying antirheumatic drugs in axial spondyloarthritis: going beyond BASDAI.

OBJECTIVES: To compare definitions of high disease activity of the Ankylosing Spondylitis Disease Activity Score (ASDAS) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in selecting patients for treatment with biologic disease-modifying antirheumatic drugs (bDMARDs). METHODS: Patients from Rheumatic Diseases Portuguese Register (Reuma.pt) with a clinical diagnosis of axial spondyloarthritis (axSpA) were included. Four subgroups (cross-tabulation between ASDAS (≥2.1) and BASDAI (≥4) definitions of high disease activity) were compared regarding baseline characteristics and response to bDMARDs at 3 and 6 months estimated in multivariable regression models. RESULTS: Of the 594 patients included, the majority (82%) had both BASDAI≥4 and ASDAS ≥2.1. The frequency of ASDAS ≥2.1, if BASDAI<4 was much larger than the opposite (ie, ASDAS <2.1, if BASDAI≥4): 62% vs 0.8%. Compared to patients fulfilling both definitions, those with ASDAS ≥2.1 only were more likely to be male (77% vs 51%), human leucocyte antigen B27 positive (79% vs 65%) and have a higher C reactive protein (2.9 (SD 3.5) vs 2.1 (2.9)). Among bDMARD-treated patients (n=359), responses across subgroups were globally overlapping, except for the most 'stringent' outcomes. Patients captured only by ASDAS responded better compared to patients fulfilling both definitions (eg, ASDAS inactive disease at 3 months: 61% vs 25% and at 6 months: 42% vs 25%). CONCLUSION: The ASDAS definition of high disease activity is more inclusive than the BASDAI definition in selecting patients with axSpA for bDMARD treatment. The additionally 'captured' patients respond better and have higher likelihood of predictors thereof. These results support using ASDAS≥2.1 as a criterion for treatment decisions.

Antifibrotics in interstitial lung disease related to connective tissue diseases - a paradigm shift in treatment and outcome.

Interstitial lung disease (ILD) is one of the major causes of morbidity and mortality in patients with connective tissue disease (CTD) and the treatments available until nowadays are in most cases unable to halt disease progression. CTD-ILD pathogenesis includes an initial inflammatory phase, followed by a fibrotic phase, in which extracellular matrix proteins are produced and fibrotic scaring tissue within the lung develops. Steroids and immunosuppressants are the weapons we currently have to treat CTD-ILD. However, mortality rates remain high and identification of new therapeutic targets is crucial. Antifibrotic drugs, which include nintedanib and pirfenidone, have been approved for the treatment of idiopathic pulmonary fibrosis (IPF) and due to similar pathogenesis between IPF and CTD-ILD, their use seems attractive in patients with CTD-IL. We report 3 cases of patients with different CTDs, with predominantly fibrotic changes in high resolution computed tomography that progressed despite immunosuppression, and who have attained disease stability after introduction of antifibrotic drugs.

Safety of Etanercept in the treatment of rheumatic disease patients with Hepatitis C virus infection.

Hepatitis C virus (HCV) infection is a major public health problem. Because Tumour Necrosis Factor (TNF) seems to have an important role in immune response to HCV infection, suppression by TNFi (TNF inhibitors) may pose a potential worsening of chronic HCV infection. We report our experience with 3 cases of patients with chronic HCV infection and advanced liver disease, with different Rheumatic diseases, treated with a TNFi, etanercept (ETN), for a period ranging from 4 months to 4 years without hepatitis C treatment and, in two of them, concomitant therapy with direct-acting antiviral agents (DAA) and afterwards. Although increasing number of clinical reports support the short-term safety and efficacy of TNFi in patients with HCV, some uncertainties remain regarding long-term. These cases suggests that the risk of HCV reactivation related to TNFi remains low even without concomitant antiviral therapy. Nevertheless, a strict collaboration between rheumatologists and gastroenterologists/hepatologists. Our results also showed a good tolerance and efficacy when used concomitantly the new direct-acting antivirals drugs with ETN.

PORTUGUESE RECOMMENDATIONS FOR THE USE OF BIOLOGICAL THERAPIES IN PATIENTS WITH PSORIATIC ARTHRITIS--2015 UPDATE.

OBJECTIVE: To update recommendations for the treatment of psoriatic arthritis with biological therapies, endorsed by the Portuguese Society of Rheumatology (SPR). METHODS: These treatment recommendations were formulated by Portuguese rheumatologists based on literature evidence and consensus opinion. At a national meeting the 16 recommendations included in this document were discussed and updated. The level of agreement among Portuguese Rheumatologists was assessed using an online survey. A draft of the full text of the recommendations was then circulated and suggestions were incorporated. A final version was again circulated before publication. RESULTS: A consensus was achieved regarding the initiation, assessment of response and switching biological therapies in patients with psoriatic arthritis (PsA). Specific recommendations were developed for several disease domains: peripheral arthritis, axial disease, enthesitis and dactylitis. CONCLUSION: These recommendations may be used for guidance in deciding which patients with PsA should be treated with biological therapies. They cover a rapidly evolving area of therapeutic intervention. As more evidence becomes available and more biological therapies are licensed, these recommendations will have to be updated.

Biologicals and switch in rheumatoid arthritis throughout time - are we being more aggressive?

OBJECTIVES: To investigate the switches performed in patients with rheumatoid arthritis under biological therapy and specifically comparing the switches from earlier days with more recent switches. PATIENTS AND METHODS: Patients with rheumatoid arthritis under biological therapy followed at Hospital Garcia de Orta, Almada, and included in the Rheumatic Diseases Portuguese Register (Reuma.Pt) were included in this study. Switches occurring before and after January 2007 were compared with respect to patients' demographic and clinical characteristics, such as disease activity and duration of biological therapy. The survival of the first biological agent was compared between patients starting biological therapy before and after 2007. EULAR response and remission rate at the last evaluation were calculated. Comparisons between groups were established using a t-test or chi--square, as appropriate. Survival curves of the first biological were compared through the logrank test. RESULTS: In total, 123 patients were included in the analysis (mean age 57.0 ± 13.1 years and mean disease duration 11.7 ± 8.0 years). A total of 85 switches were documented, 20% of which took place before 2007. Comparing the switches before and after 2007, the latter were registered among older patients (recent switches 56.2 ± 12.9 years vs older switches 48.9 ± 11.0 years, p=0.04) and with a shorter duration of the first biological agent (recent switches 461.9 ± 293.2 days vs older switches 773.7 ± 475.8 days, p=0.03). No further significant differences were found, including the disease activity. The survival of the first biological was shorter in patients starting biological therapy after 2007 (2949 days for biological onset before 2007 and 818 days for onset after 2007, p <0.001). A good EULAR response was achieved by 19% and 30% of the patients, before and after 2007, respectively (p = 0.23). Remission was achieved by 14% and 22% of the patients, before and after 2007, respectively (p = 0.30). CONCLUSIONS: Switches were more frequently performed in more recent years, in older patients and with a shorter duration of biological therapy. A trend towards a better and more targeted control of the disease could be discussed in light of our results. Although switches were more frequently performed in more recent years, in older patients and with a shorter duration of biological therapy, there is still room for improvement when aiming at remission, for example by applying a tighter therapy strategy like the "treat to target model".

[Practical guide for the use of biological agents in rheumatoid arthritis - December 2011 update]. / Guia prático de utilização de terapêuticas biotecnológicas na artrite reumatóide - actualização de Dezembro 2011.

The authors review the practical aspects of biological therapy use for rheumatoid arthritis patients, commenting safety issues before and after treatment initiation and the best treatment strategies to optimize efficacy.

Cardiovascular risk profile in systemic lupus erythematosus and rheumatoid arthritis: a comparative study of female patients.

OBJECTIVE: Premature atherosclerosis is well-documented both in Systemic Lupus Erythematosus (SLE) and in Rheumatoid Arthritis (RA) patients, but cardiovascular (CV) risk is particularly high in lupus women. Although conventional CV risk factors do not fully explain the excessive risk in inflammatory diseases, they remain major contributors to atherosclerosis. The aim of the present study was to investigate whether CV risk factors are differentially associated with SLE and RA. METHODS: One hundred women with SLE, 98 with RA and 102 controls matched on age and without overt CV or renal disease were assessed for the presence of Framingham (hypertension, hypercholesterolemia, low HDL, diabetes, smoking) and other CV risks (atherogenic index of plasma (AIP), insulin resistance, obesity, central obesity, metabolic syndrome, uric acid, sedentarism, hypothyroidism and family history of premature CV disease). RESULTS: Modifiable CV risk factors are highly prevalent and occur more frequently in SLE and RA than in age-matched controls. Some differences in Framingham risk factors were found between SLE and RA, with hypertension being more common in young lupus women, hypercholesterolemia more frequent in RA and low HDL-C more frequent in SLE. However, the estimated 10-year Framingham CHD risk or the Reynolds Risk Score was comparable in both diseases. Although hypercholesterolemia was more frequent in RA, lupus women display a more atherogenic lipid profile, with significantly lower HDL-C levels (56.5±16 mg/dl versus 63.7±18; p=0.005), and more cases above the high risk cutpoints for cholesterol/HDL-C (14% versus 4.1%; p=0.01) and for AIP (15% versus 6.1%; p=0.03). Also, uric acid levels are higher in SLE women (4.8±1.5 mg/dl) than in RA (4.1±1.1 mg/dl), p=0.001. On the other hand, insulin resistance is significantly higher in women with RA as compared with SLE (median HOMA-IR 3.5 [6.4]) versus 0.72 [2.5]; p<0.0001) and the difference remained significant after adjustment for BMI and corticosteroids. CONCLUSIONS: Cardiovascular risk profile is distinct in SLE and RA women and the contribution of traditional CV risk factors to atherogenesis may be different in these two diseases. Prospective studies are necessary to understand how the control of modifiable risks can improve CV outcome in different inflammatory settings.

Predictors of damage progression in Portuguese patients with systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) have a longer life expectancy. The occurrence of irreversible damage has become a major concern. The present study assessed damage progression in patients with SLE over a 2-year period and identified baseline features associated with damage accrual. Two hundred and twenty-one patients that fulfilled criteria for SLE and had a follow-up longer than 6 months were enrolled. Demographic, clinical, and immunological data were collected at baseline. Accumulated organ damage was scored using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI). Patients were prospectively followed and SDI assessment repeated at 2 years. At baseline 72 patients (33%) presented some irreversible damage, and after 2 years 53 had accrued new damage. The mean SDI for the whole cohort increased from 0.582 to 0.980. Damage progression was higher in ocular, cardiovascular, and musculoskeletal systems. Older age [OR = 1.045; 95% confidence interval (CI) 1.021-1.069; P = 0.03], presence of antiphospholipid antibodies (OR = 3.047; 95% CI 1.169-7.941; P = 0.02), steroid use (OR = 6.401; 95% CI 1.601-25.210; P = 0.008), azathioprine use (OR = 3.501; CI 1.224-10.012; P = 0.01), and hypertension (OR = 3.825; 95% CI 1.490-9.820; P = 0.005) were predictors of damage progression in multivariate analysis. Overall SDI increased over time, with some systems being affected more frequently. Demographic and clinical characteristics, co-morbidity, and treatment options may contribute to irreversible damage. It is necessary to determine whether the control of modifiable factors (e.g., hypertension and judicious use of medications) might prevent damage progression in SLE patients.

[Flexibilization of infliximab dose interval in the treatment of ankylosing spondylitis]. / Flexibilização do Intervalo entre as Infusões de Infliximab no Tratamento dos Doentes com Espondilite Anquilosante.

OBJECTIVE: The aim of this study was to access the maintenance of therapeutic response in patients with ankylosing spondylitis (AS) receiving infliximab, after prolongation of the interval between infusions. MATERIAL AND METHODS: In AS patients with sustained therapeutic response to infliximab administered every six weeks, a prolongation of the interval between infusions was proposed. The therapeutic response was evaluated using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), pain, stiffness, patient's global evaluation and acute phase reactants (ESR and CPR). RESULTS: Twenty patients participated in the study. Sixteen were male, with a mean age of 40.3 +- 10.9 years and mean disease duration of 12 +- 9.4 years. The initial BASDAI was 59.5 +- 22.8 and initial BASFI 50.7 +- 27. The interval between infusions was lengthened to 8 +- 1 weeks (minimum 7; maximum 10) and this change occurred between 12 and 142 weeks (median 21) of treatment. The mean followup after changing the therapeutic regimen was 86 +- 45 weeks. Sixty-five percent (13/20) of the patients maintained an adequate response. CONCLUSIONS: Two thirds of AS patients with sustained therapeutic response to infliximab administrated every six weeks maintained an adequate response with prolongation of interval between infusions. Therefore the increase of the interval between infusions seems to be an adequate option in selected patients.

[Systemic lupus erythematosus and weakness]. / Lúpus eritematoso sistémico e fraqueza muscular.

We report a case of a 13-year old young girl, with Juvenile Systemic Lupus Erythematosus and recent onset of muscle weakness. Investigations lead to the diagnosis of Myasthenia Gravis. The most important causes of muscle weakness in lupus patients are discussed.