Can we predict the risk factors for switching due to ineffectiveness in the first year of therapy with bDMARD in patients with rheumatoid arthritis?

INTRODUCTION: Biological disease-modifying antirheumatic drugs (bDMARD) have improved the clinical course and quality of life of patients with rheumatoid arthritis (RA). However, some patients failed to respond or have an insufficient response to bDMARD early in the course of the treatment. OBJECTIVES: To determine the percentage of RA patients who need to switch due to ineffectiveness in the first year of treatment and to identify specific baseline features as possible predictors of switch due to ineffectiveness in the first year of treatment. MATERIALS AND METHODS: An observational retrospective study was conducted with patients with RA that started their first bDMARD. Demographic data, disease characteristics, disease activity data scores, laboratory parameters and treatment at baseline were collected. The proportion of patients who failed to respond and who switched to another bDMARD in the first year of treatment was calculated. RESULTS: A total of 437 (364 females, 83.3%) patients with RA were included. The majority of these patients started an anti-TNF-α agent (n=315, 72.1%). Forty-eight (11.0%) patients failed to respond to the bDMARD in the first year of treatment. There were significantly more current or former smokers (p=0.030), with a history of depression (p=0.003) and positive for RF at baseline (p=0.014) in the switch group. In the multivariate analysis, anti-TNF-α agents use (OR 8.3, 95% CI 2.4-28.8, p=0.001), tobacco exposure (OR 2.3, 95% CI 1.1-4.8, p=0.02) and history of depression (OR 3.1, 95% CI 1.3-7.7) seem to predict the need to switch in the first year of treatment due to ineffectiveness. DISCUSSION AND CONCLUSION: In our study, tobacco exposure and depression appear to be modifiable risk factors associated with early switching due to ineffectiveness. Addressing these factors in daily clinical practice is crucial to enhance the overall response to therapy and improve the well-being of patients.

Can microvascular damage predict disease severity in patients with systemic sclerosis?

INTRODUCTION: Systemic sclerosis (SSc) is characterized by progressive fibrosis of the skin and internal organs, microvascular damage and cellular and humoral immunity abnormalities. Microvascular damage can be easily detected through nailfold videocapillaroscopy (NVC). MATERIALS AND METHODS: A retrospective study of patients with SSc and a NVC performed within the first 6 months after diagnosis was conducted. Visceral involvement in the first 3 years of the disease and NVC findings were collected. The severity of microvascular damage was classified into four categories, according to the worsening of the NVC patterns. The severity of organ involvement was assessed by the disease severity scale of Medsger for each organ and as a global measure of disease severity, the simple summation was used. RESULTS: A total of 86 patients with SSc were included. A moderate correlation was found between the severity of microvascular damage and the global measure of disease severity (r=0.55, p<0.001), the severity of peripheral vascular involvement (r=0.43, p<0.001) and the severity of skin involvement (r=0.34, p=0.001). The presence of a late scleroderma pattern in NVC were predictive in univariate analysis of digital ulcers (OR 6.03, 95% CI 1.52-23.86, p=0.01), muscular involvement (OR 13.09, 95% CI 1.09-156.78, p=0.04), calcinosis (OR 27.22, 95% CI 5.56-133.33, p<0.001) and worse global disease severity score (OR 1.67, 95% CI 1.17-2.38, p=0.005). Multivariate analysis adjusted for disease duration and gender confirmed late pattern as an independent predictor of calcinosis (OR 42.89, 95% CI 5.53-332.85, p<0.001). DISCUSSION AND CONCLUSION: In this study, the worsening of NVC pattern in SSc was associated with the overall disease severity, the severity of peripheral vascular involvement and extension of skin involvement. This study highlights the importance of NVC as a prognostic tool and a possible predictor of systemic visceral involvement.

Measurement properties of the Portuguese version of the rheumatoid arthritis patient-reported experience measure (CQRA-PREM): a cross-sectional single center study.

AIMS: to test the measurement properties of the Portuguese version of the Commissioning for Quality in Rheumatoid Arthritis Patient-Reported Experience Measure (CQRA-PREM) for patients with rheumatoid arthritis (RA). METHODS: This cross-sectional clinical field study recruited adult patients with RA during rheumatology appointments of a Portuguese rheumatology center. Patients completed the Portuguese version of CQRA-PREM, composed of 7 domains and 24 questions. Sociodemographic characteristics, symptoms/disease duration, current treatment, Pain-Visual Analog Scale (VAS), Patient Global Assessment (PGA)-VAS and Health Assessment Questionnaire (HAQ) were also collected from the patient. Disease Activity Score for 28 joints with C-reactive Protein (DAS28-CRP) was recorded by the rheumatologist. The assessment of CQRA-PREM measurement properties followed the Consensus-based Standards for the Selection of Health Status Measurement Instruments (COSMIN) recommendations. RESULTS: A total of 61 patients with RA were included. The domains in which patients showed better experience were the "Needs and preferences", followed by "Coordination and Communication". The domain "Information, education and self-care" was an identified area of improvement for providing patient-centered care. Ceiling effects were found in four domains of the CQRA-PREM. Internal consistency of all domains was considered good (α>0.7). Homogeneity was considered good for each question in all domains analyzed (0.30≤rp≤0.70). The divergent validity of the PREM was good, revealing that the domains were not correlated (Pain-VAS, HAQ, DAS28-CRP) or only weakly (PGA-VAS) correlated with clinical outcomes. CONCLUSIONS: The CQRA-PREM showed acceptable measurement properties and is a useful tool for evaluating quality of healthcare provided in daily practice, as perceived by RA patients in Portugal.

Interobserver Reliability and Sensitivity to Change of a Composite Ocular Inflammatory Activity Index: UVEDAI©.

INTRODUCTION: This was a multicenter, prospective, longitudinal, observational study involving eight Spanish tertiary hospitals to determine the interobserver reliability of an uveitis disease activity index, (UVEDAI) and assess its sensitivity to change in patients with receiving pharmacologic treatment. METHODS: Patients aged ≥ 18 years diagnosed with active noninfectious uveitis were included. A complete baseline assessment was performed by two ophthalmologists who determined ocular inflammatory activity using the UVEDAI index independently of each other. The principal ophthalmologist made a new visit at 4 weeks to determine the change in inflammatory activity. The interobserver reliability analysis was performed by calculating the intraclass correlation coefficient (ICC), with the values of the variables and the UVEDAI obtained by both ophthalmologists in the more active eye at the baseline visit. Sensitivity to change in the UVEDAI index was assessed at 4 weeks from the start of pharmacologic treatment by determining the clinically relevant change, defined as a change in UVEDAI of ≥ 0.8 points over baseline. The mean change between both measures was compared using the repeated-measures t-test. RESULTS: A total of 111 patients were included. In the interobserver reliability analysis, the ICC for the UVEDAI value was 0.9, and, when compared with the mean UVEDAI values obtained by the ophthalmologists, no statistically significant differences were found (p value > 0.05). As for the sensitivity to change in UVEDAI, statistically significant differences (p value = 0.00) were found for the mean values of the index compared with baseline. In all cases, the index value decreased by > 1 point at the 4-week visit. CONCLUSIONS: The interobserver reliability of the UVEDAI was high in the total sample. Furthermore, the index was sensitive in determining the change in inflammatory activity after treatment. We believe that UVEDAI is a disease activity index that enables objective comparison of results in clinical practice and trials.

Neutrophile to lymphocyte and platelet to lymphocyte ratios predict clinical response to bDMARD in naïve spondylarthritis patients.

Objective: We aim to study association between neutrophile to lymphocyte (NLR) and platelet to lymphocyte (PLR) ratios and disease activity, and their value to predict bDMARD response. Methods: A set of spondylarthritis (SpA) patients under bDMARD registered in the Reuma.pt registry was studied. Sociodemographic, clinical and laboratorial variables were assessed on bDMARD initiation, 6, 12, 18 and 24 months (M) thereafter. Univariable and multivariable generalized estimation equations models assessed associations with disease activity. The NLR and PLR predictive value was assessed using univariable and multivariable logistic regression models. Results: A total of 170 patients were included. Most were male (54.7%), with a predominantly axial phenotype (84.7%). Significant associations were observed between NLR [B=1.55, 95% confidence interval (CI) = (1.38; 1.74)] and PLR [(B=1.16, 95% CI = (1.09; 1.24)] with ASDAS-CRP (p < 0.001). Both baseline ratios predicted ∆ ASDAS-CRP ≥ 1.1 at 6 months [OR = 2.20, 95% CI = (1.21, 4.00) for NLR; OR = 1.02, 95% CI = (1.01, 1.04) for PLR, p < 0.01)]. PLR was a significant predictor of ∆ ASDAS-CRP ≥ 1.1 in all timepoints [OR (12 M) = 1.02, 95% CI = (1.00, 1.03), p < 0.05; OR (18M) = 1.02, 95% CI = (1.01, 1.03), p < 0.001; OR (24M) = 1.01, 95% CI = (1.01, 1.02), p < 0.01]. Conclusion: NLR and PLR were associated with disease activity during the follow up of these patients. They seem to be significant predictors of therapeutic response to bDMARD in naïve SpA patients.

What is the association of depression with clinical response to therapy in patients with psoriatic arthritis treated with biologic disease-modifying antirheumatic drugs?

INTRODUCTION: Psoriatic arthritis (PsA) is a chronic, progressive inflammatory joint disease that is associated with higher prevalence of depression. There is limited literature about the impact of depression, particularly regarding the response to therapy. METHODS: A retrospective cohort study with PsA patients that started their first biologic disease-modifying antirheumatic drugs (bDMARD) was conducted. In the majority of cases, a cutoff score of ≥ 8 in Hospital Anxiety and Depression Scale (HADS) was used to define cases of depression. In cases where patients did not complete the questionnaire, a previous diagnosis made by a psychiatrist was used to establish the presence of depression. Response to therapy 12 months after the start of bDMARD was evaluated and the switch rate to another bDMARD due to inefficacy was assessed at month 12. RESULTS: A total of 129 patients (66 females, 51.2%; mean age of 47.7 ± 11.0 years and mean disease duration of 10.0 ± 7.7 years) with PsA were included. Thirty-two (24.8%) patients had depression. Patients with depression and peripheral involvement had a significantly lower ACR20/50/70 responses (p = 0.001, p = 0.002, and p = 0.001 respectively) after 12 months of therapy and a significantly worse EULAR response (p = 0.002). Furthermore, patients with depression and axial involvement had a significantly worse response based on ASDAS response criteria (p = 0.031). Switch due to ineffectiveness in the first 12 months was significantly higher in patients with depression (p = 0.002). CONCLUSION: Depression in PsA is a frequent yet often understudied comorbidity. The causal relationship between depression and PsA is difficult to decrypt and further research is needed. Recognition of depressive symptoms is crucial and a multidisciplinary approach should be provided to individuals with this comorbidity. Key Points • Depression in PsA is a frequent yet often understudied comorbidity. In our study, the prevalence of depression was 24.8%. • Depression in PsA seems to be associated to lower response to therapy and higher discontinuation rates of bDMARD. • Recognition of depressive symptoms is crucial and a multidisciplinary approach should be provided to individuals with this comorbidity.

Immune-mediated skin lesions related to biological disease-modifying antirheumatic drugs: a 22-year experience of a tertiary center.

INTRODUCTION: Immune-mediated skin lesions (IMSL) can be very disabling leading to treatment discontinuation. Although these lesions have rarely been previously described, the true incidence is unknown. OBJECTIVE: To explore the cumulative incidence, management and outcomes of IMSL related to bDMARD in a large cohort of patients with chronic inflammatory rheumatic diseases. To explore possible associations and risk factors for IMSL development. METHODS: A retrospective single-center study of patients with rheumatoid arthritis (RA), spondylarthritis (SpA) and psoriatic arthritis (PsA) that had been treated with at least one bDMARD for at least 6 months was conducted. IMSL related to bDMARD characteristics and outcomes were collected. RESULTS: A total of 989 patients with RA, SpA and PsA were included. Twenty-seven patients (2.7%) presented IMSL potentially related to bDMARD, being psoriasis the most common IMSL (n=12, 44.4%), followed by drug-induced lupus erythematosus (n=6), alopecia areata (n=3) and leukocytoclastic vasculitis (n=2). IMSL led to withdrawal of bDMARD in 18 of the 27 patients (66.7%). Patients with IMSL had younger age at diagnosis (p=0.038), longer disease duration (p=0.018), longer duration of bDMARD treatment (p=0.008), and higher number of previous bDMARDs (p < 0.001) than patients without IMSL. In the group of patients with IMSL there was a significantly higher percentage of patients treated with adalimumab (p < 0.001). In multivariate regression model, the number of previous bDMARDs (OR 2.13, 95%CI 1.47-3.10, p < 0.001) and treatment with adalimumab (OR 4.60, 95%CI 1.96-10.80 , p < 0.001) were statistically significant predictive factors for IMSL development. CONCLUSION: In our study, IMSL related to bDMARDs had an estimated cumulative incidence of 2.7%. Younger age at diagnosis, longer disease duration, longer duration of bDMARD treatment, higher number of previous bDMARDs and treatment with adalimumab were independently associated with an increased risk of IMSL development.

Content validity of a patient-reported experience measure (CQRA-PREM) for patients with rheumatoid arthritis in Portugal.

TBackground: The evaluation of perceptions of patients with rheumatoid arthritis (RA) has a positive influence in their health outcomes and overall experience of care. The Commissioning for Quality in Rheumatoid Arthritis Patient-Reported Experience Measure (CQRA-PREM) was developed to provide the perceptions and the feedback of the patients with RA to the health professionals team. This PREM is already validated and in use in the United Kingdom (UK) and Netherlands. In Portugal, there is no validated PREM to evaluate the experience of patients with RA. OBJECTIVE: To translate, cultural adapt and validate the content of the CQRA-PREM for the Portuguese population. METHODS: A qualitative study using focus groups was conducted to evaluate CQRA-PREM content validity. The CQRA-PREM was first translated and cultural adapted to Portuguese by two researchers, and after back translation, a panel of experts agreed on the preliminary Portuguese version of CQRA-PREM. Patients with RA were recruited from a rheumatology center at a tertiary university hospital center to participate in focus group meetings. Before the focus group they filled in the preliminary version of CQRA-PREM, with its 7 domains and 24 items (Likert scale 1-5). RESULTS: Twelve participants (median 54 (45-58) years old; 92% female) were included in two focus groups. All domains of the questionnaire had medians of 3 or above. Seven major themes and six subthemes emerged. Participants considered the questionnaire as very clear and simple and with adequate questions. Patients pointed as extremely important being treated with dignity and respect and considered the awareness of the multidisciplinary team and the presentation of support programs and organizations as areas for improvement. CONCLUSION: The Portuguese version of the CQRA-PREM is acceptable and its content is valid in the perspective of patients with RA to assess the quality of care provided by the healthcare services.

Severe and life-threatening onset of systemic lupus erythematosus.

Macrophage activation syndrome (MAS) is a potentially life-threatening complication of rheumatic diseases. We report a unique case of a previously healthy 20-year-old female presenting with MAS as first presentation of systemic lupus erythematosus. Remission was achieved with hydroxychloroquine, intravenous methylprednisolone pulse followed by oral prednisolone and cyclosporine. However, the management of MAS is still challenging, and the mortality rate remains high.

Severe infections in Portuguese patients with rheumatoid arthritis under biologic treatment - a multicenter, nationwide study (SIPPRA-B Study).

INTRODUCTION: Despite years of experience with biological disease modifying anti-rheumatic drugs (bDMARD) in rheumatoid arthritis (RA), little is known about differences in infectious risk among bDMARDs. The aim of this study was to assess the incidence and type of infections in RA patients on bDMARDs and to determine possible predictors. METHODS: A retrospective multicenter cohort study that included patients registered in the Rheumatic Diseases Portuguese Registry (Reuma.pt) with RA, and exposed to at least one bDMARD until April 2021. RA patients under bDMARD and with at least one episode of severe infection (SI), defined as infection that requires hospitalization, use of parenteral antibiotics or that resulted in death, were compared to patients with no report of SI. Demographic and clinical data at baseline and at the time of each SI were collected to establish comparisons between different groups of bDMARDs. Comparisons between different bDMARDs were assessed and logistic regression was performed to identify predictors of SI. RESULTS: We included 3394 patients, 2833 (83.5%) female, with a mean age at RA diagnosis of 45.5±13.7 years. SI was diagnosed in 142 of the 3394 patients evaluated (4.2%), totaling 151 episodes of SI. At baseline, patients with SI had a significantly higher proportion of prior orthopedic surgery, asthma, interstitial lung disease, chronic kidney disease and corticosteroid use, higher mean age and longer median disease duration at first bDMARD. Nine patients died (6.0%). Ninety-two SI (60.9%) occurred with the first bDMARD, the majority leading to discontinuation of the bDMARD within 6 months (n=75, 49.7%), while 65 (43.0%) restarted the same bDMARD and 11 (7.3%) switched to another bDMARD (6 of them to a different mechanism of action). In the multivariate analysis, we found that chronic kidney disease, asthma, infliximab, corticosteroid use, interstitial lung disease, previous orthopedic surgery, higher Health Assessment Questionnaire and DAS284V-ESR are independent predictors of SI. CONCLUSION: This study described the incidence and types of SI among Portuguese RA patients on biologics, identifying several predictors of SI, both globally and with different bDMARDs. Physicians should be aware of the real-word infectious risk in RA patients on bDMARDs when making treatment decisions.

Hypophosphatemic osteomalacia induced by intravenous iron therapy: a case report.

OBJECTIVE: Osteomalacia is an uncommon, overlooked and debilitating metabolic bone disease with numerous aetiologies. Herein, we report an atypical cause of osteomalacia - intravenous iron therapy. METHODS: Description of a case report of hypophophatemic osteomalacia induced by ferric carboxymaltose infusions. RESULTS: A 70-year-old male with Rendu-Osler-Weber syndrome requiring repeated infusions of ferric carboxymaltose was admitted for disabling lower limb pain associated with persistent hypophosphatemia (1.6mg/dL) and increased urinary fractional excretion of phosphate (43%, UP04=118.3mg/dL), serum fibroblast growth factor 23 (324UA/mL), intact parathyroid hormone (110pg/mL) and bone alkaline phosphatase (40.1mcg/L). X-ray and CT of the feet showed severe diffuse bone demineralization. Feet MRI displayed a subchondral fracture of the cuneiform-navicular joints. Spine X-ray revealed dorsolumbar vertebral flattening. Somatostatin receptor PET scan excluded an occult tumor. Bone biopsy with histomorphometry confirmed the presence of osteomalacia. After excluding other causes, a diagnosis of hypophosphatemic osteomalacia induced by frequent ferric carboxymaltose infusions was made. The iron formulation was replaced by saccharated ferric oxide infusions and progressive titration of calcitriol up to 1.5mg/day and oral disodium phosphate up to 5740mg/day was started. After 6 months, there was a clear clinical and analytical improvement. CONCLUSION: Osteomalacia may be a consequence of prolonged hypophosphatemia induced by recurrent ferric infusions, which is an uncommon and neglected bone adverse event of this therapy. Phosphate levels and bone symptoms should be monitored during repetitive iron infusions, maintaining a high level of suspicion for osteomalacia as it is important to identify and treat it in a timely manner, minimizing its severe morbidity.

The impact of antinuclear antibodies seroconversion induced by anti-tumor necrosis factor α agents on the clinical outcomes in rheumatic patients.

INTRODUCTION: Anti-tumor necrosis factor α (anti-TNFα) agents can potentially induce the anti-nuclear antibodies (ANA) development over time. Evidence of the real impact of these autoantibodies on clinical response to treatment in rheumatic patients is still scarce. OBJECTIVES: To explore the impact of ANA seroconversion induced by anti-TNFα therapy on clinical outcomes in biologic-naïve patients with Rheumatoid arthritis (RA), axial spondylarthritis (axSpA) and psoriatic arthritis (PsA). METHODS: An observational retrospective cohort study enrolling biologic-naïve patients with RA, axSpA and PsA who started their first anti-TNFα agent was conducted for 24 months(M). Sociodemographic data, laboratory findings, disease activity and physical function scores were collected at baseline, 12M and 24M. To examine the differences between the groups with and without ANA seroconversion, independent samples t-tests, Mann-Whitney U-tests and chi-square tests were performed. Linear and logistic regression models were used to assess the effects of ANA seroconversion on the clinical response to treatment. RESULTS: A total of 432 patients with RA (N=185), axSpA (N=171) and PsA (N=66) were included. ANA seroconversion rate at 24M was 34.6%, 64.3% and 63.6% for RA, axSpA and PsA, respectively. Regarding sociodemographic and clinical data in RA and PsA patients, no statistically significant differences between groups with and without ANA seroconversion were found. In axSpA patients, ANA seroconversion was more frequent in patients with higher body mass index (p=0.017) and significantly less frequent in patients treated with etanercept (p=0.01). Regarding disease activity, DAS28 for RA patients and ASDAS-CRP for axSpA patients were significantly higher in ANA seroconversion group at 12M (p=0.017 and p=0.009, respectively). For PsA patients, CDAI was significantly higher in ANA seroconversion group at 24M (p=0.043). Overall switching rate of biologic disease-modifying antirheumatic drugs (bDMARD) was significantly higher in the ANA seroconversion group over time (p=0.025). For RA patients, ANA seroconversion predicted DAS28 (ß=-0.21, 95%CI[-1.86;-0.18], p=0.017) at 12M. CONCLUSIONS: ANA seroconversion induced by anti-TNFα agents could interfere in clinical response of patients with rheumatic diseases. The presence of these autoantibodies can be considered as a potential predictor of poor treatment response and higher need for bDMARD switching over time.

Tuberculous Osteomyelitis of The Pubic Symphysis - a Case Report of a Rare Entity Mimicking Spondyloarthritis.

Tuberculosis (TB) osteomyelitis of the pubic symphysis is an extremely rare diagnosis. Axial spondyloarthritis (SpA) is characterized by inflammatory back pain and enthesitis, and involvement of pubic symphysis is very unusual at presentation. A 36-year-old female patient with a history of inflammatory back and pubic pain was referred to Rheumatology. She had a pelvic magnetic resonance imaging (MRI) suggestive of osteitis pubis. She was started on etoricoxib 90mg/day as axial spondyloarthritis was suspected, with no improvement. Pelvic MRI was repeated and showed osteomyelitis of the iliopubic branches. An ultrasound-guided biopsy was performed, and culture was positive for Mycobacterium tuberculosis. Further imaging studies revealed small cavitations and several centrilobular micronodules with a tree-in-bud pattern in the upper lung lobes and in the upper segment of the lower left lobe. She was started on anti-tuberculous treatment for 1 year and had a good clinical and radiological response. TB osteomyelitis of the pubic symphysis is a rare entity and has seldom been reported. However, this is the first case, to our knowledge, where the clinical picture mimicked an itself unusual presentation of SpA.