Paradoxical Psoriasis: An Updated Review of Clinical Features, Pathogenesis, and Treatment Options.

The definition of paradoxical psoriasis (PP) encompasses 2 main scenarios, namely, (i) new-onset psoriasis in patients treated for a different disease and (ii) worsening as well as phenotypical change of pre-existing psoriasis. Originally restricted to the appearance of an untoward psoriasiform reaction under TNF inhibitors, the term has gained new meaning, with the progressive observation of psoriasis-like eruptions also with other medications. Although the conceptual framework of PP has expanded, a molecular and clinicotherapeutic classification is still lacking. In addition, a certain degree of confusion surrounds the correct terminology to indicate these eruptions. In this paper, evidence on the epidemiology, clinical features, pathogenesis, and treatment of PP is reviewed, providing a perspective on possible pathogenesis-driven therapeutic approaches.

Infliximab-Induced Improvement in Dercum's Disease.

Dercum's disease (DD) is a rare and poorly understood disease characterized by obesity and painful lipomas throughout the body. Although the entity is well described in the literature, its etiology, prevalence, and treatment remain unclear. Currently, treatment is focused on pain management. We describe a case of a patient with DD who showed improvement with infliximab and methotrexate.

Manifestations and Management of Inflammatory Eye Disease in Patients with Inflammatory Bowel Disease.

PURPOSE: To characterize the ocular inflammatory manifestations of inflammatory bowel disease (IBD) and examine the impact of ocular inflammation on IBD treatment. METHODS: A single-center retrospective chart review of patients with an IBD diagnosis and ophthalmology visit between January 2016 and January 2022 was conducted. Patients with a diagnosis of uveitis, scleritis, or peripheral ulcerative keratitis (PUK) confirmed by an optometrist or ophthalmologist were included. RESULTS: Charts of 1320 IBD patients were reviewed; 42 patients with uveitis, 2 patients with scleritis, and 2 patients with PUK were identified. Anterior uveitis was the most common form of uveitis (38/42, 90.5%), often in an episodic (31/38, 81.6%) and unilateral (19/38, 50.0%) pattern. Four patients (4/42, 9.5%) had posterior segment uveitis: two with panuveitis, one with intermediate uveitis, and one with posterior uveitis. Patients on systemic therapy for IBD did not routinely undergo changes to therapy following the development of ocular inflammation (27/36, 75.0%). Therapy alterations were more frequent with the development of posterior segment uveitis, scleritis, or PUK (4/6, 66.7%) compared with anterior uveitis (5/30, 16.7%). In 10 patients, uveitis onset preceded IBD diagnosis; in these patients, tumor necrosis factor (TNF) inhibitors were often used at the time of subsequent IBD diagnosis (5/10, 50.0%). CONCLUSIONS: Unilateral anterior uveitis was the most common form of ocular inflammation among patients with IBD. Development of uveitis did not routinely require modification of immunomodulatory therapies; however, therapy changes were more common with posterior segment uveitis, scleritis, and PUK.

The safety and efficacy of TNF inhibitors in patients with Behçet's disease: Retrospective study from eastern Turkey.

OBJECTIVE: We aimed to evaluate the clinical features, disease course, and associated factors for outcome in severe/refractory BD patients receiving TNF-i treatment. MATERIAL AND METHODS: This retrospective study was conducted by reviewing medical records from a tertiary referral center in Van province in Eastern Turkey. Data were obtained from patients' charts followed up between June 2019 and June 2022. RESULTS: We included 469 BD patients (59.3% male) whose 80 patients (17%) received TNF-i treatment in the study. The mean ± standard deviation of the patient age was 36.7 ± 10.1 years and the median (IQR) disease duration was 12 (12) years. IFX and ADAwere initiated in 67.5% (n = 54) and 32.5% (n = 26) patients, respectively. Overall and first-line retention rates of TNF-i were 84.7% and 92.6% for IFX and 83.3% and 80.8% for ADA, respectively. IFX was discontinued in 9 patients which were in 2 patients due to allergic reaction and tuberculosis, 3 patients for inefficacy, one patient for heart failure, and one patient for orbital zona. Although no serious adverse event was observed with ADA, 5 patients switched to IFX due to inefficacy. Overall, 72 patients (90%) resumed TNF-i at the end of the study; TNF-i was discontinued in 3 patients (3.8%) due to severe adverse events and in 5 patients (6.2%) with prolonged remission. CONCLUSION: In our study, no case of death was observed in TNF-i receiving patients. Most patients achieved attack-free and CS-free disease and retained TNF-i treatment. TNF inhibitors appear to be safe and effective in patients with severe/refractory Behçet's disease.

Ex-vivo Cell-based Assay for Assessment of Response to TNF Inhibitors in Patients with Rheumatic Diseases.

OBJECTIVE: TNF inhibitors (TNFi) comprise 5 products whose structure and signalling differ. An individual patient with a rheumatic disease may respond to one TNFi but not to another. In addition, 30-40% of the patients respond inadequately to TNFi. The different TNFi downstream signalling may lead to their clinical efficacy. Several reports showed that TNFi exhibited differential effects on Th17 cells. We analyzed the different TNFi effects on IL-17A expression in the peripheral blood mononuclear cells (PBMCs) of patients with rheumatic diseases in order to evaluate the predictive capability of responses in an ex-vivo setting. METHODS: PBMCs were co-cultured with the different TNFi or medium (control), and IL-17A mRNA levels were analyzed by qPCR. IL-17A expression levels in response to 4 TNFi (except certolizumab pegol) were compared with control. IL-17A expression in the assay was correlated to the clinical responses. Assay sensitivity and specificity for distinguishing responders from non-responders was calculated by receiver-operating characteristic (ROC) analysis. RESULTS: The results of a retrospective cohort of patients with rheumatic diseases (n = 82) correlated with their therapeutic responses to the different TNFi with 89.5% accuracy. The assay predicted the responses of a prospective cohort (n = 54) to specific TNFi with 79% accuracy. CONCLUSION: This functional assay could assist in predicting the odds for response to TNFi therapy, indicating whether a given patient is likely to respond to a specific TNFi.

Risk of Major Adverse Cardiovascular Events and Venous Thromboembolism with JAK Inhibitors versus TNF Inhibitors in Rheumatoid Arthritis Patients: A Systematic Review and Meta-Analysis.

Objective: The aim of this study was to compare the risk of major cardiovascular events (MACE) and venous thromboembolic events (VTE) between tumour necrosis factor (TNF) and Janus kinase (JAK) inhibitors in patients with rheumatoid arthritis (RA). Methods: We researched PubMed, Scopus, Cochrane Library, and clinicaltrials.gov until December of 2023 for randomised controlled trials (RCTs) and observational studies. The outcomes studied were MACE (stroke, heart attack, myocardial infarction, sudden cardiac death) and VTE (deep vein thrombosis, pulmonary embolism). We pooled data using random effects model. Risk for the reported outcomes was expressed as odds ratio (OR) with a 95% confidential interval (CI). We performed a subgroup analysis based on study design. Results: We identified 23 studies, 20 of which compared the odds for MACE and 14 the odds for VTE between JAK and TNF inhibitors in RA patients. Ten studies were RCTs and the rest were observational. Regarding MACE risk we pooled data from a total of 215,278 patients (52,243 were treated with JAK inhibitors, while the rest 163,035 were under TNF inhibitors). Compared with TNF inhibitors, the OR for JAK inhibitors in regards with MACE risk was 0.87 (0.64-1.17, p<0.01). Regarding VTE, a total of 176,951 patients were analysed (41,375 JAK inhibitors users and 135,576 TNF inhibitors users). The OR for VTE for JAK inhibitors compared with TNF inhibitors was 1.28 (0.89-1.84, p<0.01). Conclusion: According to our results, there is no statistically significant difference for MACE or VTE in RA patients who receive either JAK or TNF inhibitors.

Rheumatoid factor titers, but not Fc fragments, may be strongly associated with drug survival of anti-TNF agents in patients with rheumatoid arthritis.

OBJECTIVE: To investigate the effects of both the Fc fragment in tumor necrosis factor (TNF) inhibitors and rheumatoid factor (RF) titers on treatment survival, disease activity, and laboratory parameters in patients with rheumatoid arthritis (RA). METHODS: In this retrospective cohort study, patients with RA who had started any anti-TNF therapy between January 2017 and March 2020 and who had stayed on this treatment for at least six months were included. The data of the patients were compared separately according to continuation or discontinuation of treatment and the presence or absence of Fc portion in the structure of anti-TNFs. Patients who were taking certolizumab pegol (CZP) without the Fc fragment were placed in the "without Fc group" (wo/Fc), while patients who were taking other drugs (adalimumab, etanercept, golimumab, and infliximab) were placed in the "with Fc group" (w/Fc). RESULTS: Among the 221 RA patients whose data were available, 52 patients met the inclusion criteria and were included in the study. There was a significant difference in the DAS28-CRP score between wo/Fc group and w/Fc group in the third month of treatment (p=0.012). However, this difference did not persist at the sixth month of treatment (p=0.384). According to the cox-regression results, RF titers were determined to have a significant impact on the drug survival of anti-TNF agents when adjustments were made for the effects of other candidate predictors (Hazard ratio: 1.007 (1.002-1.012), p=0.009). CONCLUSION: Our results suggest that compared to the Fc fragment, RF titers were the more important risk factor in survival of anti-TNF drugs.

Cardiovascular Considerations and Implications for Treatment in Psoriasis: An Updated Review.

Psoriasis, a prevalent chronic inflammatory skin disorder affecting 2-3% of the global population, has transcended its dermatological confines, revealing a profound association with cardiovascular diseases (CVD). This comprehensive review explores the intricate interplay between psoriasis and cardiovascular system, delving into genetic links, immune pathways, and adipose tissue dysfunction beyond conventional CVD risk factors. The pathophysiological connections unveil unique signatures, distinct from other inflammatory skin conditions, in particular psoriasis-specific genetic polymorphisms in IL-23 and TNF-α have consistently been linked to CVD. The review navigates the complex landscape of psoriasis treatments, addressing challenges and future directions in particular relevance to CVDs in psoriasis. Therapeutic interventions, including TNF inhibitors (TNFi), present promise in reducing cardiovascular risks, and methotrexate could constitute a favourable choice. Conversely, the relationship between IL-12/23 inhibitors and cardiovascular risk remains uncertain, while recent evidence indicates that Janus kinase inhibitors may not carry CVD risks. Emerging evidence supports the safety and efficacy of IL-17 and IL-23 inhibitors in patients with CVDs, hinting at evolving therapeutic paradigms. Lifestyle modifications, statins, and emerging therapies offer preventive strategies. Dedicated screening guidelines for CVD risk assessment in psoriasis are however lacking. Further, the impact of different disease phenotypes and treatment hierarchies in cardiovascular outcomes remains elusive, demanding ongoing research at the intersection of dermatology, rheumatology, and cardiology. In conclusion, unraveling the intricate connections between psoriasis and CVD provides a foundation for a holistic approach to patient care. Collaboration between specialties, advancements in screening methodologies, and a nuanced understanding of treatment impacts are essential for comprehensive cardiovascular risk management in individuals with psoriasis.

Psoriasis is a skin condition that not only affects the skin but is also linked to issues in the body's fat tissue, which can lead to inflammation and heart problems. The fat tissue in people with psoriasis contains various immune cells, contributing to obesity and insulin resistance. Research has found a strong connection between inflammation in fat tissues and cardiovascular problems in people with psoriasis. Specific substances released by fat tissue, like leptin, resistin, and adiponectin, can impact inflammation and cardiovascular health. Psoriasis patients often show increased levels of these substances. Treatment for psoriasis may influence cardiovascular health. Some studies suggest that certain medications, like methotrexate or TNF inhibitors, may lower the risk of heart events. However, there are also concerns about potential adverse effects, and further research is needed to fully understand how psoriasis treatments affect cardiovascular outcomes. To manage the cardiovascular risks associated with psoriasis, regular screening for heart-related issues is recommended. Lifestyle changes, such as a healthy diet, stress management, and smoking cessation, are also essential. Additionally, specific medications, like statins and metformin, may be beneficial in controlling cardiovascular risk factors in people with psoriasis. Despite advancements in understanding the relationship between psoriasis and cardiovascular health, there are still challenges. Research is ongoing to develop better screening guidelines and treatment strategies. Collaboration between dermatologists, rheumatologists, and cardiologists is crucial to address the complex nature of this condition and its impact on the heart.

Relative bioavailability, immunogenicity, and safety of two adalimumab-adbm formulations in healthy volunteers: a double-blind, randomized, single-dose, parallel-arm Phase I trial (VOLTAIRE-HCLF).

OBJECTIVE: VOLTAIRE-HCLF compared the relative bioavailability of citrate-free high-concentration and reference formulations of the biosimilar adalimumab-adbm (Cyltezo®), including pharmacokinetic (PK) profiles, immunogenicity, and safety profiles in healthy volunteers. METHODS: Healthy volunteers (N = 200) aged 18-55 years and with body mass index of 18.5-29.9 kg/m2 and no prior exposure to adalimumab were randomized in a 1:1 ratio to receive a single subcutaneous injection of either adalimumab-adbm 40 mg/0.4 mL (high-concentration formulation) or 40 mg/0.8 mL (reference formulation). Participants completed 13 follow-up visits over 57 days, followed by a safety follow-up period of up to 70 days. RESULTS: The main PK parameters were similar for the high-concentration and reference groups. For all primary endpoints, the geometric mean ratios and 90% confidence intervals of AUC0-1344, AUC0-∞, and Cmax for both groups were entirely within the standard 80-125% bioequivalence acceptance range at 101.88% (93.31-111.23%), 105.38% (95.06-116.81%), and 91.29% (84.38-98.76%), respectively. There were no differences in the proportion of anti-drug antibody-positive participants or in the distribution of anti-drug antibody titers between the two formulations at any time point after drug dosing. Participants who were given the high-concentration formulation of adalimumab-adbm experienced a lower incidence of adverse events and local reactions than those who were given the reference formulation. CONCLUSIONS: Overall, the high-concentration and reference adalimumab-adbm formulations had highly similar PK and immunogenicity profiles and were safe and well tolerated. CLINICAL TRIAL REGISTRATION: NCT05203289.

Tumor Necrosis Factor and Interleukin Modulators for Pathologic Pain States: A Narrative Review.

Chronic pain, a complex and debilitating condition, involves intricate interactions between central and peripheral inflammatory processes. Cytokines, specifically tumor necrosis factor (TNF) and interleukins (IL), are key mediators in the initiation and maintenance of chronic pain states. Sensory neurons expressing receptors for cytokines like TNF, IL-1, and IL-6 are implicated in peripheral sensitization, contributing to increased signaling of painful sensations. The potential of targeting TNF and IL for therapeutic intervention in chronic pain states is the focus of this review, with preclinical and clinical evidence supporting the use of TNF and IL modulators for pain management. The physiological and pathological roles of TNF in neuropathic pain is complex. Experimental evidence highlights the effectiveness of TNF modulation in mitigating pain symptoms in animal models and displays promising outcomes of clinical trials with TNF inhibitors, such as infliximab and etanercept. ILs, a diverse group of cytokines, including IL-1, IL-6, and IL-17, are discussed for their contributions to chronic pain through inflammation and peripheral sensitization. Specific IL modulators, such as secukinumab and tocilizumab, have shown potential in managing chronic neuropathic pain, as demonstrated in various studies and clinical trials. The pharmacokinetics, safety profiles, and challenges associated with TNF and IL modulators highlight the need for cautious medication monitoring in clinical practice. Comparative evaluations have revealed distinct efficacy and safety profiles among different cytokine modulators, emphasizing the need for personalized approaches based on the specific underlying causes of pain. Further research is necessary to elucidate the intricate mechanisms by which cytokines contribute to chronic pain, as well as to understand why they may affect pain differently in various contexts. Additionally, long-term safety profiles of cytokine modulators require more thorough investigation. This continued exploration holds the promise of enhancing our comprehension of cytokine modulation in chronic pain and shaping more potent therapeutic strategies for the future.

Exploring relief for Behçet's disease refractory oral ulcers: a comparison of TNF inhibitors versus apremilast.

OBJECTIVES: Oral and genital ulcers are the hallmark manifestation of Behçet's disease (BD), significantly impacting patients' quality of life. Our study focuses on comparing the effectiveness and safety of TNF inhibitors (TNFis) and apremilast in controlling oral ulcers of BD, aiming to provide evidence-based guidance for physicians in selecting appropriate treatment modalities. METHODS: A retrospective analysis was performed on BD patients treated between December 2016 and December 2021 with TNFis or apremilast for refractory oral ulcers. The study assessed treatment response by the absence of oral ulcers at 3 and 6 months, with additional evaluations for genital ulcers and articular involvement. RESULTS: The study included 78 patients, equally allocated between TNFis and apremilast treatments. Both groups showed significant oral ulcer reduction at 3 (p< 0.001) and 6 months (p= 0.01) with no significant difference between the treatments. Apremilast had a notable corticosteroid-sparing effect by the 3-month follow-up, persisting through 6 months. Both treatments were equally effective in reducing genital ulcers, with TNFis showing greater effectiveness in addressing articular involvement. Apremilast had a higher discontinuation rate due to gastrointestinal side effects. CONCLUSION: TNFis and apremilast are both effective for treating BD refractory oral ulcers. While TNFis may offer broader benefits for other disease manifestations, apremilast is distinguished by its corticosteroid-sparing effect, especially for patients with a milder disease phenotype. Treatment selection should consider individual disease severity and clinical features to ensure a personalized and effective management strategy.

From bench to bedside - is there a role of IL-17 drugs in rheumatoid arthritis?

INTRODUCTION: IL-17 has been described as a pro-inflammatory cytokine that is relevant in the seronegative spondylarthritides with IL-17 targeted therapies being licensed for their treatment.There is evidence to demonstrate that IL-17 is found in RA joints and contributes to the pro-inflammatory cascade. This results in synovial hyperplasia and osteoclastogenesis thus causing joint destruction and bony erosions. AREAS COVERED: This review article summarizes trials that have studied the use of IL-17 targeted therapies in RA patients who have failed conventional synthetic disease-modifying therapy (C-DMARDS) and biologic DMARDS. EXPERT OPINION: The trials that have studied IL-17 inhibitors in RA patients have only shown a modest improvement in disease activity. In several trials, the primary endpoint was not achieved whilst in others, when comparing with existing licensed biologics for RA, did not demonstrate any superiority.Tissue Necrosis Factor-alpha (TNF-α) likely plays more of a pivotal role in the pathogenesis of RA with IL-17 having a synergistic effect. Therefore, in our opinion, IL-17 inhibitors as an independent therapy for RA are less likely to provide a cost-effective benefit. There may be scope to potentially combine it with TNF-α-inhibitors (TNF-i), but this requires further research especially with the potential concerns related to increased immunosuppression.

Development of anti-MDA5 autoantibody-positive dermatomyositis following the use of etanercept biosimilar in rheumatoid arthritis.

The induction of autoimmune diseases during tumour necrosis factor-alpha inhibitor (TNFi) usage has been described. Herein, we report a rare case of a 49-year-old woman with antimelanoma differentiation-associated gene 5 (MDA5) antibody (Ab)-positive dermatomyositis (DM), which developed 5 weeks after the introduction of an etanercept biosimilar to rheumatoid arthritis (RA). Four of the five known cases, including ours, of anti-MDA5Ab-positive DM complicated with RA revealed anti-MDA5Ab-positive DM following TNFi usage. When patients with RA are diagnosed with interstitial lung disease during TNFi usage, anti-MDA5 Ab-positive DM could be a differential diagnosis.

Choosing the right biologic treatment for moderate-to-severe plaque psoriasis: the impact of comorbidities.

INTRODUCTION: Psoriasis is a chronic inflammatory skin disease often associated with several comorbidities, such as psoriatic arthritis, inflammatory bowel disease, obesity, diabetes mellitus or cardiovascular diseases, infections, or cancer, among others. With the progressive aging of the population, a growing number of patients with psoriasis can be expected to present multiple comorbidities. Currently, there is a wide range of biological treatments available for moderate to severe psoriasis, including tumor necrosis alpha (TNF) inhibitors, IL12/23 inhibitor, IL17 inhibitors, and IL23 inhibitors. AREAS COVERED: This review aims to describe the specific characteristics of these drugs in relation to psoriasis comorbidities, in order to facilitate decision-making in clinical practice. EXPERT OPINION: Some of the biological treatments can influence comorbidities, in some cases even improving them. Therefore, comorbidities are a key factor when deciding on one biological treatment over another. The development of new drugs is expanding the therapeutic arsenal for psoriasis. A high level of expertise in the field with a detailed knowledge of the characteristics of every drug is imperative to provide personalized medicine.

Long-Term Outcomes of Patients with Biologically Treated Psoriatic Arthritis and Atopic Dermatitis-A Single-Center Experience.

(1) Background: Although the association between psoriasis and atopic dermatitis (AD) is reported in the literature, scarce data are known about the efficacy of biologic therapy (including TNF and IL-17 inhibitors) in patients with psoriatic arthritis (PsA) and concomitant AD. (2) Objective: We aimed to explore AD in patients with PsA undergoing biologics for their active disease, focusing on prevalence and clinical and potential therapeutic implications. (3) Material and methods: We performed a retrospective analysis of 64 patients with PsA receiving various biological agents, followed-up in an academic outpatient rheumatology department up to 10 years. (4) Results: Atopic diseases were reported in about one third of cases, with a higher incidence of AD (10 cases; 52.6%) vs. atopic rhinitis (6 cases; 31.6%) and allergic asthma (3 cases; 15.8%). Three morphological patterns of AD were recognized including chronic prurigo (3 cases), a chronic lichen simplex (1 case), and eczemas (6 cases). All PsA with concomitant AD displayed a late onset of skin atopy (in their adult life) and demonstrated a specific profile (younger), from urban settings, equally distributed among genders, and requiring switching to a higher number of biologics to achieve disease control. (5) Conclusion: PsA and AD may coexist, requiring special attention when selecting the optimal biologic agent.

Drug effectiveness of 2nd and 3rd TNF inhibitors in psoriatic arthritis - relationship with the reason for withdrawal from the previous treatment.

OBJECTIVE: To investigate real-world retention and remission rates in PsA patients initiating a 2nd or 3rd TNFi and the association with reason for discontinuation from the previous TNFi-treatment. METHODS: Prospectively collected routine care data from 12 European registries were pooled. Retention rates (Kaplan-Meier estimation) and crude/LUNDEX-adjusted rates of Disease Activity Score 28 and Disease Activity index for PSoriatic Arthritis (DAS28 and DAPSA28) remission were calculated and compared with adjusted Cox regression analyses and Chi-squared test, respectively). RESULTS: We included 5233 (2nd TNFi) and 1906 (3rd TNFi) patients. Twelve-month retention rates for the 2nd and 3rd TNFi were 68% (95%CI: 67-70%) and 66% (64-68%), respectively. Patients who stopped the previous TNFi due to AE/LOE had 12-month retention rates of 66%/65% (2nd TNFi), and 65%/63% (3rd TNFi), respectively. Patients who stopped the previous TNFi due to LOE after less vs more than 24 weeks had 12-month retention rates of 54%/69% (2nd TNFi), and 58%/65% (3rd TNFi). Six-month crude/LUNDEX-adjusted DAS28 remission rates were 48%/35% and 38%/27%, and DAPSA28 remission rates were 19%/14% and 14%/10%, for the 2nd and 3rd TNFi. CONCLUSION: Two-thirds of patients remained on TNFi at 12months for both the 2nd and 3rd TNFi, while one-third and one-quarter of patients were in DAS28 remission after 6months on the 2nd and 3rd TNFi. While drug effectiveness was similar in patients who stopped the previous TNFi due to AE compared to overall LOE, drug effectiveness was better in patients who had stopped the previous TNF due to secondary LOE compared to primary LOE.

Association of HLA-DRB1 locus with treatment response to abatacept or TNF inhibitors in patients with seropositive rheumatoid arthritis.

The strongest genetic risk factor for rheumatoid arthritis (RA) has been known as HLA-DRB1 based on amino acid positions 11, 71, and 74. This study analyzed the association between specific HLA-DRB1 locus and treatment response to abatacept or TNF inhibitors (TNFi) in patients with seropositive RA. A total of 374 Korean RA patients were treated with abatacept (n = 110) or TNFi (n = 264). Associations between HLA-DRB1 and treatment response after 6 months were analyzed using multivariable logistic regression. Seropositive RA patients with HLA-DRB1 shared epitope (SE) had a favorable response to abatacept (OR = 3.67, P = 0.067) and an inversely associated response to TNFi (OR 0.57, P = 0.058) based on EULAR response criteria, but the difference was not statistically significant in comparison to those without SE. In analyses using amino acid positions of HLA-DRB1, a significant association was found between valine at amino acid position 11 of SE and good response to abatacept (OR = 6.46, P = 5.4 × 10-3). The VRA haplotype also showed a good response to abatacept (OR = 4.56, P = 0.013), but not to TNFi. Our results suggest that treatment response to abatacept or TNFi may differ depending on HLA-DRB1 locus in seropositive RA, providing valuable insights for selecting optimal therapy.

Tumor Necrosis Factor Inhibitor Use Increases Birthweight in Pregnant Women With Rheumatoid Arthritis Independently of the Soluble Fms-Like Tyrosine Kinase-1/Placental Growth Factor Ratio.

BACKGROUND: To study whether the use of TNF (tumor necrosis factor) inhibitors (TNFi) by pregnant women with rheumatoid arthritis affects sFlt-1 (soluble Fms-like tyrosine kinase-1), PlGF (placental growth factor), or their impact on birthweight. METHODS AND RESULTS: sFlt-1 and PlGF were measured in all trimesters of pregnancy in the Preconception Counseling in Active Rheumatoid Arthritis study and were compared according to the use of TNFi. The association of sFlt-1 and PlGF with birthweight in relation to TNFi was determined. The study included 158 women, of whom 52.5% used TNFi during pregnancy. Both sFlt-1 and PlGF increased during pregnancy, whereas their ratio declined. Taking into consideration the trimester-related variation in levels of sFlt-1 and PlGF, after correction for relevant confounders, the sFlt-1/PlGF ratio was not significantly different between patients who did or did not use TNFi (sFlt-1/PlGF ratio in the second trimester compared with the first trimester: estimated change 8.17 [95% CI, 2.54-26.29], P=0.79; sFlt-1/PlGF ratio in the third trimester compared with the first trimester: estimated change 6.25 [95% CI, 1.73-22.50], P=0.25). In women who did not use TNFi, birthweight was significantly lower (3180 versus 3302 g; P=0.03), and sFlt-1 displayed a negative correlation with birthweight (r=-0.462, P<0.001) and birthweight percentile (r=-0.332, P=0.008). In TNFi users, these correlations were absent. CONCLUSIONS: TNF inhibitor use increases birthweight in pregnant women with rheumatoid arthritis independently of the sFlt-1/PlGF ratio. REGISTRATION: http://clinicaltrials.gov. Unique identifier: NCT01345071.

Combination biologics or targeted synthetic disease-modifying anti-rheumatic drugs in the treatment of spondyloarthritis: a systematic literature review.

INTRODUCTION: The advent of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) have transformed the management of immune-mediated rheumatic diseases, including spondylarthritis (SpA). However, the data about combining b/ts DMARDs in the treatment of SpA are scarce. The study objectives were to assess the efficacy and safety of combination b/tsDMARD in SpA. METHODS: We conducted systematic literature review (PubMed and Medline) with two independent reviewers, one adjudicator, exploring the efficacy and safety of combination b/tsDMARDs in the treatment of SpA. Inclusion criteria were studies published in last 20 years, English language, interventions included use of two b/tsDMARDs, and minimal three-month follow-up. RESULTS: Out of 1936 initial hits, 28 manuscripts fulfilled the inclusion criteria. Two were randomized controlled trials, and the remaining were retrospective cohort studies or case series. Combination of apremilast with bDMARD, or TNF inhibitor plus IL12/23 inhibitor were the commonest and reported good efficacy with no increased safety signal. CONCLUSIONS: There is not enough data to fully evaluate efficacy and safety of combination b/tsDMARDs in SpA treatment. Limited information shows apremilast plus bDMARD, or TNF inhibitor plus IL12/23 inhibitor combination to be efficacious and safe. Randomized controlled trials and larger cohort with a longer follow-up are required.