Do Patients with Psoriatic Arthritis Have More Severe Skin Disease than Patients with Psoriasis Only? A Systematic Review and Meta-Analysis.

BACKGROUND: Early identification of patients at risk of psoriatic arthritis (PsA) is essential to facilitate early diagnosis and improve clinical outcomes. Severe cutaneous psoriasis has been proposed to be associated with PsA, but a recent assessment of the evidence is lacking. Therefore, in this systematic review, we address the association of psoriasis skin severity with the presence and development of PsA. SUMMARY: We included articles from a review published in 2014 and supplemented these with recent literature by performing an additional systematic search to identify studies published between 1 January 2013 and 11 February 2021. A meta-analysis was performed when sufficient comparable evidence was available. Of 2,000 screened articles, we included 29 in the analysis, of which 16 were identified by our updated search. Nineteen studies reported psoriasis severity as psoriasis area and severity index (PASI), ten studies as body surface area (BSA), and two studies as "number of affected sites." Most studies show that more extensive skin disease is associated with the presence of PsA. The quantitative pooled analyses demonstrate higher PASI (mean difference [Δ] 1.59; 95% confidence interval [CI] 0.29-2.89) and higher BSA (Δ 5.31; 95% CI 1.78-8.83) in patients with PsA as compared to psoriasis patients without PsA. Results from prospective studies - that assess the risk of future development of PsA in psoriasis patients - were inconclusive. KEY MESSAGES: In patients with psoriasis, more severe skin involvement is associated with the presence of PsA, underpinning the importance of optimal dermatology-rheumatology collaboration in clinical care. There are insufficient data to support the use of psoriasis skin severity to predict the future development of PsA in psoriasis patients.

Systemic glucocorticoid use and the occurrence of flares in psoriatic arthritis and psoriasis: a systematic review.

OBJECTIVES: The use of systemic glucocorticoids (SGCs) is traditionally discouraged in the treatment of PsA and psoriasis due to the risk of psoriatic flares. However, despite this recommendation, SGCs are frequently prescribed for these patients. In this study we reappraise the old paradigm that SGCs are contra-indicated in the treatment of PsA and psoriasis. METHODS: A systematic search of MEDLINE, EMBASE and the Cochrane Library databases was performed in November 2019 to identify articles on any SGC use compared with no use in the PsA and psoriasis population. Topical glucocorticoid treatment was excluded. Our two primary outcomes focused on the prescribing characteristics and the occurrence of any type of flare. RESULTS: Our search yielded 4922 articles, and of these 21 full-text articles were eligible for inclusion. There were 11 retro- and prospective cohorts involving a total of 4,171,307 patients. Of these, 6727 (37.82%) of the patients with PsA and 1 460 793 (35.17%) of the patients with psoriasis were treated with any type of SGC. Ten observational/interventional studies did not report an increased risk or occurrence of psoriatic flares related to SGC use. CONCLUSION: Our results indicate that SGCs are frequently prescribed for PsA and psoriasis patients. The occurrence of psoriatic flares appears to be low upon SGC exposure. In patients with a clear indication for SGCs, e.g. in need of rapid anti-inflammatory therapy or bridging of therapies, the use of SGCs should be considered in view of the low risk of skin flaring. It remains of importance to weigh risks for short- and long-term SGC-related side effects in clinical decision making.

Non-Alcoholic Fatty Liver Disease (NAFLD) in Patients with Psoriasis: A Review of the Hepatic Effects of Systemic Therapies.

There is increasing interest in the association between psoriasis and non-alcoholic fatty liver disease (NAFLD), which is a prevalent liver disease characterized by excessive fat storage and inflammation that can progress to fibrosis and cancer. Patients with psoriasis have a two-fold higher risk to develop NAFLD and a higher risk to progress to more severe liver disease. Psoriasis and NAFLD share common risk factors such as smoking, alcohol consumption, and the presence of metabolic syndrome and its component disorders. In addition, both psoriasis and NAFLD hinge upon a systemic low-grade inflammation that can lead to a vicious cycle of progressive liver damage in NAFLD as well as worsening of the underlying psoriasis. Other important shared pathophysiological pathways include peripheral insulin resistance and oxidative stress. NAFLD should receive clinical awareness as important comorbidity in psoriasis. In this review, we assess the recent literature on the epidemiological and pathophysiological relationship of psoriasis and NAFLD, discuss the clinical implications of NAFLD in psoriasis patients, and summarize the hepatotoxic and hepatoprotective potential of systemic psoriasis therapies.

Tissue-Resident Memory CD8+ T Cells From Skin Differentiate Psoriatic Arthritis From Psoriasis.

OBJECTIVE: To compare immune cell phenotype and function in psoriatic arthritis (PsA) versus psoriasis in order to better understand the pathogenesis of PsA. METHODS: In-depth immunophenotyping of different T cell and dendritic cell subsets was performed in patients with PsA, psoriasis, or axial spondyloarthritis and healthy controls. Subsequently, we analyzed cells from peripheral blood, synovial fluid (SF), and skin biopsy specimens using flow cytometry, along with high-throughput transcriptome analyses and functional assays on the specific cell populations that appeared to differentiate PsA from psoriasis. RESULTS: Compared to healthy controls, the peripheral blood of patients with PsA was characterized by an increase in regulatory CD4+ T cells and interleukin-17A (IL-17A) and IL-22 coproducing CD8+ T cells. One population specifically differentiated PsA from psoriasis: i.e., CD8+CCR10+ T cells were enriched in PsA. CD8+CCR10+ T cells expressed high levels of DNAX accessory molecule 1 and were effector memory cells that coexpressed skin-homing receptors CCR4 and cutaneous lymphocyte antigen. CD8+CCR10+ T cells were detected under inflammatory and homeostatic conditions in skin, but were not enriched in SF. Gene profiling further revealed that CD8+CCR10+ T cells expressed GATA3, FOXP3, and core transcriptional signature of tissue-resident memory T cells, including CD103. Specific genes, including RORC, IFNAR1, and ERAP1, were up-regulated in PsA compared to psoriasis. CD8+CCR10+ T cells were endowed with a Tc2/22-like cytokine profile, lacked cytotoxic potential, and displayed overall regulatory function. CONCLUSION: Tissue-resident memory CD8+ T cells derived from the skin are enhanced in the circulation of patients with PsA compared to patients with psoriasis alone. This may indicate that aberrances in cutaneous tissue homeostasis contribute to arthritis development.

Long-term Safety of Oral Systemic Therapies for Psoriasis: A Comprehensive Review of the Literature.

Oral systemic therapies are important treatment options for patients with moderate-to-severe psoriasis, either as monotherapy or in therapy-recalcitrant cases as combination therapy with phototherapy, other oral systemics or biologics. Long-term treatment is needed to maintain sufficient disease control in psoriasis, but continuous use of systemic treatments is limited by adverse events (AEs) and cumulative toxicity risks. The primary aim of this comprehensive literature review was to examine the long-term safety profiles of oral agents commonly used in the treatment of adults with psoriasis. Searches were conducted in EMBASE and PubMed up to November 2018, and 157 relevant publications were included. Long-term treatment with acitretin could be associated with skeletal toxicity and hepatotoxicity, although evidence for skeletal toxicity is mixed and hepatotoxicity is rare, particularly at low doses. Other safety issues include hyperlipidaemia and potential for teratogenicity up to 2-3 years after discontinuation of treatment. There is a paucity of data on long-term treatment with apremilast. Continued exposure to apremilast does not seem to increase the incidence of common AEs, such as gastrointestinal (GI) AEs, upper respiratory tract infections and headache, while the long-term risks for depression, suicidal thoughts and weight loss are unknown. Long-term ciclosporin treatment is associated with renal toxicity, hypertension, non-melanoma skin cancer, neurological AEs and GI AEs. Long-term methotrexate treatment is associated with hepatotoxicity, GI AEs, haematological toxicity, renal toxicity and alopecia. Finally, long-term treatment with fumaric acid esters (FAE) is associated with GI AEs, flushing, lymphocytopenia, proteinuria and elevated liver enzymes. Median drug survival estimates varied considerably: ~ 2.9-9.7 months for apremilast; ~ 5.4 months for ciclosporin; ~ 8.6 months for acitretin; ~ 12.1-21.6 months for methotrexate; and ~ 54.8 months for FAE. These long-term safety profiles may help to guide clinicians to select the optimal oral systemic treatment for the long-term treatment of psoriasis in adults.

[Spectrum of psoriatic conditions]. / Spectrum van psoriatische aandoeningen.

Psoriasis is a common immune-mediated inflammatory condition that primarily affects skin and nails. 6-41% of psoriasis patients develop psoriatic arthritis (PsA). The ways in which PsA can manifest itself include peripheral arthritis, axial spondyloarthritis, dactylitis and enthesitis. This heterogeneous clinical picture makes it sometimes difficult to recognise PsA,potentially resulting in permanent joint damage and functional impairments. Some people see psoriasis and PsA as 2 manifestations of a single disease because the multifactorial origins of psoriasis and PsA are largely overlapping. Psoriatic conditions are associated with a high burden of disease, reduced quality of life and comorbidities, including psychiatric and cardiovascular conditions. In recent years, several immunological pathways, immune cells and cytokines have been identified as important factors in pathophysiology and as new therapeutic targets. For many PsA patients treatment with disease modifying anti-rheumatic drugs leads to significant improvement of symptoms and quality of life.

A 28-Year-Old Male Patient with Nail Tumors, Skin Lesions, and Epilepsy.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of benign hamartomas in multiple organs. Most patients with TSC exhibit cutaneous manifestations. METHODS: We report a 28-year-old patient with multiple pink papules at the proximal nail fold of several toes. RESULTS: Histopathological analysis of a biopsy of a papule was consistent with an ungual fibroma. Histopathological analysis of a biopsy of an elevated skin-colored plaque at the lower back was diagnostic for a Shagreen patch. These findings were consistent with a clinical diagnosis of TSC. This patient was subsequently referred to a multidisciplinary TSC clinic for further screening, which revealed a giant cell astrocytoma and multiple subependymal tubers. Annual monitoring was recommended. The skin lesions were treated with topical rapamycin ointment. CONCLUSIONS: Recognizing dermatological manifestations of TSC is of importance to allow early diagnosis. TSC should be considered as a differential diagnosis in the case of ungual fibromas, even in older patients.

Combination Therapy of Etanercept and Fumarates versus Etanercept Monotherapy in Psoriasis: A Randomized Exploratory Study.

BACKGROUND: Biologics are a safe and efficacious therapy for psoriasis. The drug survival of biologics may be disappointing, primarily due to loss of efficacy. Therefore, safe combination treatments are sought to improve their clinical response. OBJECTIVE: To assess the efficacy, safety and tolerability of the combination therapy of etanercept with fumarates versus etanercept monotherapy. METHODS: Thirty-three patients with psoriasis were randomized 1:1 to receive etanercept combined with fumarates or etanercept monotherapy. The primary outcome measure was the difference in PASI-75 response after 24 weeks; additionally, a longitudinal analysis was performed. An important secondary outcome measure was the proportion of patients with a Physician Global Assessment (PGA) of clear or almost clear. Adverse events were collected throughout the study. RESULTS: In the combination therapy group, 78% (14 out of 18 patients) reached PASI-75 at week 24 versus 57% (8 out of 14 patients) in the monotherapy group (p = 0.27). The longitudinal analysis showed a PASI reduction of 5.97% per week for the combination therapy group and of 4.76% for the monotherapy group (p = 0.11). In the combination therapy group, 94% (17 out of 18 patients) of patients had a PGA of clear/almost clear versus 64% (9 out of 14 patients) in the monotherapy group (p = 0.064). The incidence of mild gastrointestinal complaints was higher in the combination group than in the monotherapy group. CONCLUSION: Using the PGA, combination therapy showed a trend towards faster improvement in the first 24 weeks. The difference in the PASI score between the two groups was not statistically significant. Addition of fumarates to etanercept for 48 weeks appeared safe with an acceptable tolerability.

Drug-induced Fanconi syndrome associated with fumaric acid esters treatment for psoriasis: a case series.

BACKGROUND: Fumaric acid esters (FAEs), an oral immunomodulating treatment for psoriasis and multiple sclerosis, have been anecdotally associated with proximal renal tubular dysfunction due to a drug-induced Fanconi syndrome. Few data are available on clinical outcomes of FAE-induced Fanconi syndrome. METHODS: Descriptive case series with two cases of Fanconi syndrome associated with FAE treatment diagnosed at two Dutch university nephrology departments, three cases reported at the Dutch and German national pharmacovigilance databases and six previously reported cases. RESULTS: All 11 cases involved female patients with psoriasis. The median age at the time of onset was 38 years [interquartile range (IQR) 37-46]. Patients received long-term FAEs treatment with a median treatment duration of 60 months (IQR 28-111). Laboratory tests were typically significant for low serum levels of phosphate and uric acid, while urinalysis showed glycosuria and proteinuria. Eight (73%) patients had developed a hypophosphataemic osteomalacia and three (27%) had pathological bone fractures. All patients discontinued FAEs, while four (36%) patients were treated with supplementation of phosphate and/or vitamin D. Five (45%) patients had persisting symptoms despite FAEs discontinuation. CONCLUSIONS: FAEs treatment can cause drug-induced Fanconi syndrome, but the association has been reported infrequently. Female patients with psoriasis treated long term with FAEs seem to be particularly at risk. Physicians treating patients with FAEs should be vigilant and monitor for the potential occurrence of Fanconi syndrome. Measurement of the urinary albumin:total protein ratio is a suggested screening tool for tubular proteinuria in Fanconi syndrome.

Prevalence of cutaneous adverse events associated with long-term disease-modifying therapy and their impact on health-related quality of life in patients with multiple sclerosis: a cross-sectional study.

BACKGROUND: Glatiramer acetate (GA) and interferon-beta (IFN-ß) are disease-modifying therapies (DMTs) for multiple sclerosis that are administered through subcutaneous (SC) or intramuscular (IM) injections. Skin reactions associated with DMTs are common and may influence patient's health-related quality of life (QoL). We aimed to determine the prevalence of cutaneous adverse events associated with long-term DMT use, and to assess the impact of cutaneous adverse events on QoL. METHODS: A cross-sectional study among patients with multiple sclerosis who had been treated with their first DMT for at least 2 years. Cutaneous events were assessed from photographs of injection-sites by dermatologists blinded for DMT. Generic and dermatology-specific health-related QoL were assessed using validated patient-reported questionnaires. RESULTS: A total of 229 patients were enrolled, of whom 156 (68%) had at least one skin reaction. The prevalence of cutaneous adverse events was higher for SC DMTs (75-82%) compared to IM DMT (41%) (P < 0.001). Erythema and lipoatrophy were the most common skin reactions, observed in 156 (68%) and 45 (20%) patients, respectively. Dermatology-specific, but not generic, QoL was significantly lower among patients with skin reactions compared to those without. CONCLUSIONS: The prevalence of cutaneous adverse events was high in long-term DMT-treatment. Patients with cutaneous adverse events had a lower perceived dermatology-specific QoL.

Is mipomersen ready for clinical implementation? A transatlantic dilemma.

PURPOSE OF REVIEW: Mipomersen has been approved by the US Food and Drug Administration as an orphan drug for patients with homozygous familial hypercholesterolemia (HoFH). In contrast, the European Medicines Agency advised negatively on the use of mipomersen. In this review, we discuss the efficacy and safety considerations for this discrepancy. RECENT FINDINGS: On the basis of the results of clinical trials with mipomersen, safety concerns have been raised regarding cardiovascular risk reduction and development of hepatic steatosis. In addition, (long-term) tolerability concerns have been raised predominantly regarding injection site reactions. A pooled analysis of cardiovascular events in phase III trials with mipomersen did not provide evidence for either a positive or negative effect on cardiovascular disease. Although long-term studies with mipomersen are eagerly awaited, hepatic fat content appears to stabilize after 6-12 months notwithstanding continued mipomersen administration. SUMMARY: HoFH is a disease with an unmet medical need for new lipid-lowering therapies. On the basis of a mean 2.9 mmol/l LDL-cholesterol reduction, mipomersen is expected to reduce cardiovascular risk in HoFH. Available evidence suggests that the fat accumulation associated with this treatment differs from steatohepatitis, which is a progressive and damaging liver disease. No evidence is available suggesting that injection site reactions because of mipomersen treatment will result in safety issues.

Cutaneous adverse events associated with disease-modifying treatment in multiple sclerosis: a systematic review.

Glatiramer acetate and interferon-beta are approved first-line disease-modifying treatments (DMTs) for multiple sclerosis (MS). DMTs can be associated with cutaneous adverse events, which may influence treatment adherence and patient quality of life. In this systematic review, we aimed to provide an overview of the clinical spectrum and the incidence of skin reactions associated with DMTs. A systematic literature search was performed up to May 2011 in Medline, Embase, and Cochrane databases without applying restrictions in study design, language, or publishing date. Eligible for inclusion were articles describing any skin reaction related to DMTs in MS patients. Selection of articles and data extraction were performed by two authors independently. One hundred and six articles were included, of which 41 (39%) were randomized controlled trials or cohort studies reporting incidences of mainly local injection-site reactions. A large number of patients had experienced some form of localized injection-site reaction: up to 90% for those using subcutaneous formulations and up to 33% for those using an intramuscular formulation. Sixty-five case-reports involving 106 MS patients described a wide spectrum of cutaneous adverse events, the most frequently reported being lipoatrophy, cutaneous necrosis and ulcers, and various immune-mediated inflammatory skin diseases. DMTs for MS are frequently associated with local injection-site reactions and a wide spectrum of generalized cutaneous adverse events, in particular, the subcutaneous formulations. Although some of the skin reactions may be severe and persistent, most of them are mild and do not require cessation of DMT.