Review One year in review 2018: psoriatic arthritis - Clinical and ...
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Review
One year in review 2018: psoriatic arthritis
E. Calabresi1, S. Monti2,3, G. Governato1, L. Carli4
1
Rheumatology Unit, Department of ABSTRACT the spine, in particular the sacroiliac
Clinical and Experimental Medicine, Spondyloarthritis (SpA) is an inflam- joint (SIj); based on the presence of
University of Pisa; matory condition characterised by a a sacroiliitis (SI) detectable on x-ray,
2
Department of Rheumatology,
broad spectrum of clinical manifesta- they are actually classified in AS or in
University of Pavia, IRCCS Policlinico
S. Matteo Foundation, Pavia; tions, laboratory abnormalities and non-radiographic ax-SpA (nr ax-SpA).
3
PhD in Experimental Medicine, imaging features that genetically tend PsA may manifest in a number of dif-
University of Pavia; to be associated with the major his- ferent patterns, with a major involve-
4
Rheumatology Unit, AOUP, Pisa, Italy. tocompatibility complex class 1 an- ment of small joints of the hands and
Emanuele Calabresi, MD tigen, HLA-B27, and in which both feet, or predominant large joint in-
Sara Monti, MD peripheral and axial joints might be volvement, particularly in the knees,
Gianmaria Governato MD affected. In addition to arthritis, the or a combination of these. It may also
Linda Carli MD, PhD typical musculoskeletal manifestations involve the axial joints, and inflamma-
Please address correspondence to: are enthesitis and dactylitis. Extra- tion of the entheses and/or finger and
Dr Linda Carli, articular manifestations such as acute toe joints (2).
Rheumatology Unit, AOUP,
Via Roma 67,
anterior uveitis (AAU), psoriasis (PsO) At present, we could say that SpA rep-
56126 Pisa, Italy. and inflammatory bowel disease (IBD) resents one of the most intriguing is-
E-mail: 81clinda@gmail.com are also typical of SpA. In this article sues of modern rheumatology. Indeed,
Received on March 4, 2019; accepted in we have reviewed the literature of the not only does it tend to present in a
revised form on March 12, 2019. past year on one of the most important very pleomorphic way, but also, dur-
Clin Exp Rheumatol 2019; 37: 167-178. variants of SpA, i.e. psoriatic arthritis ing its progression, it tends to associate
© Copyright Clinical and (PsA) (Medline search of articles pub- with a very wide spectrum of comor-
Experimental Rheumatology 2019. lished from 1st January 2018 to 31st bidities [in particular with cardiovascu-
January 2019). lar diseases (CVD), diabetes mellitus,
Key words: psoriatic arthritis, osteoporosis (OP), psychiatric disor-
ankylosing spondylitis, imaging, Introduction ders, but renal, neurologic and pulmo-
comorbidities, quality of life The term spondyloarthritis (SpA) rep- nary disorders have also been reported]
resents a condition characterised by a and with a reduction of the ability to
broad spectrum of clinical manifesta- work and the quality of work of sub-
tions, laboratory abnormalities and jects, thus seriously compromising the
imaging features that genetically tends health-related quality of life (HRQoL)
to be associated with the major histo- of patients (3).
compatibility complex class 1 antigen, Following the previous annual reviews
HLA-B27, in which both peripheral of this series (1, 2, 4-9), we will here
and axial joints might be affected. In provide a critical digest of the recent
addition to arthritis, the typical mus- literature on one aspect of SpA, i.e.
culoskeletal manifestations are en- psoriatic arthritis (PsA). In particular,
thesitis and dactylitis. Extra-articular we performed an on-line search on
manifestations such as acute anterior MESH database, using as key terms
uveitis (AAU), psoriasis (PsO) and “chemistry”, “complications”, “diag-
inflammatory bowel disease (IBD) (in nosis”, “drug therapy”, “epidemiol-
order of decreasing prevalence) are ogy”, “genetics”, “imaging diagnosis”,
also characteristic of SpA (1, 2). “metabolism”, “microbiology”, “mor-
The majority of people with this dis- tality”, “prevention and control”, “psy-
ease have either psoriatic arthritis chology”, “rehabilitation”, “surgery”,
(PsA) or axial spondyloarthritis (ax- “therapy”; articles were published from
SpA), which includes ankylosing spon- 1st January 2018 to 31th January 2019.
Competing interests: none declared. dylitis (AS). Ax-SpA primarily affects Current recommendations on PsA
Clinical and Experimental Rheumatology 2019 167One year in review 2018: psoriatic arthritis / E. Calabresi et al.
identify up to six PsA disease domains: est in the pathogenetic mechanism in- 10) and TNFRSF1A (exons 2,3,4 and
peripheral arthritis, enthesitis, dac- volved in SpA diseases, with the aim 6) genes were performed. Their anal-
tylitis, spondylitis, and skin and nail also of identifying biochemical and ysis confirmed that HLA-B27 was
PsO. The development of comorbidi- genetic biomarkers that might help associated with AS; only the TNFA
ties might further contribute to disease the diagnostic work up and the evalu- -1031T>C was singly associated with
heterogeneity. Recent new advances ation of treatment effectiveness. Single SpA, and the haplotype C/G, resulting
in the knowledge of the immunologi- nucleotide polymorphisms (SNPs) in from -1031T>C/-308G>A combina-
cal mechanisms at the basis of PsA genes involved in TNF-α signalling, tion, was significantly associated with
allowed an improvement in therapeu- such as those in the promoter region of a reduced risk of developing SpA. Two
tical strategies that, together with the the TNFA gene, in TNFSF15 (TNF li- SNPs were identified in TNFRSF1A,
advances in imaging techniques and gand superfamily, member 15), TNFR- the R92Q and c.625+10A>G; none
the recognition of different patterns of 1 (TNF receptor 1) and TRADD (TNF of them was associated with a higher
clinical manifestations of the disease receptor type 1-associated death do- risk of developing SpA. Interestingly,
itself, might assure a progressive im- main protein), have been identified as the TNFRSF1A c.625+10 G allele was
provement in the routinary assessment potentially associated with SpA. This significantly associated with a later re-
of PsA patients, aiming at reaching a is of great interest not only because sponse to anti-TNF-α therapy. Twenty-
better quality of care (10). TNF-α is involved in the propagation one SNPs were identified in MEFV
and perpetuation of inflammation in gene, 10 with a known potential func-
Epidemiology SpA, but also because of the clinical tional significance. Variant alleles were
The incidence of PsA has been report- efficacy of treatments based on drugs extremely rare in the studied popula-
ed for an inland area of central Italy targeting the TNF-α pathway. Taking tion, except for R202Q; none of them
(CAMPO-RHE study) reporting that, into consideration the potential role was associated with SpA diagnosis.
of 1003 adult patients referred by a gen- of autoinflammation in disease patho- The authors therefore concluded at first
eral practitioner to the rheumatologic genesis, other potential candidates are that the risk of developing AS seemed
clinic of Campobasso, there were 19 the MEFV (Mediterranean fever) and to depend not only on HLA-B27, but
new diagnoses of PsA, accounting for TNFRSF1A (TNF receptor superfam- also on the protective role of TNF-α
an incident case rate of 22.59/100,000/ ily member 1A) genes, involved in the haplotype -1031C/-308G; secondly,
year on the population at risk (11). pathogenesis of the autoinflammatory the TNFRSF1A and MEFV gene SNPs
disorders familial Mediterranean fe- are not associated with a major risk of
Chemistry ver (FMF) and tumour necrosis factor developing SpA in the north-east of
Over the past 12 months there has been receptor-associated periodic syndrome Italy and finally, that the TNFRSF1A
an increasing interest in the predictors (TRAPS), respectively. The latter gene c.625+10A>G could impact on the re-
for the development of PsA, and in the encodes the TNFR-1 and genetic vari- sponse to anti-TNF-α therapy (13).
imaging or clinical features useful to ations might underlie functional altera- Long non-encoding RNAs (lncRNAs)
allow making an early diagnosis of the tions of the TNF-α signalling, while are important mediators of inflamma-
disease. The identification of potential variations in MEFV gene were shown tion and in particular in autoimmune
circulating biomarkers able to iden- to be very common among FMF Turk- diseases such as systemic lupus ery-
tify cases of undiagnosed PsA amongst ish patients with AS as a sole clinical thematosus (SLE), rheumatoid arthritis
those with cutaneous PsO has shown manifestation. Starting from these data, (RA), or PsO, they seem to modulate
promising results in a cohort of 100 an Italian research group, investigated the immune system. Considering that
PsA patients, 100 PsO, and 100 healthy whether, in addition to the established few data exist on lncRNAs in PsA,
controls. CD5-like protein, integrin ß5, HLA-B27 genetic predisposing factor, Dolcino et al. have researched the
Mac-2-binding protein, myeloperoxi- biomarkers of inflammation, SNPs in profile of expression of lncRNA with
dase, metalloproteinase 3 were candi- the promoter region of TNFA, or vari- microarray analysis in a cohort of 10
date biomarkers for PsA, performing ants of the autoinflammatory TNFRS- patients with PsA. They have found
better than C-reactive protein (CRP) F1A and MEFV genes, might be of help 259 lncRNAs that are strongly asso-
(12). in SpA diagnosis and/or in predicting ciated to PsA compared with healthy
the response to anti-TNFα treatment. controls. The role of lncRNAs found
Genetics They enrolled 137 SpA patients (82 in the blood of patients with PsA could
The delay in diagnosis, the lack of with PsA and 55 with AS; 98/137 be strongly associated with the immu-
specific diagnostic and prognostic bio- under TNF-α inhibitor therapy) and nopathogenesis of the disease, owing
markers and of complete clinical re- 373 controls coming from the north- to their association with B and T lym-
sponse even after therapy with tumour east of Italy. TNFA polymorphisms phocyte gene expression, inflamma-
necrosis factor (TNF) α inhibitors, ( - 1 0 3 1 T > C ; - 8 5 7 C > T; - 3 7 6 G > A ; - tory cytokine genes like TNF and type
such as etanercept (ETN), infliximab 308G>A;-238G>A) and HLA-B27 1 IFN, genes related to bone apposi-
(IFX), adalimumab (ADA) and goli- were assayed by RT-PCR. Direct se- tion such as WNT and genes related to
mumab (GOL), have raised the inter- quencing of MEFV (exons 2,3,5 and metabolic syndrome. From these data it
168 Clinical and Experimental Rheumatology 2019One year in review 2018: psoriatic arthritis / E. Calabresi et al.
could be supposed an epigenetic role of the early identification of patients with dysfunction, subclinical atherosclero-
lncRNA in PsA pathogenesis, through PsA (17) and supporting the importance sis and plaque instability.
their role in immunomodulation of ad- of a multidisciplinary management of Szentpetery et al. assessed the frequency
aptative and acquired immunity and in PsA in strict collaboration between the and characteristics of coronary plaque
glycolipid metabolism (14). rheumatologist and the dermatologist burden in 50 patients with PsA and 50
MicroRNAs (miRNAs) are impor- (18). Finally, duration of PsO disease age- and sex-matched controls. Plaques
tant mediators of the immune system; has been reported to be associated with were significantly more frequent in PsA
only few data on miRNA expression an increased incidence of PsA in a large compared to controls. Interestingly,
in patients with active PsA is currently cohort of 10,011 patients (19). among patients with PsA, the presence
availble. Pelosi et al. investigated their A screening clinical questionnaire – of concomitant metabolic syndrome did
action in PsA analysing a cohort of 23 Simple Psoriatic Arthritis Screening not influence the plaque burden, which
PsA patients that were divided into two (SIPAS) – to facilitate the discrimina- was associated with signs of active in-
subgroups based on the phase of their tion between PsO and PsA has been pro- flammatory disease rather than with tra-
disease (activity or remission). They posed and validated by Salaffi et al. and ditional CV risk factors (24).
found that miRNAs changed the expres- can be used to identify patients that war- A cohort of 340 patients from a tertiary
sion of TNF, MAPK and WNT signal- rant referral to a rheumatologist (20). hospital-based polulation with PsA was
ing pathways only in patients with an Another novel questionnaire (CON- studied in a retrospective and cross-sec-
active disease, suggesting a possible TEST) was developed using the most tional way for type II diabetes and other
role of miRNAs on gene expression in discriminative items to detect undiag- CV comorbidities comparing with 600
PsA transcriptoma. Interestingly, a spe- nosed PsA amongst patients with PsO controls without infammatory arthropa-
cific type of miRNA, miR-126-3p was and compared to the previously used thies. Queiro et al. found that diabetes
downregulated in patients with active Psoriasis Epidemiology Screening Tool was significantly more prevalent in PsA
PsA and was usually over expressed (PEST). CONTEST showed acceptable patients (13.8%) than controls (5%). In-
in patients with disease in remission. sensitivity/specificity (0.53 and 0.71, terestingly, the presence of diabetes was
These results highlighted that miRNAs respectively), but no superiority to the strongly associated with PsO and arthri-
could represent biomarkers of different available PEST tool (21). tis onset after 40 years, a higher count of
phases of activity of PsA; besides, they The prevalence of dactylitis in patients swollen and tender joints, a lower edu-
could help as indicators of new possible with early SpA has been reported by 609 cational level, pustolar PsO and, as ex-
therapeutic strategies (15). patients included in the ESPeranza co- pected, metabolic syndrome. After con-
IL-23 and IL-17 have a well known hort (including patients with suspected trolling for age, sex and duration of the
pathogenetic role in PsA and conse- SpA). The study showed that dactylitis disease, in particular, the authors found
quently, they are important specific tar- occurred in 9.5% of patients and was a strong association with late onset PsO
gets of biological therapy. mainly associated, but not exclusive, of and hypertension. These data confirm
Abji et al. have analysed the synovial peripheral disease and PsO (22). that type II diabetes is frequent in pa-
fluid of 14 patients with PsA and 9 An interesting approach to the assess- tients with PsA, suggesting the need for
with osteoarthritis; in particular, they ment of comorbidities was proposed by metabolic screening, particularly in pa-
isolated RNA from synovial fluids Patel et al., analysing whether patients tients with late onset PsO and PsA (25).
and used RT-PCR to study the differ- recognise that they are being assessed Remaining on CV risk associated to
ent expression of 84 genes of the Th17 and monitored for comorbidities asso- SpA, a prospective nationwide study
pathway between the two subgroups. ciated with PsA or PsO. The authors re- with cohorts of patients with AS
They found that synovial fluid from ported that patients feel they are being (n=6448), PsA (n=16063) and uSpA
patients with PsA was characterised moderately well screened for comor- (n=5190) and a general population (GP)
by increased expressions of STAT and bidities, but are mostly unsure about (n=266435) cohort in a Swedish regis-
FOXP3 genes than in patients with os- having their blood sugar and cholester- try, was performed with an 8-year follow
teoarthritis. The differences in the gene ol levels monitored, underlying a dis- up, to observe the incidence of atrioven-
expression of synovial fluid between crepancy between patients’ responses tricular (AV) block II-III, atrial fibrilla-
PsA and osteoarthritis could be useful and physician practice. These results tion (AF), pacemaker (PM) implanta-
as a possible biomarker of PsA (16). highlight the need to optimise patients’ tion and aortic regurgitation. At the end
education and endorsement in a com- of the follow-up period, it was observed
Comorbidities prehensive approach to their health, that the highest incidence rates for CV
A consensus on a list of practical rec- that would be of benefit on the outcome events were noted for AF (5.5–7.4
ommendations promoting the early of the rheumatologic disease itself (23). events per 1000 person-years), followed
identification of patients with PsA in The well-established association of by PM implantation (1.0–2.0 events per
the dermatology setting was developed PsA with metabolic syndrome and CV 1000 person-years). Hazard ratios for
based on a narrative literature review, risk was still confirmed by the litera- AV block, AF, PM and aortic regurgita-
expert review and Delphi consensus, ture published in the past 12 months, tion were significantly increased in AS
adding further strategies to implement particularly in terms of endothelial (HRs 2.3, 1.3, 2.1 and 1.9), uSpA (HRs
Clinical and Experimental Rheumatology 2019 169One year in review 2018: psoriatic arthritis / E. Calabresi et al.
2.9, 1.3, 1.9 and 2.0) and PsA (HRs 1.5, etal inflammation. Recent advances in adjacent bone destruction and have dif-
1.5, 1.6 and 1.8) compared with the GP imaging, including ultrasound (US) and ferent prognostic value. Moya Alvarado
cohort. With these results Bengsston et magnetic resonance imaging (MRI), et al. attempted to describe which US
al. proved that patients with SpA are at allow for the accurate evaluation of characteristics of nail psoriasis were as-
increased risk of aortic regurgitation, the extent of inflammation and dam- sociated with the presence of subclini-
cardiac rhythm disturbances and, as a age in the peripheral joints, spine, and cal enthesopathy in patients with PsO
probable consequence, also PM implan- enthesis. The development and valida- and asymptomatic PsA. Forty-eight pa-
tation (26). tion of outcome measures are critical tients with PsO and asymptomatic PsA
Vitamin D deficiency has been associ- steps in creating standardised evalu- were included in the study and the US
ated with several inflammatory condi- ations of musculoskeletal inflamma- assessment included Achilles tendon,
tions (i.e. connective tissue diseases, tion and damage in psoriatic patients. extensor digitorum tendon and US scan
RA), but has been poorly evaluated At the 2017 meeting of the Group for of the nail plate, nail matrix, nail bed
in SpA patients. Fernandes et al. per- Research and Assessment of Psoriasis and adjacent skin over nail matrix of
formed a study with the aim of evaluat- and PsA (GRAPPA), the GRAPPA US the five nails of each hand. The authors
ing the prevalence of hypovitaminosis group developed and validated a so- observed that 33 patients presented US
D in SpA patients (enrolled from the nographic enthesitis scoring system in evidence of extensor digitorum tendon
ASAS-COMOSPA study initiative, an PsA, which will improve the standardi- enthesopathy. The nails of the patients
international cross-sectional study of sation of disease assessment (29). with subclinical enthesopathy had a
patients with SpA) and of understanding US is the easiest and reliable way to higher Nail Psoriasis Severity Index
the possible association of vitamin D investigate joint swelling. Macia-Vil- (NAPSI) and skin thickness than the
levels with disease phenotype, activity la et al. investigated 27 PsA patients nails of the patients without subclinical
severity or comorbidities. Of the 1030 with clinical involvement of metacar- enthesopathy, confirming that there is a
patients, more than half (51.2%) had pophalangeal joints, particularly evalu- close relationship between subclinical
vitamin D deficiency, thus confirming ating by US the frequency and reliabili- enthesopathy of the extensor digitorum
the higher prevalence of this condition ty of peritenon extensor tendon inflam- tendon and the presence of nail altera-
in inflammatory diseases. Moreover, vi- mation (PTI) and intra articular synovi- tions (32).
tamin D deficiency was also associated tis (IAS). It was observed that both IAS US assessment of changes in fingernails
with active SI, suggesting an association and PTI caused metacarpophalangeal (thickness of the nail plate, nail bed, and
between low levels of vitamin D and joints swelling, where PTI is almost as matrix) have been reported to correlate
more severe forms of SpA (27). frequent as IAS as a cause of swelling with the duration of arthritis (r=0.399;
Hyperuricaemia (HU) is a laboratory and that the reliability of PTI is at least p=0.022) and with the number of swol-
finding typically associated with PsA. as good as for IAS (30). len digits (r=0.278; p=0.041) in PsA
Lai et al. performed a multicentre Predictive signs of PsA in patients with patients (33). Moreover, US findings at
cross-sectional obervational study on early arthritis have been described. the level of the nail unit might be of use
160 Asian patients, to analyse the pos- Furlan et al. have investigated the fre- to differentiate between PsA and PsO
sible association in patients with PsA quency of thickening of pulleys for and healthy controls, showing a trend
between HU and overweight, obesity, hands flexor tendons in a prospective for onycholisis and crumbling in PsA
body area involved by PsO, severity study involving 228 consecutive pa- compared to the other groups (34).
of skin disease (using PASI score) and tients with early arthritis. The authors A comprehensive US evaluation of
joint count. More than 30% of patients observed that the thickening of the pul- finger flexor tendon entheseal soft tis-
had HU. They found a significant as- leys in the flexor tendons was an easy- sue and bone changes can offer useful
sociation only between HU and BMI to-detect sign, with a good sensitivity information to differentiate PsA from
score, thus highlighting the importance (80%) of thickened pulleys for the di- RA. Peri-tendinous dermal soft tissue
of body weight control and daily prac- agnosis of PsA; however, the specific- oedema with power Doppler signal was
tice attention on this specific clinical ity (70%) and positive predictive value only found in PsA patients (p=0.003).
aspect in patients with PsA (28). (2.71) were not as high. Nevertheless, Flexor tendon enthesopathy including
the authors concluded that sonogra- new insertional bone formation and ten-
Imaging phers should report it during hand osynovitis were both significantly more
Modern imaging is a useful tool for the evaluations of patients with arthritis. frequent in PsA compared to RA (35).
diagnosis, prognosis, and monitoring Patients with diabetes were excluded US can be used to investigate multi-
of therapeutic response in SpA, by pro- as potential confounders, owing to the ple superficially located entheses and
viding sensitive measures of the extent high frequency of trigger finger pathol- abnormalities can be quantified with
of disease (also detecting a subclinical ogy in this group of patients (31). a combined score, for example, the
synovitis or enthesitis) and being able to Nail psoriasis disease is associated MAdrid Sonographic Enthesitis Index
monitor both inflammation and damage. with an increased probability of PsA, (MASEI). Last year, Wervers et al. per-
PsA is a heterogeneous disease with and its clinical signs may have differ- formed a cross-sectional study to inves-
various manifestations of musculoskel- ent correlates with the pathogenesis of tigate the frequency of US changes at
170 Clinical and Experimental Rheumatology 2019One year in review 2018: psoriatic arthritis / E. Calabresi et al. the entheses of 25 patients with a recent while no reliable T2 measurement tients’ sexuality. Two focus groups of diagnosis of PsA, 25 patients with es- could be achieved with a Carr-Purcell patients, concerned by sexuality, were tablished PsA, and 25 young healthy Meiboom-Gill (CPMG) sequence, due conducted in February 2015. Based on volunteers. They analysed by US the to insufficient signal from entheses and the verbatim transcripts, a content anal- triceps, quadriceps, patellar, Achilles tendons (38). ysis was performed by a psychologist and elbow extensor tendon insertion, trained in qualitative procedures. After and plantar fascia entheses for struc- Disease activity, quality of life an analysis of the verbatim reports by tural changes, erosions, calcifications, and working ability the research group, a preliminary ques- increased thickness, bursitis, and pow- It is well known that psychological tionnaire comprising 22 questions was er Doppler (PD) signal. Sonographic problems tend to be underrecognised drawn up; it covered the following ar- changes in the entheses were observed and undertreated in patients with PsA; eas: the quality of daily life, tolerance in young, healthy volunteers, patients however, little is known on how people of the cutaneous state by the patient, with recently diagnosed PsA, and in pa- with PsA cope with and manage their tiredness, mobility and flexibility of tients with established PsA. After hav- disease. The Common Sense Self-Reg- the joints and outside activities involv- ing excluded patellar tendon enthesis ulatory Model (CS-SRM) suggests ill- ing movement of all or part of the body. thickness and applying a new method ness beliefs, mediated by coping, may Subsequently, the questions were sub- of scoring PD, the modified MASEI influence health outcomes. Therefore, mitted to a panel of experts for selec- was able to distinguish between PsA Howells et al. planned a cross-sectional tion using a Delphi method; they were patients and healthy controls; further- observational study to investigate the questioned about item relevance and more, the authors found US abnormali- role of disease severity, illness beliefs content. After expert consensus had ties were very common from the early and coping strategies in predicting de- been reached, the instructions to par- stages of PsA (36). pression, anxiety and QoL in PsA pa- ticipants completing the questionnaire, As a result of its sensitivity, MRI can tients; moreover, they tried to assess the wording of items, and the possible be used to detect any subclinical sign the role of depression and anxiety in answers were finalised. The question- of arthritis. Mathew et al. performed an predicting QoL. One hundred and sev- naire entitled “Questionnaire of sexual observational study evaluating inflam- enty-nine adult PsA patients completed quality of life perceived by patients mation at the small joints of feet in PsO validated measures of predictor (illness with cutaneous and/or articular psoria- patients without clinical arthritis (53) beliefs, coping strategies, disease se- sis” comprised 14 questions. However, as against clinically overt PsA (30) pa- verity) and outcome variables (depres- the authors specified that the quantita- tients, using a low field magnet extrem- sion, anxiety, QoL), using an online tive step, aiming at evaluating the met- ity MRI (eMRI). The authors observed survey distributed via social media. rologic qualities (reliability, validity, that there was no statistical difference After controlling for disease severity, and responsiveness) of the question- between the median eMRI inflamma- hierarchical multiple regression mod- naire, had not yet been performed (40). tory scores in PsA and PsO patients; els indicated that more negative beliefs PSOdisk is a 10-item visual instru- in particular, evidence of inflammation about consequences and behavioural ment, aimed at assessing the burden of was present in 33.9% and 50% patients disengagement as a coping method, disease in patients with psoriasis. An in the PsO and PsA groups, respective- predicted levels of depression, and Italian study group performed an anal- ly. Early arthritis for psoriatic patients self-blame predicted anxiety. Beliefs ysis which aimed to compare PSOdisk screening questionnaire (EARP) score about consequences and the presence with the Dermatology Life Quality In- of ≥3 was significantly associated with of depression predicted QoL scores dex (DLQI), a scientifically validated imaging features of inflammation in after controlling for disease severity. questionnaire, and assessing both tools PsO group, suggesting a high propor- These data may support the use of the in relation to Psoriasis Severity Index tion of subclinical inflammation in PsO CS-SRM in explaining variation on (PASI) and patient acceptance. They patients and the need to predict risk fac- psychological outcomes in individuals studied both patients with cutaneous tors for progression to future PsA de- with PsA. Moreover, the illness beliefs psoriasis and PsA. Correlation analy- velopment in this kind of patient (37). and coping strategies identified as pre- sis between PSOdisk and DLQI was Chen et al. investigated the reliability dictors in this study could be potential performed using Pearson’s product- of three-dimensional ultrashort echo targets for interventions, addressing moment correlation coefficient. A mul- time cones (3D UTE Cones) MR se- PsA-related distress and QoL (39). tivariate linear regression was carried quences in 7 healthy volunteers and 9 The data in the literature show that PsO out to investigate the effect of PASI on PsA patients, evaluating the Achilles and PsA impact sexuality and intimate PSOdisk and DLQI scores. Moreover, tendon and its enthesis; they concluded relationships in both men and women, the authors evaluated completion times that 3D UTE Cones provided high reso- and can be associated with sexual dys- as well as patient satisfaction for both lution imaging of entheses and tendons functions. Esteve et al. performed a PSOdisk and DLQI. The mean value of and could be used for morphological study aimed at developing and validat- Cronbach’s coefficient alpha was 0.88 and quantitative evaluation of abnormal ing a specific questionnaire to assess for PSOdisk and 0.90 for DLQI, sug- entheses and tendons in PsA patients, the impact of these conditions on pa- gesting good reliability. A significant Clinical and Experimental Rheumatology 2019 171
One year in review 2018: psoriatic arthritis / E. Calabresi et al. correlation was found between PSO- spective. The PsAID was tested and culoskeletal disease, skin disease and disk and PASI. It also was associated validated on an independent cohort of HRQoL (46). with a good patient satisfaction, and patients, assessing the minimally im- DAPSA was validated for PsA in 2010 required a short completion time. A portant clinical difference for improve- and is based on the simple summation multivariate linear regression analysis ment. The PsAID proved to be a reli- of visual analogue scales (0-10 cm) of demonstrated a statistically significant able tool of the impact of disease, with patient’s global and pain assessments, effect of PASI on both the DLQI score a sensitivity to change. The minimal 66 swollen joint count, 68 tender joint and PSOdisk score, thus demonstrating detectable change was 1.41. There was count and CRP (mg/dL). 28-joint counts a good correlation between PSOdisk a strong correlation with other PROs have been found to be sufficiently valid and both DLQI and PASI (41). (such as the EQ-5D index of the FAC- in comparison to more comprehensive A Dutch cross-sectional study was con- IT-fatigue score), and a moderate cor- joint counts in patients with RA; con- ducted to clarify whether PsA patients relation with clinical outcomes (43). sequently Michelsen et al. tested the with an acceptable disease state accord- Van Mens et al. analysed a real-life potential validity of a simplified DAP- ing to the treating rheumatologist have cohort of 250 patients to compare the SA score including 28 instead of the quiescent disease defined as minimal different composite measures used to original 66/68 joint counts in patients disease activity (MiDA). An acceptable define remission or LDA for PsA. The with PsA. Data were analysed from a disease state was defined by asking following tools were used to assess cohort of 3157 patients from the Dan- rheumatologists to refer those patients disease activity: the Disease Activity ish national quality registry DANBIO whom they considered sufficiently Index for Psoriatic Arthritis (DAPSA), compared to a cohort of 3154 controls. treated. Patients were evaluated for the clinical DAPSA (cDAPSA), very The authors observed that data obtained current disease activity including clini- low disease activity (VLDA) defined if with only 28-joint counts available can cal assessments and PROs. A total of all seven items of the Minimal Disease be used to calculate DAPSA28, espe- 250 patients with PsA were screened. Activity (MiDA) were fulfilled, and cially in patients with low disease activ- The authors found that more than the Psoriatic Arthritis Disease Activity ity. DAPSA28 showed good criterion, 35% of the patients with acceptable Score. The VLDA was only reached by correlational and construct validity and disease state according to the rheuma- a minority (19.5%) of the cohort. The sensitivity to change. Still, it was not tologist did not fulfill the MiDA defi- different measures used allowed for recommended the use of DAPSA28 nition, most frequently owing to tender significantly different grades of residu- in clinical practice, as the 66/68 joint joints, patient pain and global disease al disease activity that need to be taken counts should be used in PsA whenever activity scores. Moreover, also objec- into account in clinical practice (44). feasible; despite this, to our knowledge, tive signs of disease activity as swol- A modified version of the Psoriatic DAPSA28 is the first 28 joint disease len joint count >1, enthesitis >1 and Arthritis Disease Activity Score (PAS- activity score developed and validated PASI >1, were higher in patients who DAS) has been recently proposed dem- in PsA (47). did not reach MiDA. Residual disease onstrating similar results using a shorter was more frequent in females, elderly version of the SF36 Questionnaire com- Therapy patients and those with a raised BMI, prising only 12 domains (SF12) (45). bDMARDs independently of the treatment sched- The treat-to-target strategy in PsA aims Kavanaugh et al. directly compared the ule; it negatively influenced PROs of at the attainment of remission, or, alter- disease burden and use of biologic drugs function and QoL. These data showed natively, low disease activity (LDA). between 2002 and 2013 in patients with that one third of the PsA patients with The GRAPPA and OMERACT groups PsA or RA who had been referred to the acceptable disease state according to met to develop consensus-based rec- rheumatology setting and enrolled in the treating rheumatologist did not ful- ommendations for the use of composite the Consortium of Rheumatology Re- fil the MiDA criteria and had residual measures and treat-to-target in PsA. The searchers of North America (Corrona) disease activity on both subjective and most popular measures voted by health registry, to discover whether the dis- objective disease activity measure- care professionals and patients were ease burden of PsA was different from ments, which is associated with worse the PsA disease activity score and the that of RA, whether this difference had PROs evaluation. Future strategy tri- GRAPPA composite index to be used changed over time, and whether biolog- als should be performed, to evaluate in randomised controlled trials, and ic treatment patterns had altered in the whether treatment adjustments could an average on 3 visual analogue scales wake of increases in published efficacy be beneficial for this PsA patient sub- and disease activity in the PsA score and safety data. They retrospectively group (42). for clinical practice. Nevertheless, the evaluated PsA and RA patients enrolled The Psoriatic Arthritis Impact of Dis- group failed to achieve a consensus on from January 2002 and March 2013 ease (PsAID) Questionnaire is a tool the best composite measure to be used. and grouped in 2-year intervals, assess- that was developed by a EULAR task The treatment target proposed by the ing clinical outcomes and biologic use. force to assess patient-reported out- group is that of a VLDA or MiDA. The They found an increasing in biologic come measures (PROs) to reflect the group agreed that the assessment of use over time in both cohorts, with 62 impact of PsA from the patients’ per- disease activity should comprise mus- and 52% of patients with PsA and RA, 172 Clinical and Experimental Rheumatology 2019
One year in review 2018: psoriatic arthritis / E. Calabresi et al. respectively, receiving biologics by duration of persistence with a new bD- GOL monotherapy treated patients. The 2012-2013. However, 25 and 35% of MARD – different TNFi or ustekinum- rates of serious adverse events serious patients with PsA and RA, respective- ab – was less than 12 months. Patients infections were 2.3 and 1.0/100-pa- ly, continued to experience moderate/ persisting on the first index biologic for tient-years, respectively; a quite low high disease activity. The progressive over one year were 44.5% of the popu- proportion of patients discontinued the increase in biologic use seemed to be lation (52). drug owing to adverse events (about associated to progressive decreases in Interestingly, extracting data from 329 11%), thus confirming an acceptable Clinical Disease Activity Index and patients from an Icelandic database safety profile of GOL in real life, with mean Health Assessment Questionnaire (ICEBIO), Runarsdottir et al. observed good values of SOD, particularly in AS scores. Quite surprisingly, the mean pa- that the majority of patients with PsA patients (54). tient pain, the proportion of patients re- were not eligible for randomised clini- Ruwaard et al. investigated if there porting morning stiffness, and the mean cal trials. ICEBIO registered patients were any differences in SOD and duration of morning stiffness remained with PsA who received ADA, ETN, clinical outcomes in patients with AS similar for both cohorts. Therefore, if GOL, or IFX as their first-line treat- treated with ADA or ETN. They en- these data showed that patients with PsA ment in the period from January 1, rolled biological-naïve consecutive and RA treated in the rheumatology set- 2000 to February 4, 2016. The authors AS patients; 163 were treated with ting had a comparable impact on patient described that only 34% of the patients ETN and 82 with ADA. Disease activ- quality of life and functional ability and with complete data available met the in- ity was assessed by the ASDAS-CRP; confirmed that the increased biological clusion criteria; particularly the propor- in particular, a stage of moderate dis- utilisation improved the disease burden tion of patients who met the inclusion ease activity (MDA) was defined as an in both groups, they highlighted that a criteria was highest among those who ASDAS-CRP
One year in review 2018: psoriatic arthritis / E. Calabresi et al. tively. The authors enrolled 1750 PsA QW for 12 weeks (double-blind phase) PsA; they also evaluated baseline patients (935 women). At baseline, and ETN 50 mg QW for 12 additional clinical and laboratory parameters as- women were significantly older, more weeks (open label). In this analysis, sociated with persistence on anti-TNF. often smokers, with significantly worse only 307 patients from Czech Repub- They retrospectively evaluated from PROs scores, with a significantly high- lic, Hungary, Poland and Serbia were their cohort of PsA patients, those er frequency of hospital-diagnosed included. The primary efficacy vari- who began anti-TNF therapy as first or anxiety or depression and with a higher able was the proportion of subjects second-line between 2003 and 2015. prevalence of chronic pulmonary dis- achieving a physician global assess- Demographic, clinical and laboratory ease than men. Median persistence on ment (PGA) of psoriasis status: “clear” characteristics were compared with anti-TNF alpha was 3.8 years in men or “almost clear” at week 12. The Au- TNFi persistence, using Kaplan-Meier vs. 1.4 in women (p
One year in review 2018: psoriatic arthritis / E. Calabresi et al.
Schoels et al. performed diagnostic test- ACR70 (39.2% and 39.6%) response milast 30 mg twice daily or placebo. At
ing analyses using 3- and 6-month dis- rates were sustained. A similar pattern week 16, patients whose swollen and
ease activity as tests for treatment out- was observed for PASI outcomes, while tender joint counts had not improved by
comes to understand the implications radiographic progression in all groups ≥10% were eligible for early escape. At
of early response. In regression analy- was minimal. Furthermore, the safety week 24, all patients received apremi-
ses, they estimated the probabilities for profile was consistent and the most fre- last through week 52. Among 219 ran-
achieving at least LDA. Disease activ- quently reported treatment-emergent domised patients (apremilast: n=110;
ity was measured by DAPSA. Their re- adverse events (≥4%) were nasophar- placebo: n=109), a significantly greater
sults showed that an early response to yngitis, injection site reaction, injection American College of Rheumatology 20
therapy at 3 months can be predictive site erythema, upper respiratory tract response at week 16 (primary outcome)
of future accomplishment of the target, infection, and back pain. No deaths was observed with apremilast versus
predicting 6-month and 1 year disease were reported, and serious adverse placebo (38.2 vs. 20.2%); at week 16,
activity outcomes and stressing the event frequency was 0–4% (64). apremilast significantly reduced PsA
need for a tight disease control based The role of IL17A is a well known tar- disease activity versus placebo, with
on a treat-to-target strategy (62). get of biological therapy; the role of the changes in DAS-28 CRP, HAQ-DI and
IL-17F seems to be similar in inflam- Gladman Enthesitis Index (p=0.001);
Interleukin-17A inhibition matory processes. A new biological these improvements were maintained
In a study by Nicola et al., 13 patients therapy, bimekizumab, could be a stra- with continued treatment through week
with PsO and PsA who failed at least tegic double-targeted therapy for the 52. Over 52 weeks, apremilast’s safety
one previous anti-TNF alpha, were treatment of patient with PsA. Indeed, profile was consistent with prior phase
treated with secukimumab and metho- bimekizumab is directed against both 3 studies in psoriasis and PsA; in par-
trexate, showing a rapid clinical re- these cytokines. It was studied in a pla- ticular, during weeks 0–24, the inci-
sponse of both cutaneous and articular cebo-controlled proof-of-concept clini- dence of protocol-defined diarrhoea
involvement; improving of PsO took cal trial in which the double action of was 11.0% versus 8.3% of placebo
place after 4 weeks and that of arthritis bimekizumab showed a fast and strong group; serious adverse event rates were
within 16 weeks, including also nor- ability to improve skin and articular 2.8% in the treated patients versus
malisation of the inflammatory indices disease in patients with PsA (65). 4.6% of the placebo group. These data
and improvement of the quality of the seemed to show that in biological-naïve
life parameters (63). IL-12/23 inhibition patients with PsA, the onset of the ef-
Ixekizumab (IXE) is a high-affinity The real-life effectiveness of usteki- fect of apremilast was observed at week
monoclonal antibody that selectively numab in patients with PsA, both na- 2 and continued through week 52, with
targets IL-17A and is an approved ïve or showing insufficient response to a safety profile in agreement with previ-
treatment for moderate-to-severe pso- previous TNFi, was assessed on a pro- ous reports (68).
riasis. In a recent phase III, multicen- spective observational study including
tre, double-blind, randomised study 65 patients, with a long-term follow-up New biological drugs
(SPIRIT-P1) van der Heijde et al. (24 months). Ustekinumab was pre- A new biological therapy anti-inter-
evaluated the efficacy and safety of scribed as first-line therapy only in 20% leukin 23p19, guselkumab, that has
IXE over 52 weeks in patients with ac- of cases, and mainly as second-line been approved to treat moderate-to-
tive PsA who were naive to bDMARD. bDMARD (33.8% of cases). The ef- severe PsO, in a study by Deodhar et
Patients were randomised (1:1:1:1) to fectiveness and safety of ustekinumab al., showed efficacy to treat also ac-
receive subcutaneous injections of pla- were confirmed (66). tive PsA, controlling its symptoms and
cebo (PBO), adalimumab 40 mg every Another Italian study, the real-life data mantaining a good profile of safety.
2 weeks (ADA), and IXE 80 mg every from the biologic Apulian registry Therefore, guselkumab could be a
2 weeks (IXEQ2W) or 80 mg every 4 (BIOPURE) reported on the drug sur- promising choice to treat both skin and
weeks (IXEQ4W). At Week 24 (Week vival and effectiveness of ustekinumab, articular involvement in PsA (69).
16 for inadequate responders), ADA showing the best performance (DAP-
(8-week washout before starting IXE) SA-based remission) of the drug when Supplementation therapy
and PBO patients were re-randomised used in bDMARDs-naïve patients. In- Kristensen et al. performed a ran-
to IXEQ2W or IXEQ4W. Both IXE terestingly, co-medication with metho- domised, double-blind, placebo-con-
dose regimens included an initial 160- trexate did not increase the persistence trolled study to evaluate whether the
mg starting dose. Of 417 patients ran- on therapy (67). use of n-3 polyunsatured fatty acids
domised, 381 completed the double- (n-3 PUFA) in patients with PsA could
blind period (52 weeks), at the end of Small molecules exert some effect on disease activity,
witch was observed that the IXEQ4W Nash et al. evaluated Apremilast effi- use of analgesics, and inflammatory bi-
and IXEQ2W groups (EPP), respec- cacy across various PsA manifestations omarkers levels. They enrolled 145 PsA
tively, ACR20 (69.1% and 68.8%), in biological-naïve patients with PsA. patients who received a supplement of
ACR50 (54.6% and 53.1%), and Patients were randomised (1:1) to apre- 3g n-3 PUFA/day or 3 g olive oil/day
Clinical and Experimental Rheumatology 2019 175One year in review 2018: psoriatic arthritis / E. Calabresi et al.
(control) for 24 weeks. Outcome meas- sion and no IA were twice as likely to PM: pacemaker
ures for disease activity, use of analge- be treated for hyperlipidaemia as those HU: hyperuricaemia
sics, and leukotriene formation from without IA, diabetes, or hypertension. BMI: Body Mass index
activated granulocytes were assessed at These data confirm the need to update US: ultrasound
baseline and at study end. At the end of hyperlipidaemia guidelines for patients MRI: magnetic resonance imaging
the observation period, the n-3 PUFA with IA, who should be considered as GRAPPA: Group for Research and
group showed a decrease in DAS28- an independent risk factor for CVD, to Assessment of Psoriasis and PsA
CRP, 68 tender joint count, enthesitis optimise the treatment and the clinical PTI: peritenon extensor tendon
score, and PASI, although not signifi- assessment in this kind of patient (71). inflammation
cantly different from the controls. In- IAS: intra articular synovitis
terestingly, there was a significant Abbreviations NAPSI: Nail Psoriasis Severity index
reduction in NSAID and paracetamol SpA: spondyloarthritis MASEI: MAdrid Sonographic
use compared with controls. Moreover, AAU: acute anterior uveitis Enthesitis index
the participants in the n-3 PUFA group PsO: psoriasis PD: power Doppler
had significantly lower formation of IBD: inflammatory bowel disease eMRI: extremity MRI
leukotriene B4 from stimulated granu- PsA: psoriatic arthritis EARP: early arthritis for psoriatic
locytes and significantly higher forma- ax-SpA: axial spondyloarthritis patients screening questionnaire
tion of leukotriene B5 compared with SIj: sacroiliac joint 3D UTE Cones: three-dimensional
controls. These data showed a decrease SI: sacroiliitis ultrashort echo time cones
in disease activity parameters after n-3 nr ax-SpA: non radiographic axial CPMG: Carr-Purcell Meiboom-Gill
PUFA supplementation, even if not sig- spondyloarthritis CS-SRM: common sense self-
nificantly different from the controls; CVD: cardiovascular disease regulatory model
on the contrary, the authors found a sig- OP: osteoporosis QoL: quality of life
nificant reduction in the use of NSAIDs HRQoL: health-related quality of life DLQI: Dermatology Life Quality index
and paracetamol and in the production IBP: inflammatory back pain PASI: Psoriasis Severity index
of inflammatory cytokines, in particular CRP: C-reactive protein MiDA: minimal disease activity
significantly lower levels of leukotriene TNF: tumour necrosis factor PRO: patient-reported outcome
B4 (70). ETN: etanercept PsAID: psoriatic arthritis impact of
IFX: infliximab disease
Therapy for comorbidities ADA: adalimumab LDA: low disease activity
Navarro-Millàn et al. analysed patients GOL: golimumab DAPSA: Disease Activity index for
from the Reasons for Geographic And SNPs: single nucleotide polymorphisms Psoriatic Arthritis
Racial Differences in Stroke (RE- MEFV: Mediterranean fever cDAPSA: Clinical Disease Activity
GARDS) study to understand whether TNFRSF1A: TNF receptor superfamily index for Psoriatic Arthritis
patients with inflammatory arthritis member 1A VLDA: very low disease activity
(IA) (PsA, AS and RA) were sufficiently FMF: familial Mediterranean fever PASDAS: Psoriatic Arthritis Disease
treated for dyslipidaemia, considering TRAPS: tumour necrosis factor Activity score
that hyperlipidaemia guidelines do not receptor-associated periodic syndrome PsARC: PsA response criteria
currently identify IA as a cardiovascu- lncRNAs: long non-encoding RNAs TICOPA: tight control of psoriatic
lar disease (CVD) risk factor. Subjects RA: rheumatoid arthritis arthritis
from the REGARDS study were classi- IFN: interferon MDA: moderate disease activity
fied as having IA (without diabetes and WNT: wingless/integrated TNFi: tumour necrosis factor inhibitors
hypertension), diabetes (without IA miRNAs: microRNAs SOD: survival on drug
and hypertension), hypertension (with- MAPK: mitogen-activated protein PRESTA: Psoriasis Randomised
out IA and diabetes), or no IA, diabetes kinase Etanercept STudy in subjects with
or hypertension. Multivariable logistic IL: interleukin psoriatic Arthritis
regression models examined the odds RT-PCR: reverse transcription poly- CEE: Central and Eastern Europe
of medical treatment among those with merase chain reaction PGA: physician global assessment
hyperlipidaemia. Thirty-nine partici- STAT: signal transducer and activator AIP: atherogenic index of plasma
pants had IA, 5423 had diabetes, 7534 of transcription CCI: Charlson Comorbidity index
had hypertension, and 5288 had no FOXP3: forkhead box P3 IXE: ixekizumab
diabetes, hypertension, or IA. The fully PEST: psoriasis epidemiology screen- PUFA: polyunsatured fatty acids
adjusted odds of treatment were similar ing tool NSAID: non-steroidal anti-inflamma-
between participants with IA and those CV: cardiovascular tory drug
without IA, hypertension, or diabetes. GP: general population REGARDS: Reasons for Geographic
On the contrary, patients with diabetes AV: atrioventricular And Racial Differences in Stroke
and no IA and patients with hyperten- AF: atrial fibrillation IA: inflammatory arthritis
176 Clinical and Experimental Rheumatology 2019One year in review 2018: psoriatic arthritis / E. Calabresi et al.
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