Recent advances in understanding and managing psoriatic arthritis

Why do we need to diagnose psoriatic arthritis early?

As noted above, PsA is associated with progressive joint damage, reduced quality of life and function, and increased mortality⁴. These untoward outcomes are related to preceding joint inflammation and accrued damage. It stands to reason that if we treat patients aggressively with the appropriate medications to control inflammation and prevent damage in the first place, we would improve their quality of life and function and allow a normal life span. Indeed, two recent studies support this notion. A study performed at the University of Toronto PsA clinic demonstrated that patients who were reviewed in the clinic within 2 years of PsA diagnosis fared better than those who were first evaluated in the clinic with longer disease duration⁶. The longer the disease duration prior to the patient’s first visit to the PsA clinic, the higher the risk of developing joint damage. A study performed in the PsA clinic in Dublin, Ireland, provided even more compelling evidence for the need to diagnose patients with PsA early. Haroon et al. demonstrated that even a 6-month delay in rheumatologic consultation (from the onset of symptoms) resulted in worse outcome for patients with PsA, with higher health assessment questionnaire (HAQ) scores, more erosions, and sacroiliitis⁷. Thus, it seems that the earlier that PsA patients are diagnosed, the better the outcome.

We have also recognized recently that patients with PsA suffer from a number of comorbidities, many of which are precipitated by persistent inflammation. Patients with PsA have an increased frequency of cardiovascular disease, diabetes, the metabolic syndrome, and depression⁸.

How do we diagnose psoriatic arthritis early?

Clinical features. There are several clinical features that may identify patients with psoriasis destined to develop arthritis^9–12. The extent of psoriasis is higher among patients diagnosed with PsA compared to psoriasis patients without arthritis (psoriasis cutaneous [PsC]). The location of psoriasis, especially involvement of the scalp and inter-gluteal areas, has also been reported to occur more commonly among patients with PsA than uncomplicated psoriasis. However, most dermatologists believe that scalp and inter-gluteal lesions are so common in psoriasis that they would not help identify those patients who should be referred to a rheumatologist. On the other hand, nail lesions occur in over 80% of patients with PsA compared to only about 40% of PsC patients.

In a prospective study of 464 patients with psoriasis who were confirmed not to have inflammatory arthritis at presentation to the clinic, 51 developed PsA during an 8-year follow-up, for an annual incidence of 2.7%. Baseline variables identified as risk factors for the development of PsA included severe psoriasis, low level of education, and the use of retinoids. Using a time-dependent analysis, nail pitting and uveitis remained significant in a multivariate model¹².

CASPAR criteria. The CASPAR criteria should also help to identify PsA early. While the criteria were established in patients who had long-standing disease, they work just as well in patients with early disease^13–16. However, the CASPAR criteria are based on the stem of inflammatory musculoskeletal disease. Only rheumatologists can accurately make that diagnosis. To address this issue, the Group for Research and Assessment of Psoriasis and PsA (GRAPPA) is developing criteria to identify inflammatory arthritis that can be used by non-experts¹⁷. Since it is not feasible for all patients with psoriasis to be reviewed by a rheumatologist, several groups have developed screening tools that can be administered to patients.

Screening tools for psoriatic arthritis

A number of screening tools were developed specifically for patients with psoriasis to identify those who have PsA^18–20. Two tools were developed for screening for PsA in the general population²¹. However, although all of these screening tools were very sensitive and specific in their development programs, when screening tools were compared in independent settings from those in which they were developed, they did not function very well²².

Ultrasound. The use of ultrasound may be helpful in identifying patients with PsA early, particularly among patients with psoriasis. Gisondi et al. performed an ultrasound study of entheses in 30 patients with psoriasis and 30 controls²³. They found that the entheses were thicker and the overall ultrasound score was higher in patients with psoriasis than in controls. They repeated the ultrasound assessment among the psoriasis patients 2 years later, and three of the 30 had developed PsA²⁴. However, a study that compared ultrasound in patients with PsA, patients with PsC, and healthy controls found that obesity is a confounder in distinguishing between the groups²⁵.

Biomarkers. Since psoriasis usually precedes the development of PsA, and dermatologists have difficulty identifying inflammatory arthritis, it would be helpful if clinicians had a biomarker that would identify those individuals likely to develop the disease. In the past few years, we have seen several biomarkers tested for PsA. These include genetic, epigenetic, soluble, and cellular biomarkers^26,27.

Among the genetic biomarkers, human leukocyte antigen (HLA) alleles that distinguish patients with PsA from those with PsC have been identified and replicated. In a study of 712 patients with PsA and 335 patients with PsC, Eder et al.²⁸ demonstrated that the HLA alleles B*08, B*27, and B*38 are risk factors for the development of PsA, whereas HLA-C*06 is “protective”. Similar observations were reported from the Dublin cohort, where it was also reported that the presence of HLA-B*27 was associated with the early development of PsA among patients with psoriasis but the presence of HLA-C*06 was associated with a delayed onset of PsA²⁹. Data from the immunochip studies in psoriatic disease confirmed differences between psoriasis and PsA at the HLA region and suggested that HLA-B amino acid position 45 may be driving this heterogeneity³⁰. Major histocompatibility complex (MHC) class I chain-related A (MICA) alleles have been associated with PsA; however, a study comparing PsA patients to PsC patients demonstrated that only homozygosity for the allele MICA*00801 was associated with PsA³¹.

Recent genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) near HLA-C, tumor necrosis factor (TNF) receptor superfamily member 9 (TNFRSF9), and late cornified envelope 3A (LCE3A) as being more strongly associated with psoriasis than PsA, whereas SNPs near interleukin 23 receptor (IL-23R) and TNF alpha-induced protein 3 (TNFAIP3) were more strongly associated with PsA than with PsC³². Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) was also found to distinguish patients with PsA from those with psoriasis alone³³. Gene expression profiling of patients with PsA and PsC also identified potential genes as biomarkers for PsA, including Notch 2 N-Terminal Like (NOTCH2NL), histone acetyltransferase 1 (HAT1), C-X-C motif chemokine ligand 10 (CXCL10), and SET domain containing 2 (SETD2)³⁴.

Soluble biomarkers may be more accessible in a clinic setting. Chandran et al.³⁵ found that levels of osteoprotegerin, high-sensitivity C-reactive protein (hs-CRP), cartilage oligomeric matrix protein (COMP), matrix metalloproteinase 3 (MMP-3), and the ratio of C-propeptide of type II collagen (CPII) to collagen fragment neoepitopes Col2-3/4 (C2C ratio) were higher in patients with PsA versus PsC. Two of these biomarkers, MMP-3 and hs-CRP, were replicated in a study that compared PsA patients to healthy controls, which also identified vascular endothelial growth factor as a potential screening tool for the detection of PsA³⁶. More recently, CXCL10, which has been identified in a microarray analysis as being a gene associated with PsA, was identified as a soluble biomarker for developing PsA among psoriasis patients followed prospectively³⁷. Psoriasis patients who subsequently developed PsA had higher levels of CXCL10 in the serum than those who did not develop PsA. Moreover, CXCL10 levels decreased in the serum after the development of PsA. A comparison of paired serum and synovial fluid (SF) samples from patients with PsA demonstrated higher levels in the SF compared to blood, suggesting that CXCL10 may be a biomarker for the development of PsA in psoriasis patients as well as having a pathogenetic role in the development of the disease.

Proteomic analyses of SF have also been performed to identify candidate biomarkers for PsA. Cretu et al. identified 137 proteins that were differentially expressed between PsA and control SF, of which 44 were upregulated³⁸. The expression of 12 proteins (myeloperoxidase [MPO], Mac-2-binding protein [M2BP], defensin alpha 1 [DEFA1], histone 4 [H4], histone 2A type I A [H2AFX], orosomucoid 1 [ORM1], CD5-like protein [CD5L], profilin 1 [PFN1], C4b-binding protein [C4BP], MMP-3, S100 calcium-binding protein A9 [S100A9], and CRP) was subsequently confirmed to be elevated in PsA SF using selected reaction monitoring assays. These markers are being investigated in the serum as potential biomarkers for PsA³⁹.

Cellular biomarkers have also been identified. An increased frequency of osteoclast precursors (OCPs) was found in one-third of patients with PsC and in the majority of patients with PsA⁴⁰. An increase in OCP correlated with erosive disease. The same group developed an antibody against a dendritic cell-specific transmembrane protein (DC-STAMP), which correlated with OCPs and may be another biomarker to identify patients with PsA early⁴¹. These biomarkers are currently being investigated in patients with psoriasis who progress to develop PsA.

Thus, a number of biomarkers are being sought that can identify patients with psoriasis who are destined to develop PsA. It is most likely that there will not be one biomarker but rather a combination of biomarkers that can be applied to most accurately identify patients with PsA early.

Genetic factors

Among genetic factors, the HLA loci have been the most persistently documented. Two recent case control studies confirmed the association between PsA and HLA-B*27, HLA-B*38, HLA-B*39, and HLA-C*06 compared to healthy controls^29,44. HLA-C*0602 is the allele most strongly associated with psoriasis and is also a risk factor for PsA. While HLA-C*0602 is associated with an earlier diagnosis of psoriasis, it is associated with a later diagnosis of PsA²⁹.

Non-HLA genes have also been implicated, both within and outside the MHC. Killer immunoglobulin receptor (KIR) genes, particularly KIR2DS2, have also been proposed as susceptibility genes for PsA⁴⁵. These genes are coded on chromosome 19 but use the HLA-C molecules as ligands.

GWAS have identified 40 loci in patients with psoriasis, many of which are related to immune function, including the endoplasmic reticulum aminopeptidase 1 (ERAP1), whose product is relevant to peptides binding to the MHC class I molecules, especially HLA-C*0602 and HLA-B*27⁴⁶. SNPs related to genes relevant to immune function include loci containing genes involved in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling (REL, TNF α-induced protein 3-interacting protein 1 [TNIP1], NF-kB inhibitor alpha [NFKBIA], and caspase recruitment domain family member 14 [CARD14]), interferon (IFN) signaling (interleukin 28 receptor A [IL-28RA] and tyrosine kinase 2 [TYK2]), T-cell regulation (Runt-related transcription factor 3 [RUNX3], interleukin 13 [IL-13], T-cell activation RhoGTPase activating protein [TAGAP], ever shorter telomeres protein 1 [ETS1], and methyl-CpG binding domain protein 2 [MBD2]), antiviral signaling (IFN-induced helicase C1 protein [‎IFIH1], DEXD/H-box helicase 58 [DDX58], and ring finger protein 114 [RNF114]), and genes involved in the IL-23 pathway which specifically implicate a role for Th17 cells (TNFAIP3, IL-23R, IL-12B, TNF receptor associated factor 3 interacting protein 2 [TRAF3IP2], IL-23A, and signal transducer and activator of transcription 3 [STAT3]). Most of these have also been identified in PsA, but only two of these loci were independently identified in PsA, namely IL-12B and IL-23R, with the IL-23R SNP being independent to the SNP found in psoriasis alone, and another region on chromosome 5q31 has also been identified as a marker for PsA^32,47.

Many of the genes listed above encode proteins that are important in the immune response, suggesting that genetic factors may exert their effect through immune mechanisms.

Immunological factors

The association with class I HLA alleles, the presence of activated CD8+ T cells and natural killer (NK) cells in the psoriatic synovium, and the response of the disease to immunomodulatory therapy indicate that the immune system, especially the lymphocytes, plays an important role in PsA pathogenesis⁴⁸. Both the innate and the adaptive immune responses are implicated in the pathogenesis of PsA. KIR receptors are found on NK cells and use the HLA molecules as a ligand, implicating the innate immune system. Increased levels of cytokines have been detected in the peripheral blood, skin, and synovium of patients with PsA. While the role of T cells has been suspected for many years, more recently the role of Th17 cells and the IL-17 axis has been elucidated.

Environmental factors

The association between environmental factors and psoriatic disease has long been known. Streptococcus infection followed by pustular psoriasis has been described. More recently, two studies confirm the association between infection and the development of PsA. Pattisson et al. compared the prevalence of environmental exposures among 98 British PsA and 163 psoriasis patients over a window of exposure that ranged from 5–10 years prior to the onset of arthritis⁴⁹. They identified physical trauma, rubella vaccination, oral ulcers, and moving house were found to be associated with PsA. Subsequently, another case control study was performed by Eder et al. in which they administered structured questionnaires to 159 patients with recent-onset PsA and 159 patients with PsC and found that infections that required antibiotic treatment, injuries, and occupations that involved lifting heavy weights were associated with PsA, while there was an inverse association with smoking⁵⁰. A population-based study identified obesity as a risk for developing PsA⁵¹.

Therapies under investigation

Several studies are currently ongoing in PsA. Abatacept, or CTLA-Ig, a selective T-cell costimulation modulator that is approved for the treatment of rheumatoid arthritis, was initially tested in a phase II study which demonstrated efficacy as well as reduction in MRI inflammation. A phase III study has just been completed and the results should be available soon. The Janus Kinase (JAK) inhibitor tofacitinib, also available for the management of rheumatoid arthritis, has also been tested in PsA. The results of these studies will be available soon. An IL-23 antibody has also been tested in psoriasis and will be tested in PsA.