Psoriasis to psoriatic arthritis in terms of complement proteins: A single center experience

Abstract

There are previously stated risk factors for the transition from psoriasis to psoriatic arthritis, but the immune mechanisms in this regard have not been adequately explained. In this study, we aimed to investigate this transition in terms of the complement system. Study was planned as a prospective analytical type. 46 psoriasis and 45 psoriatic arthritis patients were included in this study. Morning stiffness, nail involvement, disease activation questionnaire scores, neutrophil and lymphocyte percentage, neutrophil-lymphocyte rate, high-density lipoprotein, low-density lipoprotein, triglyceride, erythrocyte sedimentation rate, C-reactive protein, uric acid, complement 3 (C3) and 4 (C4) values were evaluated. Enthesis clinical assessment was done with the Leeds enthesis index (LEI). Ultrasonography was used to evaluate the enthesis sites. The severity of skin involvement in psoriasis was evaluated with the psoriasis area severity index (PASI). PASI scores were higher in psoriasis patients, while LEI scores, erythrocyte sedimentation rate and C-reactive protein levels were higher in psoriatic arthritis patients (P = .016, P = <.001, P = .016, P = .027, P = .020, respectively). Among psoriasis patients, C3 levels were higher in the patients with nail involvement (P = .035). C3 levels of psoriasis patients showed a moderate positive correlation between PASI and LEI scores (r = 0.368, r = 0.404, respectively). In psoriasis patients, high-density lipoprotein values were found to be moderately negatively correlated with both C3 and C4 (r = −0.311, r = −0.388, respectively). As a result of this study, C3 levels may play a role in the progression to psoriatic arthritis.

1. Introduction

Psoriasis is a disease that can affect the skin, scalp and nails as a result of excessive proliferation of keratinocytes. It is an autoimmune dermatological disease that can be triggered due to etiological reasons such as genetic, environmental and infectious.^[1] Psoriatic arthritis (PsA) is a chronic inflammatory disease, a member of the spondyloarthropathy group, in which bone erosions and/or new bone formation can occur in the axial or peripheral musculoskeletal system.^[2] Although psoriasis and PsA are 2 different diseases, they contain similar inflammatory mechanisms and common risk factors.^[3] Many factors such as scalp and nail involvement are discussed with psoriasis at increased risk of PsA transition.^[4]

While disease activation is evaluated according to the severity of skin involvement in psoriasis patients, both skin and musculoskeletal involvement are evaluated in PsA patients.^[5] C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) may increase in PsA activation, but may be also normal in active disease.^[6] There are some studies on laboratory differences between psoriasis and PsA, but data are still inconclusive.

Changes in the complete blood count due to chronic autoimmunity may be an indicator of the transition from psoriasis to PsA and systemic inflammation.^[7] In addition, components of metabolic syndrome such as hyperlipidemia and diabetes mellitus may aggravate psoriasis and accelerate disease transformation.^[8] Similarly, the pathogenic role of chronic hyperuricemia in the development of PsA does not appear to be incidental.^[9] Although the complement system has been supported by many studies to play a role in the pathogenesis of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, studies on the pathogenesis of PsA are limited.^[10,11] It has shown that high concentrations of complement 3 (C3) are found in the synovial fluid of PsA patients.^[11] Additionally studies also showed that the complement system was affected by tumor necrosis factor alpha in PsA patients.^[10,12] According to this information, there is a suspicion that “Could complement levels be a marker of transition from psoriasis to psoriatic arthritis?”. However, there is no study the effect of complement system on transition from psoriasis to psoriatic arthritis. Therefore, this study aimed to provide a detailed overview of a different immune mechanism, the complement system, that may be effective in this transition.

2. Methods

2.1. Study design and participants

This study was planned prospective analytic. The study protocol and design were approved by the Clinical Research Ethics Committee of Hatay Mustafa Kemal University Faculty of Medicine (14.10.2021/118 approval number), and it was conducted in accordance with the principles of the Helsinki Declaration. The patients attending the outpatients clinics of Giresun Faculty of Medicine, Physical Medicine and Rehabilitation, and Dermatology Departments between November 2021 and May 2022 were included. According to inclusion criteria, patients had been diagnosed psoriasis or PsA, had to be > 18 years of age. Patients with other systemic rheumatic disease, cardiovascular system disease, infectious and cancer disease, and under the age of 18 were excluded from the study. Additionally, individuals with mental retardation and pregnant women were not included.

2.2. Baseline assessment and outcome measures

Patients’ age, gender, height, body mass index, occupation, cigarette-alcohol use, presence of systemic disease, disease duration and treatment were questioned. Patients with PsA were identified according to Classification Criteria for Psoriatic Arthritis criteria.^[13] Morning stiffness, nail changes such as pitting and onycholysis in all fingers and toes, rash sites, joint pain, enthesis tenderness, enthesis changes, arthritis were evaluated in the history and examination. The severity of psoriasis was determined according to the psoriasis area severity index (PASI) score. In laboratory evaluation, neutrophil and lymphocyte percentage, neutrophil-lymphocyte rate (NLR), ESR, CRP, high-density lipoprotein (HDL), LDL, triglyceride (TG), uric acid, viral hepatitis serology, Human leukocyte antigen-B27, C3, C4 values were checked. Hyperuricemia was defined urate concentration > 6 mg/dL for woman and > 7 mg/dL for man.^[14] It was accepted as normal reference values for C3 0.86–1.6 g/L and for C4 0.17–0.45 g/L.^[15]

Psoriasis Area Severity Index (PASI) was used to determine the severity of psoriasis.^[16] Disease activity of patients with PsA was measured by Disease Activity in Psoriatic Arthritis score and Psoriatic Arthritis Impact of Disease -12 (PsAID-12) score.^[17,18] The Leeds enthesitis index (LEI) is used to evaluate the presence of enthesitis in patients. Pain and tenderness are evaluated in the lateral epicondyle, medial femoral condyle, and Achilles tendon region.^[19] The musculoskeletal ultrasonography (USG) was used for enthesis imaging and for Achilles enthesitis. It is characterized by tendon thickening, a hypoechoic appearance, increased fluid in the retrocalcaneal bursa, calcaneal cortical irregularity or enthesophyte formation, along with increased vascularity on doppler imaging (Fig.1). The calcifications and presence of bone lesions were examined as in the other studies.^[20] Findings were recorded as present or absent. USG brand used is Esoate MyLab Six (3–13 MHz MylabSix; Esaote Biomedica, Italy).

Figure 1.

Achilles enthesitis finding accompanied by calcaneal cortical irregularity.

2.3. Statistical analyses

A power analysis was performed on a study found in the literature, with a total of 96 patients (43 patients in each group); the effect size was calculated as 0.71, the power as 90%, and the margin of error as 0.005.^[12] The obtained research data were transferred to the computer environment and analyzed in the IBM SPSS (version 23.0) package program. Descriptive statistics were given as the number of units (percentage), mean ± standard deviation in quantitative data with normal distribution, and median (1st Quarter-3rd Quarter) values in non-normally distributed data. The normal distribution of the data of numerical variables was evaluated with the Shapiro–Wilk test of normality. Pearson Chi-square test or Fischer Exact test was used to compare categorical data. In the comparison of data between 2 independent groups, analysis was performed using the Student t Test for normally distributed variables and the Mann–Whitney U test for non-normally distributed variables. Spearman Rho correlation was used to show the relationship between quantitative data. As a result of correlation analysis | r | ≤ 0.30 weak correlation, 0.30 < | r | ≤ 0.70 moderate correlation, | r | > 0.70 was accepted as a strong correlation.^[21] Statistical significance level was accepted as P < .05.

3. Results

A total of 91 patients, including 45 PsA patients (26 females, 19 males) and 46 psoriasis patients (28 females, 18 males), were included in the study. No difference was found between the 2 groups in age, gender, body mass index, smoking-alcohol and comorbidity (P = .089, P = .764, P = .931, P = .303, P = .285, P = .750, P = 1.00 respectively). In PsA patients, USG findings were evident, and LEI scores, ESR and CRP levels were higher; however, PASI scores were higher in psoriasis patients (Table 1).

Table 1.

Comparison of clinical and laboratory datas of the study groups.

	Psoriatic arthritis (n = 45)	Psoriasis (n = 46)	P value
Duration of disease (years)	3.00 (1.00–11.50)	11.00 (5.00–30.00)	< .001
Morning stiffness (h)	0.75 (0.16–1)	0.00 (0.00–0.75)	.001
Medication used			NA
No	10 (22.2)	7 (15.2)
Topical	0 (0.0)	17 (37.0)
Anti-TNF	15 (33.3)	4 (8.7)
IL-17 inhibitor	4 (8.9)	6 (13.0)
cDMARD	16 (35.6)	7 (15.2)
Acitretin	0 (0.0)	5 (10.9)
Number of painful joint			.003
No	10 (22.2)a	25 (54.3)b
1–3	15 (33.3)a	13 (28.3)a
> 3	20 (44.4)a	8 (17.4)b
Enthesal changes	28 (62.2)	12 (26.1)	.001
USG	26 (57.8)	15 (32.6)	.016
Nail involvement	18 (40.0)	24 (52.2)	.244
Rash	34 (75.6)	40 (87.0)	.163
PASI	1.50 (0.15–3.75)	3.60 (1.20–8.63)	.020
PSAID-12	5.57 ± 2.30	–	U/D
DAPSA	17.30 (12.00–27.60)	–	U/D
LEI	2.00 (0.00–6.00)	0.00 (0.00–0.25)	< .001
HDL (mg/dL)*	48.23 ± 12.20	45.37 ± 10.18	.230
LDL (mg/dL)*	119.07 ± 26.55	109.13 ± 34.79	.132
TG (mg/dL)*	148.00 (111.50–203.50)	125.50 (84.25–177.25)	.078
Neutrophil%	61.05 ± 10.78	61.01 ± 8.98	.983
Lymphocyte%	29.64 ± 10.12	29.29 ± 9.32	.863
NLR	2.00 (1.47–2.96)	2.06 (1.64–3.00)	.657
HLA-B27	6 (13.3)	2 (4.3)	.158†
ESR (mm/h)	23.00 (16.00–37.00)	18.00 (9.75–23.50)	.016
CRP (mg/L)	3.69 (2.26–10.05)	2.07 (0.90–7.56)	.027
C3 (gr/L)‡	1.37 ± 0.21	1.35 ± 0.24	.622
C4 (gr/dL)‡	0.29 ± 0.10	0.27 ± 0.08	.366
Uric acid (mg/dL)‡	4.85 ± 1.35	5.06 ± 1.57	.494

The superscripts a, b show the difference between the groups. There is no difference in groups with the same letters.

Anti-TNF = anti-tumor necrosis factor, C3 = complement 3, C4 = complement 4, cDMARD = conventional disease-modifying antirheumatic drugs, CRP = C-reactive protein, DAPSA = disease activity in psoriatic arthritis, dL = decilitre, ESR = erythrocyte sedimentation rate, g = gram, HDL = high-density lipoprotein, HLA = human leukocyte antigen, L = liter, LDL = low-density lipoprotein, LEI = Leeds enthesis index, mg = milligram, mm = milimeter, n = number of patients, NA = not applicable, NLR = neutrophil-lymphocyte ratio, PASI = psoriasis area and severity index, PSAID-12 = psoriatic arthritis impact of disease-12, TG = triglyceride, U/D = unable to determine, USG = ultrasonography.

^*44 patients were analyzed in the psoriatic arthritis group.

^†Fisher’s exact test.

^‡44 patients were evaluated in the psoriatic arthritis group and 42 patients were evaluated in the psoriasis group.

C3 levels of psoriasis patients showed a moderate positive correlation between PASI and LEI scores (r = 368, r = 0.404, respectively). In psoriasis patients, HDL values were found to be moderately negatively correlated with both C3 and C4 (r = −0.311, r = −0.388, respectively). Patients were divided into 2 groups based on systemic medication use, no statistically significant differences were observed in C3 or C4 levels between the groups (P = .767 and P = .704, respectively). When psoriasis patients are grouped according to nail involvement, C3 and ESR levels were statistically higher in the group with nail involvement (Table 2); while HDL, LDL, TG, neutrophil percentage, lymphocyte percentage, NLR, CRP, C4, and uric acid values were similar between the 2 groups.

Table 2.

Comparison of inflammatory and complement parameters according to nail involvement in patients with psoriatic arthritis and psoriasis.

	Psoriatic arthritis		P value	Psoriasis		P value
Nail involvement	Yes	No		Yes	No
C3 (g/L)	1.35 ± 0.26	1.38 ± 0.16	.689	1.35 (1.25–1.59)	1.24 (1.12–1.41)	.035
C4 (g/L)	0.25 (0.21–0.33)	0.28 (0.23–0.35	.638	0.27 (0.22–0.30)	0.26 (0.20–0.32)	.751
CRP (mg/L)	4.48 (2.37–17.84)	3.61 (1.97–8.34)	.438	2.97 (1.52–9.13)	1.46 (0.70–4.51)	.075
ESR (mm/h)	25 (16,50–40,50)	22 (16–36)	.451	20 (14–31)	13 (7–23)	.029

C3 = complement 3, C4 = complement 4, CRP = C-reactive protein, dL = deciliter, ESR = erythrocyte sedimentation rate, g = gram, h = hour, L = liter, mg = miligram, mm = milimeter.

4. Discussion

In this study, which aimed to investigate the relationship between complement levels and the transition from psoriasis to PsA, we found higher serum C3 levels in patients with nail involvement. Since nail involvement is known to be a significant risk factor for PsA transmission, it can be inferred that serum C3 levels may also be a helpful laboratory predictor of this transmission.

Psoriasis and PsA are 2 closely related diseases with similar risk factors originating from a common pathophysiological mechanism. The presence of psoriasis is a risk factor for PsA and it is expected that some psoriasis patients will evolve to PsA.^[22] It is thought that some factors such as hyperlipidemia, diabetes mellitus affect severity of the disease, and scalp and nail involvement that increase risk of transition to PsA, but the effect is not clear.^[2,23,24] In some studies, it has been reported that inflammation begins in the skin, synovium, and enthesis regions before clinical symptoms appear in PsA patients. When arthritis, dactylitis, and enthesitis develop, it becomes more difficult to improve symptoms and achieve remission.^[25] While lipid panel deterioration and high uric acid levels can be detected in both diseases; in addition, an increase in C3, C4, CRP, ESR levels and changes in blood cell count can be expected in PsA.^[8–10] Detecting the disease early and preventing the conversion from psoriasis to PsA play a key role in preventing both disease activation and comorbidities. This study is the first to compare psoriasis and PsA in laboratory parameters including complement levels.

There are many studies in the literature addressing the changes in lipid metabolism in psoriasis patients. It was supported that lipid metabolism is closely related to psoriasis and PsA diseases.^[26] Research by Şirin et al^[27] had demonstrated that patients with psoriasis were compared with healthy volunteers, the monocyte-HDL ratio was found to be higher and HDL levels were found to be significantly lower in patients with psoriasis. As a results it was suggested that they could be used as markers of systemic inflammation in patients with psoriasis. Pietrzak^[28] had demonstrated HDL levels were lower in patients with psoriasis and PsA compared healthy subjects. The complement system and complement-related protein deficiency play a role in autoimmune diseases and inflammatory diseases.^[29] Ursini^[30] had found a negative correlation between C3 and HDL in PsA patients and suggested that C3 levels are associated with cardiovascular risk and metabolic syndrome. According to the data in our study, although lipid panel levels were similar between psoriasis and PsA patient groups, a moderate negative correlation was observed between HDL and C3 in psoriasis patients, and no correlation was observed in PsA patients. The absence of this relationship in PsA, as seen in psoriasis, can be explained by the possible accumulation of C3 in the joints during arthritis development.

The coexistence of psoriasis and uric acid elevation is frequently observed, and it is associated with cardiovascular disease) and metabolic syndrome. It was stated in a meta-analysis that serum uric acid level was correlated with psoriasis.^[31] It was also reported that gout and PsA have a close pathological background and similar comorbidities.^[9] In our study, when psoriasis and PsA patients were compared, uric acid levels were similar and no correlation was found between uric acid levels and PASI scores. Since the uric acid levels were normal in the majority of the patient groups and the patients were under treatment, may not be correlation was observed between skin involvement and uric acid level. The NLR has proven its prognostic value in cardiovascular disease, infections, inflammatory diseases and various types of cancer.^[32] Wang et al found that NLR was higher in psoriasis patients than in the normal population, and suggested that it was a marker of systemic inflammation,^[7] and Nabori et al^[33] also found that NLR was reduced by anti-inflammatory agents such as tumor necrosis factor inhibitors. In our study, there was no statistically significant difference in NLR between psoriasis and PsA patients. This result may have been due to the patients being under anti-inflammatory treatment.

The complement system is involved in various autoimmune and inflammatory processes.^[34] In synovial fluid the highest C3 concentration was found in PsA patients compared with rheumatoid arthritis and osteoarthritis in a research by Partsch.^[11] Some studies have suggested that C3a has a role in inflammatory diseases of the skin, especially psoriasis and allergic contact dermatitis.^[34,35] There is limited information about the role of C3a in PsA. In our study, when psoriasis patients were evaluated, a moderate positive correlation was found between PASI scores and C3. However, no correlation was observed between complement levels and disease activation assessment questionnaires (DAPSA, PSAID-12) in PsA patients. Based on these data, C3 levels may be more effective in demonstrating disease activation in psoriasis than PsA. Previous studies have shown that PsA has high concentrations of C3 in synovial fluid; this result may explain why serum C3 levels were not high in PsA patients in our study

Subclinical enthesopathy in patients with psoriasis is not uncommon. It has shown that enthesitis sensitivity develops before PsA.^[36] In our study, psoriasis patients with enthesal changes were not included in the PsA group because they did not describe enthesal tenderness. When the enthesopathy was compared between the psoriasis and PsA patient groups; LEI score was found to be higher in the PsA group. There was moderate positive correlation between LEI scores and C3 levels in psoriasis patients. Accordingly, these findings suggest a potential association between systemic inflammation and the complement system in psoriasis patients with asymptomatic entheseal changes. However, the absence of correlation between LEI scores and C3 level in PsA patients suggests that there are differences in the relationship of the underlying pathological mechanism with the complement system for the 2 diseases.

In psoriatic disease, nail lesions can manifest as pitting, onycholysis, hyperkeratosis, discoloration of the nail bed, and splinter hemorrhage. Due to the proximity of extensor tendon attachment sites to the nail root, nail involvement is associated with distal interphalangeal joint arthritis. In the current study psoriasis patients were divided into 2 groups as patients with and without nail involvement, C3 values were found to be higher in patients with nail involvement. Considering that nail involvement in a risk factor in the transition to PsA, it can be thought that C3 may also have a role in this transition. More higher ESR levels in the with nail involvement also support this.

This study has several limitations that should be considered when interpreting the results. First, the absence of healthy control group limits our ability to determine whether the observed serum C3 and C4 levels represent disease-specific alternations or reflect broader inflammatory or metabolic changes present in the general population. Second, complement levels were assessed only in serum, and synovial fluid analysis was not performed. Given that previous studies have demonstrated increased complement activation locally within the synovial compartment of PsA patients, the lack of synovial fluid data may have limited our ability to capture site-specific immune mechanisms. Finally, most patients were receiving ongoing treatment, including biologic agents, which may have influenced circulating complement levels and inflammatory markers. Longitudinal, treatment-naïve cohort studies are therefore warranted to better evaluate the predictive value of complement components in disease progression.

In summary, Serum C3 levels are associated with clinical features known to increase the risk of PsA development in patients with psoriasis, including nail involvement, disease severity, and subclinical enthesis. These findings suggest that C3 may serve as a potential biomarker for disease progression. However, longitudinal studies are required to confirm its predictive role in the transition to PsA.

Author contributions

Conceptualization: Evren Er.

Data curation: Evren Er.

Formal analysis: Evren Er, Ilker Fatih Sari.

Investigation: Evren Er, Sevgi Kulakli.

Methodology: Evren Er, Nurce Cilesizoglu Yavuz, Ilker Fatih Sari, Sevgi Kulakli.

Project administration: Evren Er, Nurce Cilesizoglu Yavuz, Sevgi Kulakli.

Resources: Evren Er, Nurce Cilesizoglu Yavuz, Fazil Kulakli, Sevgi Kulakli.

Validation: Evren Er, Nurce Cilesizoglu Yavuz, Ilker Fatih Sari, Fazil Kulakli.

Visualization: Evren Er, Nurce Cilesizoglu Yavuz, Ilker Fatih Sari, Fazil Kulakli.

Writing – original draft: Evren Er, Fazil Kulakli.

Writing – review & editing: Nurce Cilesizoglu Yavuz.