Predictive role of serum rheumatoid factor in different disease pattern of psoriasis and psoriatic arthritis

Psoriasis is a multisystem inflammatory disorder with variable morphology, clinical pattern and multiple comorbidities. Interplay between genetic and environmental factors leading to an aberrant immune response in the skin may contribute to disease development. The assessment for risk factors, signs, and symptoms of potential comorbid diseases is an important component of patient management. The aim of this study is to determine rheumatoid factors (RF) positivity and its levels in psoriasis patients, and describe its relationship with the demographic and clinical characteristics, comorbidities, and disease patterns of psoriasis. Rheumatoid factor was positive in psoriatic patients more than control,30% of patients had positive rheumatoid factor while only 10% of control had positive results. Rheumatoid factor level was 63.8 ± 186.7 IU/ml in psoriasis vs. 9.3 ± 12.3 in control. Thirty percent of psoriasis patients have positive rheumatoid factor vs. 10% of control. There was no significant statistical difference between psoriasis patients with or without arthritis as regard rheumatoid factor positivity and titer; rheumatoid factor was positive in 20% in psoriatic patients with arthritis vs. 26% in psoriatic patients without arthritis. In psoriatic patients, the status of rheumatoid factor did not relate to disease severity, onset, course, site of affection, presence of scalp, nail affection, and presence of dactylitis (p value>0.5). Psoriasis was associated with higher seropositivity of RF compared to age-matched non-psoriatic healthy controls. Occurrence and level of rheumatoid factor were not associated with severity or clinical pattern of psoriasis.


Background
Rheumatoid factors (RFs) are antibodies against the Fc portion of immunoglobulin G (IgG), Although they gain their name because of their first detection in RA patients, RFs are found in patients with other autoimmune and non-immune diseases, as well as-in healthy people. RF is not routinely detected in the absence of an antigenic stimulus; as direct infection by virus, chronic antigenic stimulation by immune complexes [1,2]. RF has some potentially pathogenic and other potentially beneficial activities. There is evidence that RF may promote pathological inflammatory cytokine production through interactions with anti-citrullinated peptide antibodies (ACPA) immune complexes in rheumatoid arthritis. Possible beneficial functions include processing of antigens in immune complexes, Presentation of antigens to T lymphocytes, Immune tolerance, amplification of the humoral response to infection and Immune complex clearance [3][4][5].
Psoriasis is a chronic inflammatory papulosquamous cutaneous disease with dysregulated keratinization manifested by well-demarcated, erythematous plaques with silver scales and associated with variable comorbidities.

Open Access
The Egyptian Journal of Internal Medicine Different presentations might occur such as guttate, pustular, erythrodermic, inverse, and nail psoriasis. The international prevalence of psoriasis is approximately 2-3% with a much lower prevalence in younger ages. The peak age at onset in adults is in the third and fourth decade of life, with a slight more prevalence in males. There is no clear definition or diagnostic criteria proposed for psoriasis and the diagnosis is essentially clinical [6,7]. Dysregulation of the immunity is now recognized as a critical event in this disease; suggested by the inflammatory response in the psoriatic skin and synovial lesions. IL-23 and IL-12 produced by activated dendritic cells promote the development of Th17 and Th1 cells [8].
Psoriatic arthritis (PsA) is a type of inflammatory arthritis that occur in up to 30% of patients with psoriasis; which may be peripheral, axial, or both. It present as an asymmetric oligoarthritis, symmetrical polyarthritis, arthritis of the distal interphalangeal (DIP) joints, as a destructive arthritis (arthritis mutilans), or as a spondyloarthritis. Patterns often overlap; enthesitis, dactylitis, and tenosynovitis can also occur. Other forms of arthritis can occur in patients with psoriasis, such as rheumatoid arthritis, osteoarthritis, gout, reactive arthritis, and the arthritis of inflammatory bowel disease [9]. The exclusion of other arthropathies is dependent on the pattern of joint involvement, serological markers, joint imaging, and synovial aspirate analysis. Certain clinical features may suggest PsA in the absence of psoriasis (psoriatic arthritis sine psoriasis), such as distal joint involvement, an asymmetric distribution, nail lesions, dactylitis, and the family history [10,11].
Laboratory findings in psoriasis and PsA are nonspecific and not differentiate it from other forms of inflammatory arthritis. Autoantibodies such as rheumatoid factor, anti-nuclear antibodies (ANA), and anti-citrullinated peptide antibodies (ACPA) are present in a minority of patients. RF is found in 2 to 10% of psoriatic arthritis patients [12].
The aim of this study is to assess the frequency and levels of rheumatoid factor in psoriasis patients, and describe its relationship with the different disease patterns of psoriasis including the demographic, clinical patient characteristics and comorbidities.

Study design
This case control study was carried out between April 2018 and March 2020 on total number of 90 subjects divided into 2 groups: group (I): 50 patients with psoriasis vulgaris as patient group and group (II): 40 ageand sex-matched healthy volunteers as a control group and was conducted with approval of ethical committee in faculty of medicine Menoufia University. The diagnosis of psoriasis was based on clinical findings and assessment by dermatologist.
Patients with history of malignancies, other dermatological diseases than psoriasis vulgaris, symptoms of any infection were excluded from the study.
A formal consent that was in accordance with the Helsinki Declaration in 1975 (revised in 2000) was obtained from all participants before starting the study.
Assessments were carried out by face-to-face clinical interviews and patients were excluded if they had a history of rheumatoid arthritis, or other autoimmune disease and pregnancy. Serum rheumatoid factor was measured to patients and controls was measured by nephlometric method.
Complete general examination, thorough dermatological examination with determination for the site of the lesion, the course of psoriasis was evaluated as progressive or stationary during history taking and the onset of psoriasis was classified as early onset which arises at or before the age of 40 and late-onset psoriasis which occurs afterwards the age of 40.
Sample size calculated with right size software assuming the prevalence of psoriasis. Data were collected on a specifically designed questionnaire to record sociodemographic and clinical details such as comorbid diagnoses, age at onset of illness, duration of illness, and family history.

Statistical analysis
The data collected were tabulated and analyzed by SPSS (statistical package for the social science software) statistical package version 20.0 (IBM Corp., USA). Continuous variables are presented as mean ± standard deviation (SD). Student's t test was used for normally distributed data and Mann-Whitney U test for the not normally distributed data comparison between the 2 groups. For the qualitative data, it was expressed in the form of number and percentage (No and %) then it was analysed by applying χ2 (chi-square) and Fisher's exact for comparison between two or more independent qualitative variables normally distributed. The level of significance was set at P < .05.

Results
The baseline sociodemographic profile characteristics of the patients who had psoriasis (case subjects) and those who remained free of psoriasis (controls) are shown in  Table 2).
Twenty-percent of psoriasis patients have psoriatic arthritis. Thirty-percent was axial and 70% was peripheral arthritis. Eighteen percent of psoriasis patients had only arthralgia without true arthritis (Table 3).
There was significant statistical difference between psoriasis patients and control as regards rheumatoid factor positivity and titer. Rheumatoid factor was positive in 30% of psoriatic patients while only 10% of control had positive result. Rheumatoid factor level was 63.8 ± 186.7 IU/ ml in psoriasis vs. 9.3 ± 12.3 IU/ml in control (Table 4).
There was no significant statistical difference between psoriasis patients with or without arthritis as regard rheumatoid factor positivity and titer. Rheumatoid factor was positive in 20% in psoriatic patients with arthritis vs. 26% in psoriatic patients without arthritis. RF was 43.2 ± 103.2 IU/ml in psoriatic patients with arthritis vs. 40.2 ± 53.5 IU/ml in psoriatic patients without arthritis (Table 5).
There was no significant statistical difference in rheumatoid factor in psoriasis patients as regard disease severity, onset, course, site of affection, presence of scalp, nail affection, and presence of dactylitis (Table 6).

Discussion
Psoriasis encompasses several distinct clinical phenotypes representing a morphological, anatomical, and qualitative spectrum of the same disease. Disease  [15,16]. Arthritis appears after skin lesions in most patients with PsA. Conversely, the arthritis precedes the skin lesions in 13 to 17% of patients [17].
There are no clear guidelines regarding the indications for ordering RF in psoriasis. When RF is combined with other clinical data (such as C-reactive protein and joint count), prediction could be improved. Rheumatoid factors have been found in up to 4% of healthy individuals. The reported incidence may be higher in older subjects without rheumatic disease, ranging from 3 to 25%. However, other studies have reported that the prevalence of RF among healthy older individuals is low and does not increase with aging [18].
The present study assessed the frequency and level of rheumatoid factor in psoriasis patients and healthy controls. There was significant statistical difference between psoriasis patients and control as regard rheumatoid factor positivity. Rheumatoid factor was positive in 30% of psoriatic patients while only 10% of control had positive result. Rheumatoid factor level was 63.8 ± 186.7 IU/ml in psoriasis vs. 9.3 ± 12.3 IU/ ml in control. Thirty percent of psoriasis patients have positive rheumatoid factor vs. 10% of control. These findings are not in line with the seronegativity concept of psoriasis [19]. This might be explained by racial factors or associated occult rheumatoid arthritis in psoriasis patients.
This study revealed no significant statistical difference between psoriasis patients with or without arthritis as regard rheumatoid factor positivity. Rheumatoid factor was positive in 20 % in psoriatic patients with arthritis vs. 26% in psoriatic patients without arthritis. It was 43.2 ± 103.2 IU/ml in psoriatic patients with arthritis vs. 40.2 ± 53.5 IU/ml in psoriatic patients without arthritis. 20 % of psoriasis patients have psoriatic arthritis. Thirty percent was axial and 70% was peripheral arthritis. Eighteen percent of total psoriasis patients have only arthralgia without true arthritis.   There is a significant risk of psoriatic arthritis (7-48%) in patients with plaque-type psoriasis. Hence, it is recommended to evaluate for its presence by history and clinical examination, and if necessary, by appropriate imaging. PsA is a seronegative arthritis; RF and CCP are negative in most patients with PsA, and if patients do have positive test for RF or CCP, the titers are usually low [19]. In a study comparing patients with RA or PsA and controls, the mean RF and anti-CCP titer values were higher in patients with RA compared with PsA. Titers in patients with PsA were similar to values in controls [20].
Average severity of psoriasis was moderate in the participants in this study. Illness severity assessment showed that 40% have mild disease instead 38% have moderate disease and 22% have severe disease. There is no associated relationship between rheumatoid factor status and severity of psoriasis in both sexes. Psoriasis severity was rated on BSA scale which is dependent on body surface area. the psoriasis area severity index appears to be the most reliable severity score in the assessment of psoriasis [21]. Many potential factors contribute to severity of psoriasis. Genetic factors include HLA-Cw6 and mutations of CARD14. Environmental risk factors have been implicated also, including infections, medications, hypovitaminosis D, and lifestyle [22,23].
There was a significant statistical difference between both groups as regard positive family history of psoriasis. Thirty-two percent of patients with psoriasis have positive family history of psoriasis vs. 7.5% in control group.
There are multiple clinical subtypes of psoriasis. Chronic plaque psoriasis, the most common presentation of psoriasis, most commonly presents with sharply defined erythematous plaques with overlying silvery scale. The scalp, extensor elbows and knees are common locations for plaque psoriasis. A diagnosis of psoriasis can be made by history and physical examination in most cases. Occasionally, a skin biopsy is needed to rule out other disorders. Nail affection in psoriasis include nail pits and onycholysis occur in about 80 % of patients with Psoriatic arthritis. The severity of  psoriatic nail involvement correlates well with severity of both skin and joint affection [24,25]. Plaque psoriasis is the most common pattern of psoriasis in this study, accounting for more than 90% of all cases. In this study, analysis of clinical characteristics of psoriasis patients reveals that 54% have early onset disease vs. 46% have late onset disease. Sixty-eight percent have progressive course while 32% have stationary course. Fifty-eight percent have scalp affection, 30% have nail affection, 56% have palm affection, 45% have kobenerization, and 6% have dactylitis. Among our patients with psoriasis, 26% have axial affection, 32% have extremities affection, and 52% have axial and extremities affection.
The inclusion of patients with variable patterns of psoriasis is an important advantage of this study; clinical diagnosis is established on clinical diagnosis of psoriasis. RF is a simple test used, and a major advantage of RF lies in its easy availability in most medical laboratories. Further, the study participants were systematically recruited. Based on these data, our sample seems to be representative for Menoufia population of patients diagnosed with psoriasis in tertiary hospital care.
Role of biomarkers is not only limited up to etiopathogenesis of psoriasis but also correlate with severity of the current psoriasis flares. The recent knowledge of the role of the immune system in psoriasis has had a significant impact on therapeutics that target specific immunologic aspects of psoriasis [26,27]. It is recommended that more epidemiologic studies should be conducted in Egypt for estimating the accurate prevalence of psoriasis patterns.

Limitations of the study
Study global sample size may be an important limitation of the study, and also the interviewers were not blinded. Isotypes of Rf(IgA and IgG), anti-ccp, and HLA B 27 were not evaluated. The absence of other medical disorders in subjects was based on history given by the subjects and not by any clinical workup of participants. Finally, we investigated a sample of patients to rheumatology and dermatology tertiary hospital care, and consequently, our findings cannot be generalized to patients with milder psoriasis treated in primary care.

Conclusions
This study included psoriasis which is a major health issue in general population and explored the role of immune dysregulation along. Psoriasis was associated with higher seropositivity of RF compared to age-matched non-psoriatic healthy controls. Raised RF was not associated with severity or pattern of psoriasis. In conclusion, our study suggests that immune dysregulation has an important role in the.