Association of serum calcium level and serum uric acid level in psoriasis and its correlation with severity of psoriasis

INTRODUCTION

Psoriasis is a common, chronic, disfiguring, inflammatory and proliferative condition of the skin, in which both genetic and environmental factors play a critical role [1]. A number of risk factors have been recognised in the etiopathogenesis of psoriasis, including family history and environmental risk factors such as diet, obesity, smoking, stress, and alcohol consumption. Psoriasis tends to worsen during periods of stress, during adverse environmental conditions such as cold weather, low humidity, with the administration of certain drugs, during the course of infection in addition to ethnic factors [1]. Increased mitotic activity in the basal cell layer results in rapid cell turnover in the epidermis with the cell cycle being cut short to 3–5 days from the normal 28 days. Mitosis involves purine metabolism, the end product of which is uric acid. Therefore, increased mitotic activity in psoriasis is expected to show a rise in uric acid levels [2]. Elevated serum uric acid levels are a frequent finding in psoriasis. Consequently, a relationship might well be expected between hyperuricemia and the extent of psoriatic skin involvement [3]. Many studies have especially identified a direct association between serum uric acid levels and psoriatic arthropathy although its relation to the extent of skin involvement has not yet been proven beyond doubt [4]. Currently available studies have shown that hyperuricemia is not only directly related to gout, but also to cardiovascular disease (especially sudden cardiac death), hypertension, diabetes, metabolic diseases, etc. [5, 6].
Hyperproliferation of the skin in psoriasis is controlled by intracellular calcium. It also controls the keratinocyte differentiation [7]. It has been observed that there is a disturbance in the metabolism of calcium in few cases with psoriasis e.g. “Pustular psoriasis of von Zumbusch” is associated with mild hypocalcaemia [8]. It has also been shown that decreased serum calcium levels exacerbate psoriasis. This is because calcium has an important role in the regulation and differentiation of keratinocytes. Cell adhesion molecules can be damaged by hypocalcaemia [9] leading to increased turnover of keratinocytes.

OBJECTIVE

The aim of this study was to analyse serum calcium and uric acid levels in patients with psoriasis in comparison with non-psoriatic controls and correlate them with disease severity.

MATERIAL AND METHODS

This was a cross-sectional observational, hospital-based study conducted at a tertiary care hospital, after obtaining approval from the institutional ethical committee. A total of 100 patients (above 18 years of age and irrespective of gender) attending the skin OPD during a period of 3 months were enrolled in the study by the convenient sampling method and divided into two groups, A and B.
Group A consisted of 50 patients with different types of clinically (morphological appearance, positive Grattage test, and Auspitz sign) and histopathologically diagnosed psoriasis. Group B consisted of 50 patients with other pruritic dermatoses of various aetiologies such as infections (superficial fungal infections), infestation (scabies), autoimmune (lichen planus), other immune-mediated dermatoses (urticaria, chronic actinic dermatitis, eczema, etc.) to be compared against psoriasis which is an autoimmune-mediated pruritic skin condition.
The patients who fulfilled inclusion criteria were recruited for the study after taking informed written consent.
Exclusion criteria: patients unwilling to completely adhere to the study protocol, known history of any chronic medical disease like diabetes mellitus, hypertension, tuberculosis, and gout, patients currently taking (supplementing) vitamin D (within 2 months), those receiving concomitant treatments with the ability to influence serum calcium and serum uric acid, pregnancy, and lactation.
The data regarding age, sex, symptoms, duration of disease, treatment history, smoking and alcohol, family history, history of chronic renal failure and gout were recorded in a pre-designed pro form. Both groups were matched in terms of gender and age distribution. A detailed general and dermatological examination was conducted. The type and distribution of lesions were noted. Severity of psoriasis was assessed according to Psoriasis Area Severity Index (PASI) and Body Surface Area (BSA). Patients were categorized into mild (PASI 11–20, BSA < 10%), moderate (either PASI > 21 or BSA > 10%) and severe (PASI > 21, BSA > 10%). Serum calcium and serum uric acid was estimated in all the patients and recorded. Hypocalcaemia was defined as serum calcium level < 8.5 mg/dl and hyperuricemia was defined as serum uric acid level ≥ 7 mg/dl as per the kits available.

Statistical analysis

All the results were recorded, tabulated, and analysed according to statistical proportions and the correlation was analysed using Pearson c2 test. The level of statistical significance was set at p < 0.05.

RESULTS

The age of the patients ranged from 22 years to 81 years in Group A and 20 years to 74 years in Group B. Most patients (26%) belonged to the 40–49 years age group in Group A and 28% belonged to the 18–29 years age group in Group B.
The mean age was 48.54 ±15.47 years (Group A) and 45.0 ±16.9 years (Group B). Group A comprised of 27 (54%) males and 23 (46%) females. Group B comprised of 31 (62%) males and 19 (38%) females.
Among the psoriatic group, 45 patients had plaque psoriasis (90%), 2 patients had palmoplantar and pustular psoriasis each (4%) and 1 patient had erythrodermic psoriasis (2%) (fig. 1).
According to BSA and PASI, the psoriatic group (Group A) was categorised as mild (50%), moderate (22%) and severe (28%) (fig. 2).
The control group of other pruritic dermatoses comprised of superficial fungal infection (64%), scabies (12%), eczema (14%), urticaria (2%), chronic actinic dermatitis (2%), lichen planus (4%), and prurigo nodularis (2%) (fig. 3).
Hypocalcaemia (< 8.5 mg/dl) was seen in 44% of psoriasis patients, whereas it was seen in only 12% of control patients. Hyperuricemia (> 7 mg/dl) was seen in 22% of patients of the psoriatic cases whereas it was seen in only 14% of patients of the control group.
Table 1 shows that the difference of serum calcium levels between cases (8.87 ±1.01 mg/dl) and controls (9.66 ±0.71 mg/dl) was significant (p = 0.01). Table 2 shows that the difference between mean serum uric acid levels of cases (5.84 ±1.78 mg/dl) and controls (5.38 ±2.41 mg/dl) was not statistically significant (p = 0.280).
Table 3 shows that the mean serum calcium level (mg/dl) was 9.17 ±0.83, 9.21 ±0.93 and 8.21 ±1.12 in mild, moderate, and severe psoriasis, respectively. 24% of mild, 45% of moderate and 79% of severe psoriasis showed hypocalcaemia. All three patients with the severe variants of psoriasis, i.e. generalised pustular psoriasis and erythrodermic psoriasis had hypocalcaemia and normal serum uric acid levels.
The mean serum uric acid level (mg/dl) was 5.56 ±1.36, 4.76 ±1.49 and 7.30 ±1.60 in mild, moderate, and severe psoriasis, respectively. 8% of mild, 9% of moderate and 57% of severe psoriasis showed hyperuricemia.
Table 3 also depicts the comparative values of serum calcium and serum uric acid among different severity categories in the psoriasis group. The p-value calculated for inter-level comparisons was statistically significant (0.012 and 0.000, respectively).
The post-hoc test showed that p-value of comparison between mild and severe disease and moderate and severe disease was < 0.05, which was statistically significant. Table 4 shows that the mean serum calcium levels were significantly lower in psoriasis patients compared to the controls. Serum calcium level was compared across severity of psoriasis. Severity (PASI and BSA) was negatively correlated to the serum calcium level (Pearson correlation coefficient –0.320).
The mean serum uric acid levels were significantly higher in psoriasis patients compared to the controls. Severity in terms of PASI and BSA was positively correlated to the serum uric acid level (Pearson correlation coefficient 0.446).
Table 5 shows that the correlation between age and, serum calcium and serum uric acid was not significant.

DISCUSSION

Psoriasis is a chronic inflammatory, hyper-proliferative disease, characterised by increased frequency of mitosis in epidermal basal cells. In psoriasis, the skin lesion is a result of hyperplasia of the epidermis in which the rate of cellular reproduction is accelerated to such an extent that maturation of the epidermal cells and the process of normal keratinization do not occur. By analogy with the hyperuricemia seen in myeloproliferative diseases, it is possible that the hyperuricemia of psoriasis may reflect an increased nucleic acid turnover resulting from the marked acceleration of epidermal proliferation that occurs in this disease. Several studies have demonstrated a close relation between psoriasis and serum calcium level. However, data regarding correlation of serum calcium and uric acid level with severity are scarce.
In our study, we found that the mean serum calcium levels were significantly lower in psoriasis patients compared to the controls. Also, severity (PASI and BSA) was negatively correlated to serum calcium level (Pearson correlation coefficient –0.326), i.e. as the PASI and BSA increased, mean serum calcium levels decreased.
The difference of serum uric acid levels between cases and controls was not found to be statistically significant. However, severity in terms of PASI and BSA was positively correlated to serum uric acid level (Pearson correlation coefficient 0.446) i.e. as the severity of psoriasis increases, so does the serum uric acid level.
Qadim et al. carried out a study similar to the present study where they compared 98 psoriasis cases with 100 cases without psoriasis [10]. Hypocalcaemia was seen in 37 patients out of 98 (37.2%) psoriatic cases compared to only 9% among the controls. They also found that the mean serum calcium levels were significantly low in cases as compared to the controls. The authors concluded that for psoriasis patients, hypocalcaemia was a significant risk factor and they recommended to include calcium rich foods for psoriasis patients [10].
Chaudhari et al. studied 80 psoriasis patients vs. 80 controls and found that mean serum calcium levels were significantly lower in psoriasis patients compared to the controls. However, in their study no correlation was found between the PASI and serum calcium levels [11]. In our study we found that the serum calcium levels were negatively correlated to the PASI.
Bijina et al. observed hypocalcaemia in 38% of 100 psoriatic subjects. High serum uric acid levels were seen in 26.6% [12]. Our study showed similar results with 44% of psoriatic subjects showing hypocalcaemia and 22% showing hyperuricemia. In their study a significant correlation was observed between hypocalcaemia and PASI score in psoriasis patients. However, there was no such correlation between hyperuricemia and PASI [12]. On the contrary, we found a significant correlation between PASI and hypocalcaemia as well as hyperuricemia and PASI.
Chand et al. studied 50 psoriatic cases and 25 controls and found that the serum uric acid level was elevated in 14% of cases and all controls showed a normal serum uric acid level. Although this rise in uric acid levels in psoriasis had no correlation to the extent of skin involvement in this study [13].
Intracellular calcium plays an integral part in the regulation of proliferation and differentiation of keratinocytes. Although hypocalcaemia has been reported to be a trigger factor for generalized pustular psoriasis, it has been demonstrated that decrease in serum calcium leads to intensification of lesions and extending the lesions in most patients [10]. Combination therapy may provide advanced therapeutic relief for recalcitrant patients and potentiate treatment outcomes owing to the synergistic effect [14]. Methotrexate (MTX) is an inexpensive first-line systemic therapy for moderate-to-severe psoriasis [15]. Since the action of methotrexate is most prominent on rapidly dividing cells, it was originally thought that its beneficial effects in psoriasis were a result of the inhibition of epidermal proliferation, but the effectiveness may be due to an anti-inflammatory effect [16]. Calcium is also known to influence MTX accumulation in hepatocytes [17]. MTX may act through a calcium–dependent mechanism and the synergistic effects between calcium and MTX on keratinocyte growth have been proven in vitro and psoriasis-like model mice in vivo [18].
Although this present study did not yield a relation between hyperuricemia and psoriasis specifically, as compared to other pruritic dermatoses, it did yield a positive correlation between the severity of lesions in psoriasis and serum uric acid levels. Up until now a relation between high uric acid levels and the severity of skin lesions was not established. Previous studies, however, have demonstrated the relation between hyperuricemia and psoriatic arthritis, metabolic syndrome, and cardiovascular comorbidities [19]. Logic dictates that uric acid lowering agents would have a significant benefit in treating psoriatic arthritis and other comorbidities associated with psoriasis and hyperuricemia. Likewise a study by Tamer et al. which included 224 patients, 100 females and 124 males, who were treated with TNF-α, IL-17, IL-12/23, and IL-23 inhibitors. Uric acid levels were significantly higher in men compared to women, higher in overweight and obese patients compared to those with normal weight, and higher in patients with severe versus mild psoriasis. The mean serum uric acid level decreased significantly from 5.89 ±1.53 mg/dl to 5.41 ±1.39 mg/dl in all patients 3 months after biological treatment. A statistically significant decrease in serum uric acid levels was detected in patients treated with adalimumab, infliximab, ixekizumab, secukinumab, and ustekinumab. The study concluded that high serum uric acid levels have been associated with an increased risk of cardiovascular diseases and metabolic syndrome, treatment of psoriasis with adalimumab, infliximab, ixekizumab, secukinumab, and ustekinumab may have a positive impact on cardiometabolic comorbidities [20].
Nash et al. in a randomised double blinded study of 190 patients with plaque psoriasis and active psoriatic arthritis conclusively proved that the response of joint pain as well as skin lesions was better in patients treated with leflunomide as compared to those treated with placebo (27.2 vs. 8.9%, respectively) [21]. Although it has not yet been proven without a doubt that the improvement in the skin lesions was due to lowering of uric acid levels.
It would be interesting to note the effect of other uric acid lowering agents such as allopurinol, febuxostat, etc. in adjunct to first line drugs used in psoriasis in controlling the skin lesions and clinical flares along with reducing the risk of comorbidities occurring due to hyperuricemia.
The strength of our study lies in comprehensive evaluation of two biochemical parameters (serum calcium and serum uric acid) simultaneously in the severity of psoriasis and its comparison with the control group whereas previous studies were either uncontrolled or evaluated only one of the parameters.
Limitations of this study are a relatively small sample size and the type of study (cross-sectional) due to which all types of psoriasis could not be assessed properly and the outcome of patients following treatment of hypocalcemia and hyperuricemia could not be assessed as there was no follow-up.

CONCLUSIONS

There is an association of hypocalcaemia with psoriasis as compared to other dermatoses, whereas no such association was found between hyperuricemia and psoriasis as compared to other pruritic dermatoses.
There was a negative correlation between serum calcium and PASI score, i.e. hypocalcaemia was significantly associated with severity of psoriasis, and a positive correlation was observed between the serum uric acid level and PASI, i.e. hyperuricemia was associated with severity of psoriasis.
Serum calcium and uric acid should be an integral part of routine laboratory investigations in all types of psoriasis for improved outcome. Treatment modalities focusing on treating these abnormalities could result in favorable outcomes of psoriasis even in severe disease. Further interventional studies on large populations need to be carried out to prove the role of calcium supplements and uric acid lowering agents in reducing the severity of psoriasis of any type.

FUNDING

No external funding.

ETHICAL APPROVAL

Ethical number: 1220134-134.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

References