ABSTRACT
Background: Naftalan is a specific form of medicinal earth oil, and a number of subtypes are used in topical therapy for psoriasis and psoriatic arthritis. In the present study, yellow naphthalan oil that is enriched with steranes but that has a reduced content of polyaromatics was used.
Objective: The aim of the study was to assess the effect of naphthalan on psoriatic skin lesions, on painful and swollen joints, and on functional status of patients with psoriatic arthritis.
Methods: The study included 28 patients with chronic stationary psoriasis (psoriasis vulgaris) and 12 patients with psoriatic arthritis.
Results: In the psoriasis vulgaris study arm, the mean ± SD Psoriasis Area and Severity Index score was 23.1 ± 7.5 at baseline; it was 7.95 ± 4.08 after 3 weeks of naphthalan treatment. In the majority of patients, naphthalan treatment reduced articular pain and edema and improved mobility of affected joints.
Conclusion: Naphthalan provides efficacious therapy in the management of mild to moderate psoriasis and psoriatic arthritis.
Introduction
The Naftalan Special Hospital for Medical Rehabilitation is a unique institution both in Europe and worldwide for the management of psoriasis, psoriatic arthritis, and rheumatic diseases. Naphthalan as a specific form of medicinal earth oil is rare, and the naphthalan found at the Križ oil field near Ivanić Grad in Croatia is the only one in Europe and one of only two in the world. The medicinal properties of naphthalan have been known for more than 100 years. In the review by Ostrogovic´ and Perin, the authors cite a book by Jäger on medicinal properties of naphthalan. Originally written in German in 1898, and subsequently translated into Russian in 1904, the book describes the effects of naphthalan oil on various organ systems. In that historical publication, particular interest is directed toward the treatment of skin and joint diseases.
At the Naftalan Special Hospital for Medical Rehabilitation, brown naphthalan has been used for 15 years as an option for topical treatment of psoriasis. Naphthalan is obtained from naphtha, a complex mixture of various compounds, mostly hydrocarbons. Today, several versions of naphthalan products are used in medicine. The yellow version is currently available at our hospital. This naphthalan product is enriched with steranes, constituents believed to represent active naphthalan components, and with a reduced content of polyaromatics. Experimental model studies have revealed no genotoxicity. The product is available in the form of oil for topical treatment. In Croatia, the prevalence of psoriasis has been estimated as 2%. Psoriatic arthritis is a chronic autoimmune, systemic, inflammatory articular disease associated with psoriasis and usually negative rheumatoid factor. The prevalence of psoriatic arthritis ranges from 0.3% to 1%. Psoriatic arthritis develops in up to a third of psoriasis patients. The aim of the present study was to assess the effect of naphthalan therapy on cutaneous lesions, painful and swollen joints, and the functional status of patients with psoriasis and psoriatic arthritis treated as inpatients at Naftalan Special Hospital.
Patients and methods
The study was approved by the ethics committee of the Naftalan Special Hospital. It included 28 inpatients (8 women, 20 men) aged 33 to 76 who had chronic stationary psoriasis (psoriasis vulgaris) and 12 patients with psoriatic arthritis. The mean age of psoriasis patients was 50.7 (women, 50.4; men, 50.9) years. In the group of patient with psoriatic arthritis, the mean age was 52.4 (women, 53.3; men, 48.5) years. In psoriasis patients, systemic therapy was discontinued 3 months and topical therapy 3 weeks before the study began. Patients with pustular and erythrodermic psoriasis and those with exudative skin lesions were excluded. During the study, patients with psoriatic arthritis received only nonsteroidal antirheumatics. Informed consent was obtained in writing from all study patients; then, naphthalan oil was applied all over the surface of the skin once daily.
In four patients, keratolytics were applied prior to naphthalan therapy for scale removal. In addition to naphthalan oil application over the skin surface, naphthalan compresses and naphthalan iontophoresis and sonophoresis were applied on the affected joints of patients with psoriatic arthritis. In both patient groups, naphthalan oil was left on the skin for 2 hours; then, patients showered and applied moisturizer. The treatment lasted 3 weeks. The Psoriasis Area and Severity Index (PASI) score7 in patients with psoriasis was recorded on days 0, 7, 14, and 21 of treatment. PASI score assessment was performed by one coauthor (GKP) in all patients. In patients with psoriatic arthritis, therapeutic effect was assessed by use of the modified Stanford Health Assessment Questionnaire (HAQ),8 which was performed at study entry and after 3 weeks of naphthalan therapy. The number of painful and swollen joints was recorded at study entry and after 3 weeks of naphthalan therapy.
Statistics
The PASI scores measured at baseline (day 0) and on days 7, 14, and 21 of treatment were compared with Wilcoxon matched pairs signed rank test. A statistically significant reduction in PASI score was set at P ≤ .05. Measured HAQ scores, the number of painful joints, and the number of swollen joints at baseline and after treatment were compared by use of Student t test for dependent samples. The level of statistical significance was set at P ≤ .05.
Results
The reduction in erythema, desquamation, and infiltration was recorded in all the patients with psoriasis (figures 1 and 2). The reduction in PASI score was observed at each consecutive weekly assessment (figure 3). Descriptive statistical data are shown in table 1. The mean PASI score was 23.01 ± 7.5 at baseline and 7.95 ± 4.08 after 3 weeks of treatment. Individual PASI scores at baseline and at the end of treatment are shown in figure 4 (asterisks indicate the four patients in whom keratolytics were applied for scale removal). According to Wilcoxon matched-pairs signed rank test, the reduction in PASI scores was statistically significant (z = 4.622599; P = .000004). Three weeks of naphthalan therapy reduced articular pain and edema and improved mobility of affected joints in most patients with psoriatic arthritis. On initial examination, the mean modified HAQ score was 1.31 (SD, 0.66; minimum, 0.25; maximum, 2.12; SE, 0.19). On repeat examination after therapy completion, the mean modified HAQ score was 0.60 (SD, 0.47; minimum, 0.00; maximum, 1.25; SE, 0.14) (figure 5). Student t test for dependent samples yielded a statistically significant modified HAQ score decrease (t = 5.50; P = .00019).
Painful Joints
On initial examination, the mean number of painful joints was 26.33 (SD, 9.79; minimum, 4; maximum, 39; SE, 2.83). On repeat examination after naphthalan therapy, the mean number of painful joints decreased to 13.92 (SD, 3.73; minimum, 0; maximum, 38; SE, 3.73). Student t test for dependent samples showed the decrease in the number of painful joints to be statistically significant (t = 4.18; P = .00153).
Swollen Joints
On initial examination, the mean number of swollen joints was 7.25 (SD, 7.66; minimum, 0; maximum, 24; SE, 2.21). On repeat examination after naphthalan therapy, the mean number of swollen joints was 3.75 (SD, 4.16; minimum, 0; maximum, 14; SE, 1.20). Student t test for dependent samples showed the decrease in the number of swollen joints to be statistically significant (t = 2.88; P = .01498). Figure 6 shows the decrease in painful and swollen joints. Naphthalan therapy was well tolerated by all patients. Patients were screened for skin irritation, such as erythema and itching, and for phototoxic and photoallergic reactions. No irritation was observed.
Discussion
This was an open-label study, lacking a placebo control group; thus, the improvement could in part be attributed to a placebo effect. Unfortunately, it was difficult to avoid this obvious limitation, as all patients were admitted to hospital to be treated for their conditions. Because this hospital’s specialty is naphthalanotherapy, patients expect to be treated with naphthalan. Hypothetically, at best, the design could have been single blinded, as naphthalan’s distinct fragrance is easily recognized by clinicians. Thus, double blinding would be virtually impossible. The authors are aware of these limitations and would like the data presented to be regarded as encouraging and indicative. To provide strong evidence of naphthalan’s healing properties, at least a single-blinded, controlled study should be performed. The antipsoriatic properties of heavy naphthalan oil are the basis of an antipsoriatic treatment regimen that has been used over the last decade at Naftalan Special Hospital in Ivanic Grad, Croatia. A number of previously published studies investigated naphthalan products for their bioactive properties. In one study, Thaci et al9 demonstrated in vitro its antiproliferative effect on immortalized keratinocytes and increased expression of the differentiation markers keratin 10/11 and involucrin. Vržogic´ et al10 investigated naphthalan’s effect on epidermal proliferation activity and CD3, CD4, and CD8 lymphocyte count. The results pointed to a significant naphthalan antiproliferative activity and an ability to decrease the immunocompetent cell count in psoriatic lesions, thus probably reducing epidermal hyperplasia and the rate of epidermopoiesis in patients with psoriasis vulgaris. With another study group, Vržogic´ et al11 examined the effect of naphthalan therapy on angiogenic factor in psoriatic lesions by immunohistochemistry analysis and demonstrated a significant difference in the mean number of new blood vessels before and after naphthalan therapy. Naphthalan therapy appears to reduce the rate of neovascularization in psoriatic lesions. Krnjevic´ et al12,13 also investigated the effects of naphthalan on intraepidermal proliferative activity, epidermal and dermal CD4 and CD8 lymphocyte count, intraepidermal apoptotic cell count, and antiangiogenic activity. Because of its previously reported inhibitory effect on intraepidermal proliferative activity, on intraepidermal and dermal inflammatory cells, and on neoangiogenesis, naphthalan should be considered as a topical therapeutic option for mild and moderate forms of psoriasis.
The keratolytics used in our selected patients may have helped to decrease the PASI score. Figure xy shows the improvement rates in the particular patients who used keratolytics. Because keratolytics were only used in a small number of patients, the overall effect on the majority of the study population cannot be attributed to keratolytics.
Although potentially important, all naphthalan products contain steranes as a minor group of compounds. In addition to steranes, many other cycloalkanes are found in naphthalan. Isoalkanes are present in abundance, whereas normal alkanes and compounds containing functional groups are present in low concentrations. Brown naphthalans contain aromatics of different structures and concentrations, constituting up to half of the content.14-17 Aromatics include potentially carcinogenic compounds, and so a common goal is to use naphthalan products containing as few aromatics as possible. Safety data showed that neither hematologic nor biochemical parameters were altered after 3 weeks of applying the product in 30 patients with psoriasis.18 Other possible adverse effects of naphthalan have been tested, but the data are pending for publication and are not yet available publicly. Ames’ test on Salmonella typhimurium TA 98 and TA 100 strains showed that the product is not genotoxic; tests on keratinocyte and fibroblast cell cultures (assessed by 3-[4,5- dimethylthiazol2-yl]-2,5-diphenyl tetrazolium bromide [MTT] and lactate dehydrogenase [LDH] activity) showed a lack of cytotoxicity; a murine model (C57Bl mice fed with naphthalan for 7 days) showed a lack of acute toxicity according to Organisation for Economic Co-operation and Development guidelines. These results support the safe application of naphthalan.
Steranes are considered to be bioactive components in naphthalans used in the management of epithelial hyperproliferative and inflammatory diseases such as psoriasis. Their prospective indications may also include other immune-mediated inflammatory conditions such as atopic dermatitis, rheumatoid and psoriatic arthritis, as well as potentially precancerous oral lesions such as oral lichen planus and leukoplakia.
Numerous naphthalan product versions are currently in medical use. Yellow naphthalan, used in 28 Krnjevic-Pezic et al. | psoriasis forum, Vol. 17, No. 1 spring 2012 the present study, is rich in steranes and contains a small amount of aromatic compounds. Furthermore, our previously published clinical trial of steraneconcentrated and dearomatized naphthalan fraction showed a PASI score reduction of 25% to 93% in 15 patients after 3 weeks of treatment (a statistically significant decrease according to Student t test for dependent samples).14 In the management of psoriatic arthritis, nonpharmacologic procedures are as useful as pharmacologic therapy. Although no data are available in the literature on the mechanism of action of naphthalan in patients with psoriatic arthritis, our clinical experience points to its efficacy in reducing pain in the involved joints. At this stage, we are not certain about the mechanism involved and can only speculate about systemic absorption or deep local absorption into affected joints.
Conclusion
Based on our clinical observations and previously published results of immunohistochemistry and in vitro analysis, we conclude that naphthalan is a useful topical agent for the treatment of mild to moderate psoriasis and psoriatic arthritis.
