Liang, George C.; Barr, Walter G.
Psoriasis is a common form of chronic dermatitis affecting approximately 1%–3% of the population (1). Inflammatory arthritis has been reported to occur in 7%–42% of patients with psoriasis, and the prevalence of psoriatic arthritis in the general population is estimated from 0.04% to 0.08% (2). Sulfasalazine, methotrexate, cyclosporine A, retinoid, vitamin D derivatives, and corticosteroids have been shown to be effective for the treatment of both psoriasis and psoriatic arthritis (3). Other remedies are not convincingly effective or only effective for either skin or joint disease, but not both. Etanercept (Enbrel) has recently been added to the list of medications effective for both psoriasis and psoriatic arthritis (4).
Leflunomide is a new disease-modifying anti-rheumatic drug (DMARD) approved for the treatment of rheumatoid arthritis (5). The active metabolite of leflunomide, A77 1726, inhibits dihydroorotate dehydrogenase, an important enzyme for de novo biosynthesis of pyrimidine nucleotides. It thus regulates mitogen induced T-cell proliferation because entering into the S phase of the cell cycle from G1 requires expansion of pyrimidine pools (6, 7). Psoriasis and/or psoriatic arthritis are now seen as autoreactive inflammatory disorders, driven by an ongoing chronic T-helper-1 (Th-1) cell response in the skin as a result of presentation of foreign antigens by antigen-presenting cells or as a result of various mechanisms of autoreactivity (2, 8). Leflunomide might, then, prove to be effective in treating both psoriasis and psoriatic arthritis.
One of our patients (case 1) requested a trial of leflunomide for her recalcitrant inflammatory polyarthritis associated with psoriasis as soon as it became commercially available. Leflunomide was started and both her psoriasis and arthritis dramatically improved within a few weeks. This success prompted us to start the open trial of leflunomide in patients with psoriasis and psoriatic arthritis.
PATIENTS AND METHODS
Twelve consecutive psoriatic arthritis patients seen in the Arthritis Clinic of Northwestern Medical Faculty Foundation, Chicago, IL, who had failed to respond to at least one DMARD, were started on leflunomide (Arava, Aventis Pharmaceuticals, Parsippany, NJ). The age, sex, ethnic origin, and duration of their skin or joint disease are listed in Table 1. The ages of these patients ranged from 40–69 years. There were 6 males and 6 females. All were Caucasians. The duration of skin disease was 3 to 40 years, and the duration of arthritis 1 to 23 years. The pattern of psoriatic arthritis was characterized as the symmetrical, polyarticular rheumatoid type in all patients.
These patients had failed to respond to 1–7 of the DMARDs auranofin, azathioprine, chloroquine, doxycycline, hydroxychloroquine, methotrexate, penicillamine, aurothioglucose, and sulfasalazine (Table 1). Nine patients failed to respond to 3 or more DMARDS. Methotrexate was given in doses ranging from 5 mg to 15 mg/wk. In those patients receiving 12.5 mg/wk or less, higher doses were limited by the following side effects: headache, gastrointestinal intolerance, stomatitis, and abnormal liver function tests. One patient with a history of hypercholesterolemia died unexpectedly 3 weeks after the initiation of leflunomide, probably due to an acute myocardial infarction (autopsy was not granted). He was excluded from the analysis.
Leflunomide was administered using the standard rheumatoid arthritis protocol of 100 mg per day for 3 days and then 20 mg per day. When patients developed any toxicity, leflunomide was temporarily withheld until the toxicity cleared. Treatment was then resumed at a lower dose (10 mg per day, cases 2, 4, 6, and 7). Three patients were continued on previous partially successful DMARDs (azathioprine, sulfasalazine, or aurothioglucose, 1 patient each). All patients were allowed to continue analgesics or nonsteroidal anti-inflammatory drugs (Table 1). Two were on low dose prednisone (10mg per day or less).
Physicians’ global assessments of improvement of skin lesions (psoriasis) and arthritis in all patients were scored 2 to 3 months after the initiation of leflunomide according to a scale of 0–3 (0: no improvement, 1+: mild improvement, 2+: moderate improvement, 3+: marked improvement). Tender and swollen joint counts, grip strengths, patients’ and physicians’ global assessment of arthritis (0 to 10 scale, 10 being most severe) of 6 patients before and after therapy were available for statistical analysis. The tender joint count of 1 additional patient was also available for analysis. The tender joint count was performed according to American College of Rheumatology (ACR) disease activity measures with one modification; all proximal interphalangeal, metacarpophalangeal, and metatarsophalangeal joints on 1 side were counted as 1 joint area, the acromioclavicular joint was combined with the glenohumeral joint as 1 on each side, and lumbar spine and sacroiliac joints were counted as 1 joint area, with a total score of 24. The swollen joint counts were evaluated in a similar fashion except for the cervical, lumbar spine, and hip joints, which were not assessed for swelling, with a total score of 20. Grip strengths were measured by using a tailor-made hand-gripper attached to a mobile mercury sphygmomanometer with a maximum of 280 mmHg. Statistical analysis of the tender joint count, swollen joint count, patients’ global assessment, physicians’ global assessment, average of right and left grip strengths before and after therapy were analyzed using a Student’s t test for paired observations.
Six patients obtained marked improvement of psoriasis, 2 obtained moderate improvement, and 3 had no improvement (Table 1). Four patients achieved marked improvement in arthritis, 5 achieved moderate improvement, 1 achieved mild improvement, and 1 had no improvement. Overall, 8 patients had combined moderate to marked improvement in both psoriasis and psoriatic arthritis. Seven of these 8 patients had failed to respond to more than 3 DMARDs in the past.
The following clinical parameters of 6 patients were available for
Seven of these 8 patients had failed to respond to more than 3 DMARDs.
comparison before and after the initiation of leflunomide: tender and swollen joint counts, grip strengths, and patients’ and physicians’ global assessment of arthritis. The tender joint count of 1 additional patient was also available (Table 2). The improvement in tender joint counts, patients’ global assessments, and grip strengths reached statistical significance (Table 3). Physicians’ global assessments revealed a trend toward improvement but did not reach a statistically significant difference. The swollen joint counts also did not reach a statistically significant difference.
In 3 of these 11 patients, leflunomide was discontinued permanently because of lack of efficacy (case 4), lost to follow-up (case 2), and alopecia (case 12). Case 3 experienced unexpected death. In 3 patients (cases 2, 6, and 7), leflunomide was discontinued temporarily because of toxicity, but was resumed later at a lower dose. Arthritis improved in all these 3 patients, while psoriasis improved in 2 at the lower dosage. One patient (case 6) developed vaginal bleeding when her gynecologist started hormonal replacement simultaneously with leflunomide for her symptoms of menopause. Leflunomide was discontinued, and methotrexate, which had been used previously with partial success, was resumed. The patient could not obtain adequate relief, and leflunomide was resumed at a lower dose with concurrent methotrexate. Vaginal bleeding did not reoccur.
In a long term analysis (over 2 years), leflunomide was discontinued in 1 patient (case 8) after 8 months because of sensory neuropathy of the lower extremities. A complete neurological work-up failed to established any cause of neuropathy. His arthritis greatly improved during this time and gradually worsened after leflunomide was discontinued. Seven patients were still on leflunomide with duration of usage ranging from 24–31 months. The maintenance doses of leflunomide were one 10mg/week, two 10 mg/day, two 20 mg/day, one 20 mg/day with one extra 20 mg q 3rd day, and one 30 mg/day. Efficacy of joint improvement was maintained in 6 of the 7 patients, and skin improvement was maintained in 4 of the 7 patients. The improvement in swollen joints at 2 or more years reached statistical significance with a p value of 0.005.
Treatment of psoriasis and psoriatic arthritis can be optimally managed through a cooperative effort between dermatology and rheumatology. Treatment of psoriasis is dictated both by the extent and subtype of disease (9). Limited disease is controlled by topical preparations including dithranol, coal tar, corticosteroids, and vitamin D3 analogs. More extensive disease requires the use of systemic therapies including psoralen plus ultraviolet A radiation (PUVA), UVB, acitretin, methotrexate, or cyclosporine A. Treatment of psoriatic arthritis consists of nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular corticosteroid injections, with the second line drugs (DMARDs), usually as a single agent, being reserved for resistant or progressively destructive arthritis. While NSAID therapy can reduce pain and inflammation of arthritis, it can inhibit the cyclooxygenase pathway and redirect products of the inflammatory arachidonic acid cascade into the lipoxygenase pathway, thereby increasing leukotriene load and precipitating a flare of skin lesions. Systemic corticosteroids can markedly improve psoriasis and psoriatic arthritis, but their withdrawal may result in a rebound worsening of psoriasis, sometimes producing a generalized pustular (Von Zumbusch) form of the disease.
There are a few systemically administered medications that can control both psoriasis and psoriatic arthritis, but toxicity has restricted their use. Sulfasalazine has been shown to be effective in the treatment of both skin (10) and joint (11) involvement of psoriatic patients. Its main limiting factor is GI intolerance, with up to 40% of patients unable to tolerate the full dose. Low dose weekly methotrexate intramuscularly or orally has been used for decades to control severe forms of psoriasis, which fails to respond to conventional topical therapy. It has also been shown to be effective in treating psoriatic arthritis (3). Its use is limited largely by its liver toxicity, especially in psoriasis patients. Cyclosporine A is also effective for severe cases of psoriasis, and recent open prospective studies have shown that it is effective for active psoriatic arthritis (3, 12). In a review of the literature in which 170 patients were treated with cyclosporine A in 16 studies, only 10 (6%) discontinued the drug because of reversible nephrotoxicity (12). Psoriasis improved sooner than arthritis in the patients receiving cyclosporine A. Psoriasis worsened within days after discontinuing the drug, and the arthritis flared after several weeks. Cyclosporine A and methotrexate used in combination were effective in the patients resistant to previous second line therapy (12). The use of cyclosporine A alone or in combination is limited by toxicity and cost. In a recently reported abstract, a double-blind, placebo-controlled study of 60 patients showed that etanercept (a selective inhibitor of tumor necrosis factor) improved both psoriasis and psoriatic arthritis and was safe and well-tolerated (4).
There are very few well controlled trials to guide us in the treatment of psoriatic arthritis. In a meta-analysis of randomized controlled trials of drugs in the treatment of psoriatic arthritis, parenteral high-dose methotrexate and salazopyrin were the only 2 agents with well-demonstrated efficacy. The improvements observed in the placebo group strongly suggest that uncontrolled trials should be approached cautiously to guide management decisions in this condition (13).
The long term results of second line therapy (DMARDs) in psoriatic arthritis can be disappointing, as illustrated by the use of multiple DMARDs in most of our patients. Poor cumulative probabilities of taking DMARDs were also described in a large, prospective, long-term study involving 172 patients with psoriatic arthritis from Italy (14). From a Kaplan Meier life table analysis, the drug survival rate for cyclosporine A was only around 10% in 4 years and 25% for methotrexate. The total frequency of discontinuation because of toxicity and inefficacy was significantly lower with methotrexate than with cyclosporine A. After 2 years, 7 of the original 12 patients are still on leflunomide. The long-term drug survival and safety data for etanercept are not yet available, but the cost is currently burdensome.
This pilot study demonstrates that leflunomide alone or in combination with a previously inadequate DMARD was effective in amelioration of both skin and joint disease in 8 out of the 12 patients with psoriasis and psoriatic arthritis. All of these patients had the polyarticular rheumatoid type of psoriatic arthritis and were resistant to 1–7 known available DMARDs. Nearly all had tried methotrexate. Three patients failed to respond to 15 mg/wk of methotrexate, while 7 patients took only from 5 to 12.5 mg/wk of methotrexate because drug toxicity was experienced at higher doses. For those patients whose clinical parameters were available for statistical analysis before and after therapy, the tender joint counts, patients’ global assessments, and grip strengths demonstrated significant improvement.
There are very few well controlled trials to guide us.
The physicians’ global assessments showed a trend toward improvement, but the swollen joint counts did not reach a statistically significant difference. However, in a long-term follow-up of these patients, the swollen joint counts did reach statistically significant improvement. The onset of improvement began within 1–2 months of drug initiation as noted during follow-up examinations by the authors in the outpatient clinic. Arthritis improved sooner than psoriasis. The synovial aspects of psoriatic arthritis may be more responsive to leflunomide than the cutaneous manifestations. Partially successful DMARDs in 3 of our patients were continued. It is unclear if the continuation of prior DMARD therapy was necessary in these patients. In a long-term observation, we were able to divide patients into responders or nonresponders according to their skin or joint disease. There were 7 of 11 responders for skin and 8 of 11 for joint. None of the patients experienced worsening of skin disease during the period of observation.
From our limited clinical observation, we conclude that leflunomide may prove to be a useful agent for recalcitrant cases of psoriasis and psoriatic arthritis. Successfully treated patients typically respond within 2–3 months. Leflunomide can then be continued at the same dose or be adjusted according to response. Alternate DMARDs or the addition of low dose methotrexate (15) should be considered for the nonresponders after 3 months. Leflunomide appears to be well tolerated and less expensive than some other available alternatives. The initial dosing is the same as that approved for use in rheumatoid arthritis.
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© 2001 Lippincott Williams & Wilkins, Inc.