Dermatology Online Journal

A case of tuberculosis in a patient on Efalizumab and Etanercept for treatment of refractory palmopustular psoriasis and psoriatic arthritis
Gene Kitamura, Neda Mehr MD, Nancy Anderson MD, Melissa Sirichotiratana
Dermatology Online Journal 15 (2): 11

Department of Dermatology, Loma Linda University, California. gkitamura@llu.edu

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Abstract

We discuss a patient with a history of a positive tuberculin skin test, who presented with severe, recalcitrant palmoplantar pustular psoriasis with psoriatic arthritis whose symptoms did not resolve with monotherapy of etanercept (Enbrel®) or efalizumab (Raptiva®) alone, but did respond to a combination of both biologics. However, our patient was later found to have re-activation tuberculosis after long-term treatment. This case highlights many key points for treatment of psoriasis and psoriatic arthritis with biologics. Namely, that recalcitrant psoriatic skin lesions may have good clearing on one biologic, such as efalizumab, and arthritic symptoms can be well-controlled with etanercept, leading patients to be on two different biologics concurrently to control symptoms. However, it also highlights the importance of determining a patient's tuberculosis status, initiating prophylactic anti-tuberculosis therapy prior to starting treatment with etanercept, and setting up an adequate treatment regime if the patient develops active tuberculosis during therapy with etanercept.

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Introduction

Psoriasis is a chronic inflammatory condition that presents with scaling plaques and papules, frequently involving the scalp, intertriginous areas, and extremities. Less commonly, a subtype known as pustular psoriasis may display chronic outbreaks of pustules, which may be limited to a palmoplantar distribution [1]. In addition to the skin lesions, arthritis is also commonly associated with psoriasis.

Among the most promising treatments for psoriasis and psoriatic arthritis are the biological response modifying therapies or "biologics" [2]. The two main groups of biological treatments are those that target tumor necrosis factor-alpha (TNF-α) (e.g., etanercept, infliximab, adalimumab) and those that target T cells [3] (e.g., efalizumab, alefacept). These agents are typically used as monotherapy. One of the primary concerns for patients on biologics, particularly TNF-antagonists, is an increased risk of tuberculosis [3, 4].

We discuss a patient with a history of a positive tuberculin skin test, who presented with severe, recalcitrant palmoplantar pustular psoriasis with psoriatic arthritis whose symptoms did not resolve with monotherapy of etanercept or efalizumab alone, but did respond to a combination of both biologics.

Case

A 47-year-old African American female presented to our University-based dermatology clinic in 1998 with a 3-year history of moderate to severe pustular psoriasis. The lesions demonstrated a diffuse pattern of involvement, primarily affecting the hands and feet with some involvement of the scalp and trunk. Concurrently, the patient had been experiencing non-disabling joint pain in both knees and wrists for several years. Her medical history was significant for hepatitis C, smoking, and a positive tuberculin skin test in childhood with a history of negative chest X-rays.

Initially, the patient's psoriatic lesions were managed with a variety of topical regimens including triamcinolone, betamethasone, calcipotriene, tacrolimus, tazarotene, and halobetasol. However, all of these medications provided only minimal clearing of her skin lesions. The patient had also been treated with cyclosporine, UVA, and UVB in the past, but had experienced only mild relief with these treatments.

The patient was initially started on etanercept at 25 mg twice weekly in April of 2003 and the dose was increased to 50 mg five months later to enhance clearing of her skin lesions. The plaques on her trunk demonstrated marked improvement, but the psoriatic lesions on the scalp, palms and feet were only mildly improved. Interestingly, the arthritic pains that involved her bilateral wrists and knees demonstrated a significant improvement with etanercept to where the patient denied any joint pains. At this time, additional topical medications including calcipotriene, halobetasol, and urea were added to help control her residual palmoplantar psoriasis that was not cleared by the etanercept. However, the residual lesions were unresponsive to these measures.

In order to enhance clearing of the patient's persistant palmoplantar psoriasis, etanercept was discontinued and the patient was switched to efalizumab in July of 2005. Her loading dose was 50 mg (0.7 mg/kg) and she was continued on a weekly dose of 80 mg (1.0 mg/kg). Along with the topical use of acitretin and clobetasol, the patient demonstrated significant improvement of her persistent palmar and plantar psoriasis. However, along with her improving psoriatic symptoms, the patient started to experience a relapse of her arthritic pains. Patient was prescribed acetaminophen with codeine for the pain, but it only moderately alleviated her symptoms. A trial of methotrexate was also attempted at this time; even though her liver function tests (LFTs) were within normal limit, the patient discontinued the medication secondary to gastrointestinal side effects associated with its use.

With her progressively worsening arthralgias, the patient was started on combination therapy with both etanercept and efalizumab in July of 2006. With this new regimen, the patient experienced significantly improved mobility and a rapid decrease in her joint pains. Along with the two biologics, topical betamethasone and calcipotriene were used as an adjunct to control her occasional cutaneous flare-ups. Currently, our patient's psoriasis and psoriatic arthritis are very well-controlled on etanercept and efalizumab alone, with only occasional use of topical medications to control mild flare-ups.

Interestingly, our patient developed a chronic cough with sputum production around June of 2007, four years after she was first started on etanercept. A chest X-ray in January of 2008 demonstrated a 4 mm calcified mass in the right upper lobe of the lung. Prior interim chest X-rays had been negative. Subsequently, a CT scan demonstrated three other granulomas, all in the range of 2-4 mm, involving the right and left upper lobes. Considering her past history of a positive tuberculin skin test and her long-term use of immunosuppressants including, but not limited to, etanercept and efalizumab, a diagnosis of tuberculosis was made after being worked-up by the pulmonary service; our patient was recently started on isoniazid to complete a six-month course for treatment of her tuberculosis infection.

Discussion

Our patient with recalcitrant pustular psoriasis and psoriatic arthritis was placed on biologics, particularly efalizumab and etanercept, because she did not demonstrate any significant improvement with more conventional medications.

Etanercept is a soluble TNF receptor antagonist that prevents TNF from initiating inflammatory intracellular processes [5]. It has been shown to provide significant benefits to patients with psoriasis, with one study reporting that 54 percent of the patients were nearly clear of lesions after 12 weeks of treatment [3]. One dangerous adverse event seen in patients on etanercept is tuberculosis, with a reported incidence rate of 114 per 100,000 patients [6]. This incidence was seven times higher when patients failed to adequately treat latent tuberculosis prior to treatment, as with our patient [6]. Other more commonly encountered side effects include upper respiratory infection and injection site reactions [5]. Etanercept has also been shown to have significant benefits for arthritic symptoms in patients with psoriasis [2]. Prior studies with etanercept have demonstrated a 44 percent response improvement over placebo [7] and a halting of radiographic psoriatic arthritis progression [5].

Efalizumab is a recombinant IgG-1 monoclonal antibody directed against CD11a, and it functions to inhibit many of the steps central to the pathogenesis of psoriasis such as T cell activation, trafficking, and reactivation in the dermis [8, 9]. The non-response rate to efalizumab in patients with psoriasis is generally reported to be around 14-40 percent [10]. Up to 17 percent of the patients may experience mild flu-like symptoms with treatment [10]. The more concerning side effect during treatment is moderate to severe inflammatory exacerbation of psoriasis, with a reported incidence of 3.2 percent in one study [9]. Psoriatic arthritis does not seem to occur with any higher incidence with efalizumab, but cases of severe arthritis have been demonstrated with higher incidences in the patients with pre-existing joint symptoms [11]. Unlike the TNF-antagonists, efalizumab does not increase the patients' incidence of tuberculosis infection [4], and it is actually considered a first line biologic in high risk patients with latent tuberculosis [3]. Although rare, the more serious adverse events, such as severe infection, malignancy, and thrombocytopenia have also been reported in patients treated with efalizumab [10].

Our patient is interesting because her combination of psoriasis and psoriatic arthritis did not clear on either biologic, etanercept, or efalizumab, as a monotherapy for her symptoms. The diffuse psoriatic plaques and pustules did not demonstrate any significant clearing when she was initially started on etanercept alone. This is not uncommon, as a previous report has shown that only 30 percent of patients on etanercept demonstrated a Psoriasis Area and Severity Index (PASI) improvement of 75 percent [12]. However, etanercept has been demonstrated to have significant benefits in terms of reducing symptoms associated with psoriatic arthritis [2, 5], a benefit we also observed in our patient. Furthermore, once our patient was taken off etanercept and switched to efalizumab to enhance clearing of her psoriatic skin lesions, her arthritic symptoms returned. Our case, therefore, supports previously cited reports that efalizumab is ineffective in the treatment of psoriatic arthritis [9, 13, 14].

Our patient also had two concerning co-morbidities: hepatitis C and history of a positive tuberculin skin test. Limited studies have shown that use of the etanercept in patients with hepatitis C do not have any significant effects on liver function tests or viral loads [3, 15]. Similarly, our patient also had no significant change in her liver function tests or viral loads while on etanercept.

With a history of a positive tuberculin skin test, reactivation of latent tuberculosis was a cause for concern in our patient. A screening chest X-ray demonstrated a right upper lobe calcified granuloma late in the patient's treatment course, and our patient was subsequently diagnosed with reactivation tuberculosis. Fortunately, for efalizumab, the risk of tuberculosis doesn't seem to be significantly increased [3, 4]. However, this adverse event is of significant concern in patients on anti-TNF therapy, as TNF plays a key role in host immunity [3, 16]. In murine models, TNF mediates the formation of protective granulomas and is therefore essential in containment of tuberculosis [4]. It has been proposed that patients with a positive tuberculin skin test receive anti-TNF treatments only after initiating therapy for latent tuberculosis, usually with isoniazid to complete a 6-9 month course [4]. Our patient did develop reactivation tuberculosis and is currently undergoing treatment with isoniazid therapy.

This case highlights many key points for the treatment of psoriasis and psoriatic arthritis with biologics. Namely, that recalcitrant psoriatic skin lesions may have good clearing on one biologic, such as efalizumab, and arthritic symptoms can be well-controlled with etanercept, leading patients to be on two different biologics concurrently to control symptoms. However, it also emphasizes the importance of determining a patient's tuberculosis status and initiating adequate anti-tuberculosis therapy prior to starting treatment with etanercept. Our patient's concurrent symptoms of diffuse, recalcitrant psoriatic skin lesions, combined with her arthritic symptoms could only be adequately controlled with combination therapy with both etanercept and efalizumab. This combination of systemic treatments should perhaps be considered in patients who present with poor skin clearing on one biologic, such as etanercept, or lack of arthritic coverage with efalizumab. Of course, patients on combination therapy should always be monitored for the reactivation of latent tuberculosis, as occurred in our patient, while on long-term combination therapy with etanercept and efalizumab for treatment of psoriasis and psoriatic arthritis.

References

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