Disseminated Tuberculosis in a Psoriasis Patient under Adalimumab Treatment despite the Chemoprophylaxis of Latent Tuberculosis: A Case Report.

Recently, biologic therapy has become a major advance in the management of moderate-to-severe psoriasis. Although the overall safety profile of biologics is favorable, primary infection or reactivation of latent tuberculosis (TB) is the major concern in the setting of tumor necrosis factor-alpha inhibitor therapy. Therefore, the treatment of latent tuberculosis infection (LTBI) before starting biologics is mandatory to prevent the reactivation of LTBI. A 27-year-old female was treated with adalimumab due to psoriasis. As latent TB was detected by the interferon-γ release assay, we started isoniazid treatment (300 mg/day) 3 weeks before starting adalimumab and maintained this for 6 months. Although the patient's psoriatic skin lesions improved, after 45 weeks of adalimumab therapy, she visited the emergency department because of fever and back pain for 2 weeks. Abdominopelvic computed tomography (CT) and chest CT revealed multiple nodular lesions on both lungs, peritoneal wall, mesentery, and spleen, along with ascites. In the ascitic fluid, adenosine deaminase was increased to 96.4 U/L, and Mycobacterium tuberculosis grew in an acid-fast bacilli culture. The patient was diagnosed with disseminated TB and treated with conventional TB medication with discontinuation of adalimumab. Five months after the completion of TB treatment, the ustekinumab, an interleukin (IL)-12/IL-23 inhibitor, was administered. Until now, her skin lesions are under excellent control without reactivation of TB for 9 months after starting ustekinumab.

INTRODUCTION

Recently, biologic therapy has become a major advance in the management of moderate-to-severe psoriasis. Although the overall safety profile of biologics is favorable, primary infection or reactivation of latent tuberculosis infection (LTBI) is the major concern in the setting of tumor necrosis factor-alpha (TNF-α) inhibitor therapy. Therefore, screening and treatment of LTBI before starting biologic agents are mandatory1.

TNF-α is a proinflammatory cytokine that plays an important role in psoriasis development2. Adalimumab is a recombinant human immunoglobulin G1 monoclonal antibody against TNF-α which is used for the psoriasis patients who are unresponsive to conventional treatment3. Herein, we report a case of disseminated tuberculosis (TB) in a patient with psoriasis treated with adalimumab despite receiving adequate chemoprophylaxis for LTBI and discussed the management of patients with LTBI requiring biologic therapy briefly.

CASE REPORT

A 27-year-old female who had been diagnosed with psoriasis 8 years ago visited the dermatology department due to aggravation of psoriasis. On physical examination, scattered erythematous scaly papules and plaques were seen on the patient's entire body, especially on her lower legs. Although she was treated with narrowband ultraviolet B, cyclosporine, and methotrexate for 9 months, her symptoms gradually worsened (Psoriasis Area Severity Index [PASI] 10.5), and we considered biologic therapy (Fig. 1A).

Fig. 1

Clinical findings of the patient. (A) Erythematous scaly papules and plaques on the lower legs before adalimumab treatment. (B) After 4 months of adalimumab treatment, her skin lesions improved (We received the patient's consent form about publishing all photographic materials).

Before starting biologics, laboratory tests were performed, including complete blood count, liver and kidney function test, hepatitis markers, venereal disease research laboratory and screening tests for TB. The patient had a history of Bacillus Calmette–Guérin (BCG) vaccination. Laboratory test results were all within normal limits. A chest radiograph was normal, but the tuberculin skin test (TST) and interferon-γ release assay (IGRA) were both positive, with findings of 16 mm (normal, <10 mm in BCG-vaccinated person) and 7.78 IU/ml (normal, <0.35 IU/ml), respectively, which indicated LTBI. In accordance with the Centers for Disease Control and Prevention guidelines, we started isoniazid treatment (300 mg/day) 3 weeks before starting the biologics and maintained it for 6 months. After 16 weeks of adalimumab therapy, the skin lesions improved (PASI 0.8) (Fig. 1B).

After 45 weeks of adalimumab therapy, the patient visited the emergency department with a complaint of 2 weeks of fever with back and abdominal pain. Her body temperature was 39℃, and a positive sign for costovertebral angle tenderness was observed. On laboratory examination, white blood cell (WBC), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were 4,450/µl (normal, 4,000~10,000/µl), 2.9 mg/dl (normal, <0.5 mg/dl), and 39 mm/hour (normal, <25 mm/hour). A chest radiograph showed a slightly enhancing lesion on the apex of the right lung (Fig. 2A). Chest computed tomography (CT) revealed multiple nodules in both lungs with enlarged lymph nodes. Abdominopelvic CT showed nodular thickening of the peritoneum and many hypoattenuated lesions on the spleen with abundant ascites (Fig. 2B). On ascitic fluid examination, WBC and adenosine deaminase were 1,920/µl (normal, <500/µl) with 73% lymphocytes and 96.3 U/L (normal, <40 U/L), respectively. Acid-fast bacilli cultures of sputum and ascitic fluid revealed Mycobacterium tuberculosis. Finally, the patient was diagnosed with disseminated TB with pulmonary, peritoneal and spleen involvement. She didn't have a history of contact with a patient infected with TB during treatment.

Fig. 2

Radiographic images of the patient. (A) Chest radiograph shows a slightly enhancing lesion on the apex of the right lung, with a mild bilateral pleural effusion. (B) Abdominopelvic computed tomography shows nodular thickening of the peritoneum (arrowheads) and many hypoattenuated lesions on the spleen (arrows), with abundant ascites.

Adalimumab treatment was discontinued immediately, and the patient was started on empirical treatment for TB with a combination of isoniazid (300 mg/day), rifampicin (600 mg/day), ethambutol (1,100 mg/day), and pyrazinamide (1,600 mg/day) for the first 2 months. Then, the treatment was followed by a continuation phase of isoniazid (300 mg/day), rifampicin (600 mg/day), and ethambutol (1,200 mg/day) for another 4 months.

After 6 months of TB medication along with excimer laser and topical agents, the patient's psoriatic patches spread gradually (PASI 12.7). The patient longed for receiving the biologics again and therefore ustekinumab, an interleukin (IL)-12/IL-23 inhibitor, was administered 5 months after the completion of TB treatment along with a normal chest radiograph. Until now, the patient is being monitored carefully, and her skin lesions are under excellent control without reactivation of TB for 9 months after starting ustekinumab.

DISCUSSION

LTBI is the state in which human is infected with M. tuberculosis without clinical symptoms and radiographic signs, or microbiological evidence of active TB4. The risk of TB infection among the recipients of TNF-α blockers is 1.5~17 times higher than that in the general population12. TNF-α inhibitors are approved for many immune-mediated inflammatory diseases. Although the overall safety profile is favorable, some side effects have been identified35.

TNF-α is a proinflammatory cytokine that plays an important role in forming and maintaining granuloma to protect against mycobacterium. TNF-α inhibitor-associated TB has an unusual presentation with more severe and extrapulmonary patterns, which could result in a delayed diagnosis and disseminated TB6. Similar to our case, there have been two other cases of TB development in a psoriasis patient during adalimumab therapy despite chemoprophylaxis, and all of these patients had extrapulmonary symptoms7.

For screening of TB infection before initiation of biologics, thorough history taking, physical examination and a chest radiograph should be necessary6. If clinical symptoms or findings on radiographs are suggestive of TB, an evaluation for active TB should be performed. If the results are normal, the appropriate method of the TST/IGRA combination test or the IGRA single test can be selected78.

The patient with LTBI should receive chemoprophylaxis with isoniazid for 6 to 9 months, rifampin for 3 to 4 months, or both drugs combined for 3 months. Although the 9-month treatment of isoniazid may be more effective, the 6-month regimen is preferred due to cost-effectiveness with better patient compliance. In addition, no significant differences in 6-month versus 12-month treatment regimens in reducing active TB risk have been shown910. However, in this case, the patient developed disseminated TB despite the 6-month of INH chemoprophylaxis of LTBI.

If TB is diagnosed during the use of biologics therapy, it must be discontinued immediately, and conventional TB therapy should be started7. It is safe to restart the biologic therapy after the completion of successful conventional treatment. However, if the treatment is urgent, after 2 months of intensive TB treatment, biologics can be started again along with TB treatment, only if the TB is not severe and responds well to general treatment7. Restarting anti-TNF therapy after treating patients successfully for a recurrence of TB seems to be safe although the study is limited. Abitbol et al.11 reported that no recurrence of TB during a median time of ~3 years of follow-up after reintroduction of biologics in inflammatory bowel disease patients. Additionally, the rate of TB reactivation in patients receiving anti-TNF agents has been reported to be 1.5~17 fold higher for TNF-α inhibitors, while a low or absent risk is associated with non-anti-TNF targeted biologics2121314. Therefore, if a patient is diagnosed with LTBI on screening, other biologics rather than TNF-α inhibitors might be the better choice, even though receiving chemoprophylaxis. Therefore we administered ustekinumab (IL-12/23 inhibitor) 5 months after the completion of TB treatment and her skin lesions are under excellent control without reactivation of TB for 9 months.

In conclusion, TNF-α inhibitor therapy increases the TB risk, such TB symptoms are much more severe, and extrapulmonary types are more common than in general cases. Therefore, it is preferable to do a prompt examination for suspected TB symptoms, rather than regular chest radiograph1516. Also, the possibility of reactivation of LTBI and reinfection of TB remains despite the appropriate chemoprophylaxis, especially in an endemic area. Thus, during treatment with TNF-α inhibitors, dermatologists should always remain alert for symptoms of TB with continual monitoring including a chest radiograph and contact history with an infectious TB patient at yearly intervals117181920, even if the chemoprophylaxis for LTBI was completed.