Report of the APLAR 2002 Meeting
Over 1000 participants from more than 25 countries presented over 300 clinical and research papers at the Asian Pacific League Against Rheumatism (APLAR) meeting held early December 2002 in Bangkok, Thailand. Although the majority of papers were derived from studies on patients in Asia, they contained several interesting and important points for US rheumatologists. For example, an increasing number of US rheumatology patients travel to Asia as tourists and may be exposed to diseases common in these regions (ie, tuberculosis, malaria, dengue or gastrointestinal infections). They may even require hospitalization in Asia, where they may receive drugs that are unfamiliar to US clinicians. Furthermore, these tourists may develop disease manifestations (eg, malaria) or be carriers of enteric infections after they return to the United States. Additionally, these patients are spending more extended time in Southeast Asia as the global workforce increasingly extends into Asia.

Some of these patients, particularly those on anti-tumor necrosis factor (TNF) inhibitors, will develop tuberculosis (TB) at a much higher rate or may develop septicemia with "local organisms" after receiving chemotherapy for their systemic lupus erythematosus (SLE) or vasculitis.

In addition to the growing number of US patients traveling to Asia, there is an increasing number of patients immigrating from Asia to the United States. These patients often bring their older family members who may have latent TB or a history of diseases not commonly found in the United States. For example, certain conditions native to Asia (eg, Behcet's and Takayasu's vasculitis) can be seen in these patients, US rheumatologists can learn more about their presentations, pathogeneses and therapies.

When these patients and their families give a history of herbal medications that is distinct from current US clinical experience, 2 primary concerns are raised. First, it is virtually impracticable to identify toxicities and interactions associated with these herbal medications. Second, it is not known whether therapies widely used in patients in the United States and Europe have similar pharmacologic profiles in their counterparts from Asia, particularly if these Asian patients continue to take herbal therapies prevalent in their own countries.

In terms of response to new therapies, a large number of presentations (and pharmaceutical company-sponsored symposia) dealt with the use of new therapeutic agents such as cyclooxygenase-2 (COX-2) inhibitors (eg, celecoxib, rofecoxib) and disease-modifying agents (including, leflunomide, and the TNF inhibitors etanercept and infliximab) in Asia. Reports on the use of COX-2-selective agents in patients from Japan, India, Taiwan, Republic of China, Malaysia, and Thailand were presented. The conclusion of these studies was that no unexpected surprises were encountered in terms of efficacy or short-term toxicity other than those reported in the widely published US studies. However, the use of TNF inhibitors may be a different story. The major concern was the risk of reactivation of TB in the treated rheumatoid arthritis (RA) population because TB is highly endemic in Asia and because of earlier experience with TNF in eastern Europe. These TNF-treated patients are being observed carefully. But it has been difficult to evaluate the relative increased risk thus far because of the high rate of past exposure, the unusual clinical presentation of TB and re-activation of TB even in the absence of TNF inhibitors (discussed below).

Several reports outlined the features of TB infection in patients with RA even in the absence of TNF inhibitors. Yoshinaga and colleagues from Okayama, Japan reported that older patients with RA (median age, 72 years) had a high frequency (> 70%) of past exposure to TB based on skin tests and chest x-ray findings. Among 15 patients with RA admitted with clinically active during the past 2 years, only 2 gave a prior history of TB requiring prior treatment (with isoniazid); 7 of these admissions did not have symptoms suggestive of TB (ie, cough, fever, and increased sputum) but changes on chest x-ray led to diagnosis. Extrapulmonary TB was found in 8 of these 15 patients with RA, including those presenting with miliary TB and amyloidosis. Although a controlled population was not available to assess the role of RA therapy (generally treatment with methotrexate and/or corticosteroids), it was the clinical impression that these treatments played a role in disease reactivation.

In Iraq, Adhadh reported that TB of both the spine and peripheral joints (particularly the knee) could closely mimic RA involvement. Asavatanabodee from India reported TB causing sacroiliitis that mimicked Reiter's syndrome. In regard to the clinical presentation of TB and RA as differential diagnostic entities, it is important to remember that the initiation of gold therapy for RA at the turn of last century was predicated on the belief that RA was a manifestation of TB and thus the use of heavy metal therapy (ie, gold) which was thought to be useful in the treatment of TB. The Asian experience causes one to doubt that clinical presentations of increased polyarticular disease reflect only more active RA and that the diagnosis of TB can be excluded if the flare is not monoarticular.

The potential similarity of expressions of TB and arthritis is further underscored by the reactivation of TB in US patients treated with TNF inhibitors. Thus, mechanisms of iNOS and p38 may contribute to pathogenesis of RA and are known to be stimulated by TNF-induced mechanisms. Conversely, inhibition of these TNF-driven mechanisms leads to dramatic remission of RA. However, the same mechanisms that utilize TNF serves to prevent the activation of TB. The take-home lesson for US rheumatologists is that US patients with RA on TNF inhibitors in Asia, as tourists or employees, may be at risk for impaired response to TB infection. Thus far, clinical reports have focused on reactivation of TBC in patients with pre-existing infections, However, there was consensus that the possibility of patients on TNF inhibitors receiving infection from other active TBC patients has not been clearly ruled out. This will be much more of a problem in Asia than in the US, since the number of active TBC patients is so much higher. Of importance, Mok and colleagues from Hong Kong found that isoniazid chemoprophylaxis did not prevent the reactivation of TB in 44 patients in a cohort of 652 patients who subsequently received immunosuppressive drugs.

In summary, TNF inhibitors are too expensive for general use by the typical Asian patient with RA. However, certain wealthier Asian patients may use these medications and US patients working in Asia may be continuing their therapy with TNF inhibitors. For US rheumatologists, awareness of unusual manifestations of TB must be considered as these patients (or their families) return to the United States for clinical reevaluation. This will be a difficult task, as they will likely have converted their PPD status and recommendations for therapy will need to be developed.

Septic arthritis is relatively common in SLE patients who receive cyclophosphamide, according to Kriwapan and coworkers in Taiwan, who reported 139 cases. Of interest, salmonella septic arthritis was the most common cause of septic arthritis and was more frequent than staphylococcus. Kong and colleagues from Singapore reviewed the case records of lupus patients admitted during the past 4 years and developed a predictive model for septicemia among SLE patients. Risk factors included active nephritis, cerebral lupus, lupus carditis, pulmonary hemorrhage, leukopenia, leukocytosis, and thrombocytopenia. The US rheumatologist must be aware of these risk factors if our patients in Asia return to the United States and then receive chemotherapy and become leukopenic.

During the workshop on Behçet's disease, it was noted that this disease is seen most often along the ancient Silk Road, with the highest incidence in Iraq which decreases as one travels along the Silk Road toward China. Of particular interest, epidemiologic studies evaluated the frequency of Behçet's disease among patients (and individuals at higher risk with HLA-B51) as they have moved from the Silk Road to other regions including Southern China, Thailand, and Australia. The incidence of Behçet's among these genetically predisposed individuals drops dramatically as they move away from the Silk Road and approaches the rate in the new geographical area. These results have been interpreted by Xiaomei and investigators as reflecting a strong influence of a still-unidentified environmental factor(s) in pathogenesis. In India and Singapore, the rates of Behçet's disease among these "migrants" are low and similar to those among the native populations, according to Kumar and colleagues and Cheng and colleagues, respectively.

The Asian experience with herbal medicines is also important. Herbal medicines are an increasingly common form of alternative therapy in the United States. A 1997 survey estimated that 12% of adults had used herbal medicines in the prior year compared with 2.5% in 1990. Thus, US rheumatologists not only need to learn more about herbal medicines that may be used by their patients while in Asia but also about the experience of Asian rheumatologists who routinely deal with these agents.

Kertia and coworkers in Indonesia and Petrenco and coworkers in Moldova reviewed the use of herbal drugs for RA and osteoarthritis. A wide variety of herbal extracts are commonly used, often in combination with traditional COX-1 nonsteroidal anti-inflammatory drugs. However, controlled trials involving most of these extracts have not been conducted. However, extensive discussions were presented in the workshops on several herbs that have been extensively studied and are available in the US. Since participants in these workshops have published their results in English journals, the references to the studies available on National Library of Medicine are also noted below.

Perhaps the most widely used antiarthritic herb is Tripterygium wilfordii Hook F, also known as "thunder god vine." Recent studies have shown that this agent interferes with the production of inflammatory cytokines IL-1 and TNF when injected into mice. Chen and coworkers from Shanghai have isolated an active component (triptolide, a diterpenoid triepoxide) which inhibits NF-kappa at a site distinct from that of cyclosporin A. In a phase 1 trial in 1993, RA patients showed no significant hematopoietic toxicity, but further controlled trials have not been reported. Despite the potential therapeutic benefits, there is ample documentation that this agent is toxic, targeting, among other things, the hematopoietic system, and its use has resulted in cases of leukopenia, thrombocytopenia, and aplastic anemia. The use of an ethyl alcohol extract of T wilfordii Hook yielded efficacy in a subset of patients with RA during a phase 1 trial without significant hematopoietic toxicity, but further controlled trials have not been done. Even among the discussants from different regions of China, dramatically different levels of enthusiasm for the efficacy for Tripterygium were expressed. However, all agreed that the availability of other disease-modifying agents in Asia have led to a rather dramatic decrease in the usage of this herb among Western-oriented rheumatologists. However, its use remains prevalent in rural areas. The consensus seemed to be that the herbs had efficacy but also toxicity, much like our past experience with phenylbutazone. Perhaps the consensus was best summed up by 1 rheumatologist from China who stated that when rapid efficacy was required and money was in short supply, potent herbs would be used, and only the survivors returned for refills. However, according to the discussion, the main reason for decreased utilization of Tripterygium is that Chinese female patients complain that they undergo skin changes (wrinkling), which makes them appear older. It is perhaps a tribute to the cosmetic industry and current advertising policy, that patients are more concerned by wrinkles than by the potential hematopoietic risks.

The field of herbal medications (and their controlled trials) has recently been reviewed by De Smet, including observed toxicities and drug interactions. Among the reported phase 2 controlled trials of herbal medications in this recent review, none were used for RA or osteoarthritis nor were any controlled herbal trials reported at the APLAR meeting. However, drug interactions of other herbs with antiarthritic medications (including piroxicam, cyclosporine, tacrolimus, and warfarin) were reported in the review and at APLAR.

Although the use of herbal therapies is on the rise in the United States, most rheumatologists are not adequately educated to meet patients' requests for information on herbal products. Unfortunately, there is relatively little regulation of herbal therapies by the FDA and the amount of the herb listed on the bottle may bear little relationship to the amount of active ingredient. Potentially unsafe herbs may include high levels of borage, calamus, coltsfoot, comfrey, life root, chaparral, germander, and ma huang extract.