Yusuf Yazici, MD

Significant changes have taken place in the way rheumatoid arthritis (RA) has been managed over the past 15 years. Most notably, studies have shown that early, aggressive treatment to a target value of at least low disease activity and, preferably, remission improves long-term outcomes of patients with RA. In addition, combination therapy has been used more frequently and earlier in the disease course.

The exact choice of which agents to combine is still a matter of debate, but in patients who have not had an adequate response to methotrexate (MTX), the value of a combination disease-modifying antirheumatic drug (DMARD), with or without a biologic agent, is not in dispute. Such treatments work well for a large number of patients, and new medications on the market offer hope for many more persons with this disease.

 In this article, I review the current state of RA treatment and monitoring.


MTX emerged as the drug of choice in the mid 1980s. However, most patients also were treated with a combination of parenteral gold and other modestly effective drugs, such as d-penicillamine, sulfasalazine (SSZ), and hydroxychloroquine (HCQ). Patients typically stopped taking the ineffective DMARD and started a new one. The process was repeated as needed.

Initially, DMARDs were reserved for patients who showed evidence of advanced disease or erosions and for those for whom NSAIDs were not successful. Aggressive treatment programs evolved with the introduction of MTX, although physicians initially were worried about toxicities, which have been shown to be milder than previously assumed.

 Early on, MTX was not the initial DMARD used. Until recently, SSZ was the most frequently used DMARD in Europe.

A new and different paradigm evolved during the early to mid 1990s. The Tight Control for Rheumatoid Arthritis (TICORA) study demonstrated that with tight control of disease activity, high degrees of remission could
be achieved with traditional DMARDs.

 The following important factors have led to this more aggressive approach in the modern treatment of patients with RA:

•The disease is now associated with significant mortality, morbidity, diminished quality of life, and disability.

•Aggressive treatment effectively improves symptoms and quality-of-life measures.

•DMARD therapies effectively retard the radiographic progression of disease.


MTX was, and still is, the cornerstone of DMARD regimens. Recent trials that used biologic agents offered valuable information about MTX and its efficacy in RA treatment. In one study, when trials of tumor necrosis factor Î± (TNF-Î±) inhibitors versus MTX in MTX-naive patients (those who had not been treated with MTX before) were examined, MTX was not as effective as the TNF-Î± inhibitors in controlling the disease activity and radiographic progression.

The introduction of TNF-Î± inhibitors in 1998 provided new options for RA management. Remission has become a possibility for more patients, especially when these drugs are used in combination with MTX. This development was demonstrated in the PREMIER study, in which a combination of adalimumab with MTX was more effective in controlling radiologic progression and symptoms than MTX or adalimumab alone.

When evaluating results from randomized clinical trials (RCTs) of all new and upcoming treatments, keep in mind that patients enrolled in trials rarely are similar to patients seen in routine care, the majority of patients with RA.

 Thus, data from RCTs may have limited applicability to some patients seen in routine care.


In addition to the initial 3 TNF-Î± inhibitors, other MOA biologics have come on the market and have been shown to be equally effective. As the field has advanced, the choice of medications has grown with it, providing powerful therapeutic tools and more treatment options for patients with RA. These agents are abatacept; rituximab; more recently, golimumab and certolizumab, 2 new TNF-Î± inhibitors; and this year, the interleukin-6 blocker tocilizumab.

Current RA treatment for new patients often begins with MTX, the anchor drug for RA at the start of treatment or within the first 3 months. The dosage is increased from 7.5 to 10 mg/wk to 20 to 25 mg/wk to achieve maximum response within 3 to 6 months.

Disease progress should be monitored by measuring disease activity levels with one of the many composite indices, such as the 28-joint Disease Activity Score (DAS 28), Clinical Disease Activity Index (CDAI), or Routine Assessment of Patient Index Data 3 (RAPID3).

 I prefer the RAPID3 because it is the simplest to use in routine patient care, requiring 5 to 10 seconds to perform rather than 100 to 120 seconds, without the need for a formal joint count

; also, it is strongly correlated with the DAS 28 and the CDAI.

RA treatment is a fast-changing and advancing area. Use of existing drugs is improving, new medications are available, and more are on the way. The main challenge is to identify the patients who are responding to the treatments. Objective quantification of the response or nonresponse also is needed.


The TICORA and Behandel Strategien (BeST) studies have demonstrated the importance of close monitoring of patients.

 However, few rheumatologists use quantitative measures in making clinical decisions. In fact, fewer than 10% of US rheumatologists use questionnaires in routine clinical care, and fewer than 15% perform a formal joint count at each visit.

The Health Assessment Questionnaire (HAQ) and its derivatives have been shown to be the best predictors of functional and work disability, costs, need for joint replacement surgery, and mortality. They are at least as useful for predicting these outcomes as joint counts, radiographs, and laboratory tests.16 In addition, patient questionnaires may be used for all rheumatologic diseases, including osteoarthritis, systemic lupus erythematosus, fibromyalgia, scleroderma, and ankylosing spondylitis.

The American College of Rheumatology (ACR) core data set was developed to provide a consistent set of outcome measures for RA. Seven measures thought to be important in all RA trials are (1) tender joint count, (2) swollen joint count, (3) function, (4) pain, (5) patient global assessment, (6) physician global assessment, and (7) laboratory marker for inflammation (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP] level). ACR 20, 50, and 70 responses-measures of a medication’s efficacy evidenced by at least a 20%, 50%, or 70% improvement in various ACR core measures, respectively-are useful tools. Opinions differ as to which one is more clinically relevant18; as a group, they are cumbersome to use in real-world clinical care, leading to a need for alternatives to be developed for both RCTs and clinical care.

A “truer”reflection
of disease activity


The DAS and its derivatives, the DAS 28 and the DAS-CRP (using the CRP level in place of the ESR), are used widely in RCTs. The advantage of providing a score for current disease activity, rather than a change score as in the ACR 20, 50, and 70 responses, makes these measures a truer reflection of disease activity. However, a calculator is required to compute the score, with a complicated formula. A scoring tool is provided by a Web site (http://www.reuma-nijmegen.nl/www.das-score.nl/index.html), but because of the difficulties and the need for at least a 28-joint count for the score, this tool is rarely used in clinical practice.

The simplified disease activity index (SDAI) and its simpler version, the CDAI (no measurement of acute-phase reactant level needed), have been proposed. Both are strongly correlated with the DAS, but because they share most of the components of the DAS, that is to be expected. The CDAI has the advantage of allowing for calculation right at the time of the patient visit because it does not require a laboratory test.

The RAPID3 instrument was developed with the aim of solving an important problem in monitoring of patients in clinical care, meeting the need for easy use by both patients and rheumatologists while performing as well as or better than the other available scores. This index of only 3 patient-reported outcome measures from the core data set-physical function, pain, and global estimate-distinguishes active from control treatments in clinical trials as effectively as do ACR and DAS criteria.

 The calculation of the score requires no gadgets, blood test results, or joint count. It takes less time than the DAS 28 or HAQ scoring and is highly correlated with the DAS 28 and the CDAI in routine clinical practice.

The need to use a tool to assess patients is obvious, and all the measures just discussed perform within the same range of response and are robust. The most “user friendly”measures have the best chance of succeeding and improving both patient care and rheumatologists’ efficient use of time. We currently use the RAPID3 instrument in our clinics and some of the private practices, and we teach our fellows to do the same. With more hands-on experience, most rheumatologists probably would find this a useful and acceptable tool.


Despite all these advances, about 30% to 40% of patients with RA do not have a satisfactory response to their initial treatment with MTX and other DMARDs.

 The usual next step is to add a biologic agent to MTX. Four biologic agents that currently are candidates for first-line biologic therapy, in chronological order of FDA approval in the United States, are etanercept, infliximab, adalimumab, and abatacept. There is adequate evidence of significant responses to these agents in patients with RA who had an inadequate response to MTX or combinations of DMARDs.

Even after this first round of biologics in these combinations, 20% to 30% of patients with RA continue to have active disease.

 Among patients who have good initial disease control, with MTX alone or in combination with a biologic agent, some will lose this favorable response.

 The question then is, which biologic agent is next?

Experience from published reports suggests that switching from one TNF-Î± inhibitor to another is effective in some patients to a degree similar to that with switching to another MOA biologic DMARD, such as abatacept, rituximab, or tocilizumab.

 In addition to available efficacy data, adverse-effect profiles and ease of use issues contribute to what the next choice should be for treatment of patients with RA who have tried multiple medications.


Triple therapy that combines MTX, SSZ, and HCQ has been used for the past 15 years as a good alternative to DMARD monotherapy or a combination with a biologic agent. Some data in 6- to 12-month trials suggest that at least in a small group of patients, triple therapy is as effective as MTX and a biologic agent combination; such therapy may be an option for patients who are not willing to use a biologic agent. The use of multiple medications and the frequent pill-taking with triple therapy may adversely affect treatment adherence, but the cost is much less than that of a biologic combination. All these factors should be kept in mind when a treatment decision is being made.


Emphasis on “best care”for patients with RA is appropriate, and “care that you would give your mother”even may be substituted as the gold standard, which may help place things into perspective. Cost is always a concern, but the greatest consideration is to offer the best treatment.


Currently, the best strategy for managing RA arguably is to start with MTX, with or without low-dose corticosteroids, and treat the patient aggressively. Monitoring of patient response with one of the available instruments-such as the DAS 28, SDAI, CDAI, RAPID3-is needed, and treatment should be adjusted according to these scores. To optimize treatment results, patients with inadequate response after 3 to 6 months should receive one of the biologic agents in addition to MTX. Current data suggest that if MTX is not successful, a combination of MTX and a TNF-Î± inhibitor or abatacept would be a good option. Therefore, rather than change to another drug, the right action would seem to be to add a new DMARD.

In spite of the very good results seen with MTX and TNF-Î± inhibitor combinations, about 10% to 15% of patients still do not have an adequate response to treatment.

 The new medications on the market and the newer ones coming out, like new cytokine inhibitors with a different mode of action, will be the next treatment options for these patients.

After some time, when all these agents have been in use long enough, the main determinant as to which agent to use will be patient preferences, adverse-event profiles, ease of use, and the most likely pharmacogenomic profile of each patient. Treatments currently are working for a large number of patients, and the future of treatment looks promising for the rest of the patients who have RA.

 Yazici Y. Treatment of rheumatoid arthritis: we are getting there. 

 Yazici Y, Sokka T, Kautiainen H, et al. Long term safety of methotrexate in routine clinical care: discontinuation is unusual and rarely to the result of laboratory abnormalities. >Ann Rheum Dis . 2005;64:207-211.

 Pincus T, Yazici Y, Sokka T, et al. Methotrexate as the “anchor drug”for the treatment of early rheumatoid arthritis.

 Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. 

 Yazici Y, Yazici H. Tumor necrosis factor alpha inhibitors, methotrexate or both? An inquiry into the formal evidence for when they are to be used in rheumatoid arthritis.

Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment.

Sokka T, Pincus T. Eligibility of patients in routine care for major clinical trials of anti-tumor necrosis factor alpha agents in rheumatoid arthritis. 

 Sokka T, Pincus T. Most patients receiving routine care for rheumatoid arthritis in 2001 did not meet inclusion criteria for most recent clinical trials or American College of Rheumatology criteria for remission. 

 Gogus F, Yazici Y, Yazici H. Eligibility for inclusion criteria in use for rheumatoid arthritis clinical trials in a Turkish cohort.

Yazici Y, Kulman I. Majority of rheumatoid arthritis patients in routine care do not meet inclusion criteria for RA clinical trials.

 Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. 

 Yazici Y, Bergman M, Pincus T. Time to score quantitative rheumatoid arthritis measures: 28-Joint Count, Disease Activity Score, Health Assessment Questionnaire (HAQ), Multidimensional HAQ (MDHAQ), and Routine Assessment of Patient Index Data (RAPID) scores. 

 Pincus T, Swearingen CJ, Bergman M, Yazici Y. RAPID3 (Routine Assessment of Patient Index Data 3), a rheumatoid arthritis index without formal joint counts for routine care: proposed severity categories compared to disease activity score and clinical disease activity index categories.

 Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. 

 Pincus T, Segurado OG. Most visits of most patients with rheumatoid arthritis to most rheumatologists do not include a formal quantitative joint count. 

 Pincus T, Sokka T. Quantitative measures for assessing rheumatoid arthritis in clinical trials and clinical care.

 Pincus T, Wolfe F. Patient questionnaires for clinical research and improved standard patient care: is it better to have 80% of the information in 100% of patients or 100% of the information in 5% of patients? 

 Felson DT, Anderson JJ, Lange ML, et al. Should improvement in rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in core set measures, rather than twenty percent? 

 Pincus T, Yazici Y, Bergman M, et al. A proposed approach to recognise “near-remission”quantitatively without formal joint counts or laboratory tests: a patient self-report questionnaire routine assessment of patient index data (RAPID) score as a guide to a “continuous quality improvement.” 

 Pincus T, Chung C, Segurado OG, et al. An index of patient reported outcomes (PRO-Index) discriminates effectively between active and control treatment in 4 clinical trials of adalimumab in rheumatoid arthritis. 

 Smolen JS, Aletaha D, Koeller M, et al. New therapies for treatment of rheumatoid arthritis. 

 Duclos M, Gossec L, Ruyssen-Witrand A, et al. Retention rates of tumor necrosis factor blockers in daily practice in 770 rheumatic patients.

 Hjardem E, Ãstergaard M, PÃ¸denphant J, et al. Do rheumatoid arthritis patients in clinical practice benefit from switching from infliximab to a second tumor necrosis factor alpha inhibitor? 

Articles

The significant changes in the way rheumatoid arthritis has been managed include earlier, more aggressive treatment with combination therapy.

Rheumatoid arthritis 2010: Treatment and monitoring

Behet syndrome is a systemic vasculitis of small and large vessels of both the venous and arterial systems the cause of which is unknown.

 Hulusi Behet first described Behet syndrome in 1937 in 3 patients who had a triple symptom complex of aphthae, genital ulcers, and hypopyon uveitis.

 Subsequent studies showed that this entity is a multisystem disease characterized by variable clinical manifestations. Virtually all patients have recurring oral aphthae, followed in order of frequency by genital ulcers, skin lesions, arthritis, uveitis, thrombophlebitis, and GI and CNS involvement.

The diagnosis of Behet syndrome is based on recognition of a group of clinical features, because there is no specific symptom or sign. Outcomes have improved over the past 20 years because treatment strategies have been instituted earlier and more aggressively, although vascular involvement and CNS problems are areas that still require better management. Treatment is tailored to the type and severity of symptoms and the patient's sex and age.

In this article, we describe the epidemiology, clinical manifestations, pathology and pathogenesis, and diagnosis and differential diagnosis of Behet syndrome. Then we discuss disease prognosis and management.

Behet syndrome is most common in the Mediterranean countries and the Far East along the ancient "Silk Route," suggesting that the putative agent or agents, including several genetic factors (eg, 

 In field surveys carried out in Turkey, the prevalence was between 20 and 421 cases per 100,000 adults

; however, there was not a single patient among 47,000 children in another field survey from the same country.

 The disease occurs less frequently in the rest of the world.

 Prevalence estimates range from 0.64 cases per 100,000 persons in the United Kingdom to 6.4 cases in Spain to 8.6 cases in the United States.

 However, Turks living in Germany have a very high rate of 77 cases per 100,000 persons; this statistic may point to genetic background rather than environmental elements as the key factor.

Some manifestations show regional differences. GI involvement is common in patients from the Far East

 but rather uncommon in those from Turkey.

Although a positive pathergy test result is common in patients from Turkey, the Mediterranean countries, and Japan, a positive result is seen less frequently in the Northern European countries and the United States.

 association is most pronounced in patients from the Middle East and the Far East.

Disease onset usually occurs in the third decade of life; the condition is rare in older persons (older than 50 years) and younger persons.

 The sexes are affected equally, but the syndrome runs a more severe disease course in men, as well as in younger persons.

Almost all patients with Behet syndrome have recurring oral ulcerations. These often are the first symptom, and they may precede the other disease manifestations by many years. Minor aphthous ulcers (less than 10 mm in diameter) are the most common type (85%); major or herpetiform ulcers are less common. Although aphthae usually are multiple and occur more frequently in Behet syndrome, they are indistinguishable from those of recurring oral ulcers resulting from other causes.

In men, genital ulcers usually occur on the scrotum and are less common on the shaft or the glans penis; urethritis or dysuria is not a part of Behet syndrome. In women, both the major and minor labia are affected. The ulcers usually heal in 2 to 4 weeks; large ulcers often leave a scar, but small ulcers and those on the minor labia heal without one.

Skin lesions of various kinds are seen in about 80% of patients with Behet syndrome.

 Acne-like, or papulopustular, lesions are mainly of cosmetic concern. These lesions often are seen not only at the usual acne sites (eg, the face, upper chest, and upper back) but also at unusual sites (eg, the legs and arms). They are indistinguishable from acne vulgaris in both appearance and pathology. 

Nodular lesions are observed in 50% of patients.

 They usually are confined to the lower limbs in the form of erythema nodosum–like lesions or superficial thrombophlebitis; distinguishing one lesion from the other with the naked eye can be difficult.

The pathergy reaction is a nonspecific hyperreactivity of the skin to trauma, such as a needle prick. A papule or pustule typically forms in 24 to 48 hours after an intradermal injection with a 20-gauge needle. The pathergy positivity is quite specific to patients with Behet syndrome.

 Less common skin concerns include skin ulcers in the axillary and interdigital areas, Sweet syndrome, pyoderma gangrenosum, leukocytoclastic vasculitis, and true arterial lesions.

Eye disease is seen in half of patients with Behet syndrome but is more common and more severe in men and younger patients.

 Eye involvement, which typically occurs within 3 years of disease onset, is a chronic relapsing bilateral uveitis that includes both the anterior and posterior chambers and is a significant cause of morbidity.

Anterior uveitis with intense inflammation (hypopyon) is observed in only a small fraction of patients with eye involvement; typically, it is associated with severe retinal vasculitis. Isolated anterior uveitis occurs infrequently, and conjunctivitis is rare.

 Recurring attacks of eye disease result in structural changes, such as synechiae and retinal scars. If unmanaged, these events eventually lead sto loss of vision.

Joint disease is observed in half of patients with Behet syndrome in the form of arthritis or arthralgia, each having a similar prevalence.

 Arthritis usually is monarticular or oligarticular but can be symmetrical. Joint disease resolves in a few weeks and seldom leads to deformity and radiological erosions. The knees are involved most often, followed in frequency by the ankles, wrists, and elbows. Back pain is quite rare; controlled studies have not shown increased sacroiliac joint involvement.

Patients with Behet syndrome who have arthritis have more acne lesions than those who do not.

 In addition, patients with arthritis and acne lesions have significantly higher enthesopathy scores than patients without acne,

 suggesting a link with acne-associated arthritis.

Vascular involvement, which may include both the venous and arterial systems, is more common in men than in women.

 One-third of patients have thrombophlebitis of the deep or the superficial veins, usually in the lower extremities. In rare cases, occlusion of suprahepatic veins can cause Budd-Chiari syndrome, which is associated with a high mortality rate. Although thrombophlebitis occurs very frequently, thromboembolism is rare, most probably because of adherence of thrombi to the diseased veins.

Arterial disease occurs less frequently (in fewer than 5% of cases) but is a serious cause of morbidity and mortality, especially when it involves the pulmonary arteries. Aneurysms may be observed or, less frequently, occlusion of the abdominal aorta or carotid, femoral, popliteal, or coronary arteries.

The mortality rate with pulmonary arterial aneurysms is high,

 especially with an aneurysm less than 3 cm in diameter.

 The main symptom is hemoptysis. Aneurysms may be detected on radiographs, and their presence can be confirmed with CT or MRI.

Involvement of the CNS, which occurs in 5% to 10% of patients, is one of the most serious manifestations of Behet syndrome, resulting in increased morbidity and mortality.

 Most patients (80%) have parenchymal brain involvement, which mainly affects the brainstem; it is manifested by pyramidal, cerebellar, and sensory symptoms and signs; sphincter disturbances; and behavioral changes. Nonparenchymal disease (20% of cases) takes the form of intracranial hypertension resulting from dural sinus thrombosis and manifested by headaches and papilledema. Simultaneous involvement of the dural sinuses and brain parenchyma is uncommon. The peripheral neuropathy often seen in other vasculitides is rare.

Symptoms include anorexia, vomiting, dyspepsia, diarrhea, and abdominal pain. Mucosal ulceration is seen most frequently in the ileum, followed by the cecum and other parts of the colon.

Ileocecal ulcers have a distinct tendency to perforate.

Unlike in many other systemic vasculitides, glomerulonephritis is uncommon in Behet syndrome. AA-type amyloidosis is seen sporadically.

 Epididymitis is seen in about 5% of patients.

Although vascular injury is quite common in Behet syndrome and can involve all sizes of vessels in the venous and the arterial systems, frank necrotizing vasculitis of the small and medium-sized arteries of the type seen in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides is uncommon. Giant cells and immune complex–type cutaneous venulitis also are uncommon. As a result, vascular involvement in Behet syndrome is rather unique.

In addition, there is little evidence of vasculitis in some common lesions of Behet syndrome, no evidence of vascular injury in the papulopustular lesions of the skin, and scanty evidence of a frank vasculitis in CNS lesions. Rather unique findings are diffuse inflammatory disease in all layers of the big veins, characteristically involving large segments of the vessel wall; pulmonary arterial aneurysms specific to this condition; and pseudoaneurysms of the big arteries, most probably resulting from vasculitis of the vasa vasorum.

The genetics of Behet syndrome also are uncertain. No clear mendelian pattern emerges. In areas where the disease is endemic, another family member is involved in about 1 of 10 families. The sibling recurrence rate in Turkey has been estimated at 11 to 53 cases per 100,000 persons.

 The most consistent association has been with 

 which explains only about 20% of the heritability.

There may be some clustering in disease expression in Behet syndrome.

 Through a series of mainly clinical observations, 2 clusters have been described: (1) superficial vein thrombosis, deep venous thrombosis (DVT), and dural sinus thrombi

 and (2) acne, arthritis, and enthesitis.

 antibodies and the presence of inflammatory bowel disease may be another cluster.

 The presence of these clusters may suggest the operation of more than 1 disease mechanism in this complex disorder.

There are no specific laboratory findings for Behet syndrome. The erythrocyte sedimentation rate and C-reactive protein level usually are moderately elevated, and they do not correlate well with disease activity.

 Serum immunoglobulin levels sometimes are elevated. Complement levels also may be high. Rheumatoid factor, antinuclear and anticardiolipin antibodies, and ANCA are absent.

In 1990, the International Study Group published a set of diagnostic (classification) criteria for Behet syndrome. They were based on data obtained by computer analysis of the clinical features of 914 patients with Behet syndrome and 308 controls with disease features that may be confused with those of Behet syndrome.

 These new criteria (sensitivity, 91%; specificity, 96%) have been validated and are used widely (

 Recognizing the full-blown syndrome usually is not difficult, but the so-called incomplete forms may present problems (

Many patients with Behet syndrome go into remission with the passage of time.

 Younger patients and men usually have more severe disease-with an increased frequency of mortality and morbidity related to eye, vascular, and neurological disease-than do women and older patients. Loss of useful vision is seen in fewer than 10% to 15% of patients with eye involvement compared with three-fourths of patients 20 to 30 years ago. Although many patients may be managed symptomatically-especially older women-younger men with potentially blinding and lethal disease require aggressive treatment, especially early in the disease course.

This agent is used widely for every lesion of Behet syndrome, but it was useful only for erythema nodosum and arthralgia in a controlled study.

 In a more recent 2-year, placebo-controlled trial, 1 to 2 mg/d of colchicine was beneficial only for genital ulcers, erythema nodosum, and arthritis in women and only for arthritis in men.

In a 2-year, placebo-controlled trial, the use of azathioprine (AZA), 2.5 mg/kg/d, decreased hypopyon uveitis attacks and the development of new eye disease in patients without eye involvement and preserved visual acuity.

 AZA also was beneficial for oral and genital ulcers and arthritis and, possibly, preventing DVT. However, AZA usually is underdosed and at least 3 months of treatment is required for a beneficial response. Early treatment with AZA also improves patients' long-term prognosis.

As a rather quick-acting agent, cyclosporine (CYC) usually is the treatment of choice for sight-threatening and progressive uveitis, especially when there is retinal vasculitis

; it is now used at 5 mg/kg/d or at lower dosages because of its adverse effects. Close monitoring is required for hypertension, nephrotoxicity, and neurotoxicity, even at these lower dosages. In resistant cases, CYC often is combined with AZA.

Success with tumor necrosis factor Î± (TNF-Î±) inhibitors (infliximab, then etanercept and adalimumab) has been reported in more than 300 patients with various concerns, such as eye, mucocutaneous, GI, and neurological disease and even pulmonary artery aneurysms. Infliximab has been the most frequently used TNF-Î± inhibitor in the reports. In a recent position paper, infliximab was recommended as add-on immunosuppressive therapy for select patients with Behet syndrome who are refractory or intolerant to traditional immunosuppressive agents.

 In the only placebo-controlled study of a TNF-Î± inhibitor in Behet syndrome, etÎ±nercept significantly decreased the mean numbers of oral ulcers and nodular and papulopustular lesions.

Corticosteroids are used widely for Behet syndrome. In a recent placebo-controlled study, the authors tested the efficacy of depot corticosteroids, 40 mg of methylprednisolone acetate, against placebo in patients with skin-mucosa disease.

 In this trial, depot corticosteroids were useful only in controlling erythema nodosum lesions in women (but not in men).

The European League Against Rheumatism published guidelines for managing Behet syndrome in 2008.

 The recommendations provide good guidance for the management of disease in organ systems other than vascular, neurological, and GI, simply because there is a lack of controlled studies related to the pathologies. Topical measures, including application of local corticosteroids, are sufficient for isolated oral and genital ulcers.

Immunosuppressive agents, such as corticosteroids and AZA, are used instead of anticoagulants because the main pathology is inflammation of the vessel wall, and there is a lack of thromboembolism in spite of thrombophlebitis occurring frequently. Cyclophosphamide pulse therapy and corticosteroids are useful for pulmonary and peripheral arterial aneurysms, especially early in the disease course.

 Sulfasalazine, corticosteroids, AZA, TNF-Î± inhibitors, and thalidomide may be tried for GI disease before surgery. Although corticosteroids are effective for dural sinus thrombosis, managing parenchymal involvement of the CNS is difficult. Corticosteroids, interferon Î± (IFN-Î±), AZA, cyclophosphamide, and TNF-Î± inhibitors may be used.

More formal, controlled studies are needed for direction in evidence-based treatment of patients with thrombophlebitis and neurological, GI, and arterial involvement. In addition, head-to-head comparisons of TNF-Î± inhibitors and IFN-Î± with more traditional drugs (eg, CYC) would be helpful.

 Sakane T, Takeno M, Suzuki N, Inaba G. BehÃ§et's disease. 

 Yurdakul S, Hamuryudan V, Fresko I, Yazici H. BehÃ§et's syndrome. In: Hochberg MC, Silman AJ, Smolen JS, et al, eds. 

 4th ed. Philadelphia: Mosby-Elsevier; 2008:1561-1565.
	

 BehÃ§et H. Behcet H. Ãber rezidivierende, aphthose, durch ein Virus verursachte Geshwure am Munde, am Auge und an den Genitalien. 

 Verity DH, Marr JE, Ohno S, et al. BehÃ§et's disease, the Silk Road and 

 historical and geographical perspectives. 

 Demirhindi O, Yazici H, Binyildiz P, et al. Silivri Fener kÃ¶yÃ¼ ve yÃ¶resinde BehÃ§et hastaligi sikligi ve bu hastaligin toplum icinde taranabilmesinde kullanabilecek bir yÃ¶ntem. 

 Yurdakul S, GÃ¼naydin I, TÃ¼zÃ¼n Y, et al. The prevalence of BehÃ§et's syndrome in a rural area in northern Turkey. 

 Azizlerli G, KÃ¶se AA, Sarica R, et al. Prevalence of BehÃ§et's disease in Istanbul, Turkey. 

 Ozen S, Karaaslan Y, Ozdemir O, et al. Prevalence of juvenile chronic arthritis and familial Mediterranean fever in Turkey: a field study. 

 Yamamoto S, Toyokawa H, Matsubara J, et al. A nation-wide survey of BehÃ§et's disease in Japan. 

 Jaber L, Milo G, Halpern GJ, et al. Prevalence of BehÃ§et's disease in an Arab community in Israel. 

 Papoutsis NG, Abdel-Naser MB, Altenburg A, et al. Prevalence of Adamantiades-BehÃ§et's disease in Germany and the municipality of Berlin: results of a nationwide survey. 

 Salvarani C, Pipitone N, Catanoso MG, et al. Epidemiology and clinical course of BehÃ§et's disease in the Reggio Emilia area of Northern Italy: a seventeen-year population-based study. 

 Calamia KT, Wilson FC, Icen M, et al. Epidemiology and clinical characteristics of BehÃ§et's disease in the US: a population-based study. 

 Shimizu T, Ehrlich GE, Inaba G, Hayashi K. BehÃ§et disease (BehÃ§et syndrome). 

 Yurdakul S, TÃ¼zÃ¼ner N, Yurdakul I, et al. Gastrointestinal involvement in BehÃ§et's syndrome: a controlled study. 

 Yazici H, Chamberlain MA, TÃ¼zÃ¼n Y, et al. A comparative study of the pathergy reaction among Turkish and British patients with BehÃ§et's disease. 

 Yazici H, TÃ¼zÃ¼n Y, Pazarli H, et al. Influence of age of onset and patient's sex on the prevalence and severity of manifestations of BehÃ§et's syndrome. 

 Mat C, Goksugur N, Engin B, et al. The frequency of scarring after genital ulcers in BehÃ§et's syndrome: a prospective study. 

 Ergun T, GÃ¼rbÃ¼z O, Dogusoy G, et al. Histopathologic features of the spontaneous pustular lesions of BehÃ§et's syndrome. 

 Tursen U, Gurler A, Boyvat A. Evaluation of clinical findings according to sex in 2313 Turkish patients with BehÃ§et's disease. 

 TÃ¼zÃ¼n Y, Yazici H, Pazarli H, et al. The usefulness of the nonspecific skin hyperreactivity (the pathergy test) in BehÃ§et's disease in Turkey. 

 Tugal-Tutkun I, Onal S, Altan-Yaycioglu R, et al. Uveitis in BehÃ§et disease: an analysis of 880 patients. 

 Yurdakul S, Yazici H, TÃ¼zÃ¼n Y, et al. The arthritis of BehÃ§et's disease: a prospective study. 

 Yazici H, Tuzlaci M, Yurdakul S. A controlled survey of sacroiliitis in BehÃ§et's disease. 

Behçet syndrome is a multisystem disease characterized by variable clinical manifestations. The diagnosis is based on recognition of a group of clinical features.

Author | Yusuf Yazici, MD

Articles

Rheumatoid arthritis 2010: Treatment and monitoring

Behçet syndrome: Taking a systemic approach