Outcome evaluations in gout

Methods to measure outcomes in gout still require consensus and validation. This Special Interest Group was assembled to identify domains of interest and is now evaluating a series of outcomes for features of acute gouty arthritis and chronic gout. To accomplish this, working groups have been formed and domains identified. Delphi methodology has been used to address gouty flares as an outcome of greatest interest. Studies addressing other outcome measures were reported at the OMERACT 8 meeting and validation has begun on some outcomes. There has been progress on developing a definition of a flare, and validating reproducibility of some chronic gout outcome measures in some domains, such as tophus size and patient perceptions. Use of these outcomes as well as a health-related quality of life measure are being studied in clinical trials. Pain on a Likert scale appears to be a valid outcome in acute gout. Final validation of these outcomes has not yet been achieved. In summary, the unique problems of evaluating outcomes in gout are finally being addressed. While no measures are available for use yet, an agenda has been developed.     

Tophus measurement as an outcome measure for clinical trials of chronic gout: progress and research priorities

Despite the recognition that tophus regression is an important outcome measure in clinical trials of chronic gout, there is no agreed upon method of tophus measurement. A number of methods have been used in clinical trials of chronic gout, from simple physical measurement techniques to more complex advanced imaging methods. This article summarizes methods of tophus measurement and discusses their properties. Physical measurement using Vernier calipers meets most aspects of the Outcome Measures in Rheumatology (OMERACT) filter. Rigorous testing of the complex methods, particularly with respect to reliability and sensitivity to change, is needed to determine the appropriate use of these methods. Further information is also required regarding which method of physical measurement is best for use in future clinical trials. The need to develop and test a patient-reported outcome measure of tophus burden is also highlighted.     

Outcome measures for acute and chronic gout

Gout provides some unique challenges in classification and measurement of outcomes. Our aim was to evaluate criteria for classification and to develop and validate optimal instruments to measure outcomes for acute and chronic gout. A planning committee and interested attendees met to propose classification criteria and domains for outcomes. Seven of the current American Rheumatism Association preliminary criteria for classification were proposed as the best current criteria for acute gouty arthritis, pending further studies. The presence of gout is best established by crystal identification, although this technique has limitations. Five domains for acute gout outcomes and 9 for chronic gout were identified along with proposed instruments for testing and validation. The unique problems of gout evaluation can and will be addressed.     

Assessment of outcome in psoriatic arthritis

PURPOSE OF REVIEW: A number of drugs for psoriatic arthritis have been tested in randomized clinical trials, and more agents are likely to be evaluated in the future. Such studies have highlighted the relative lack of well-validated or agreed-on outcomes that should be assessed. RECENT FINDINGS: Consensus exercises have identified core domains for intervention studies in psoriatic arthritis. Many of the tools used to measure these domains have been borrowed from rheumatoid arthritis or ankylosing spondylitis, but increasing data relate to psoriatic arthritis specifically. Nonetheless, there are gaps in the measurement toolkit, particularly with respect to assessing dactylitis and axial inflammation. Further validation of functional disability instruments, radiologic scoring methods, and enthesitis instruments is also required. Currently available composite responder criteria are based principally on peripheral joint inflammation and may not be inclusive enough to represent fully the spectrum of patients with psoriatic arthritis. SUMMARY: There have been significant developments in robust tools for assessing outcome in psoriatic arthritis. Since October 2002, much of the activity in this area has been developed by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis and will have culminated in the Outcomes Measures in Rheumatology Clinical Trials meeting in May 2004. Relatively little of this work has been published at the time of this review. Nevertheless, this effort will have a significant influence on the design and reporting of clinical trials in psoriatic arthritis.     

Computed tomography measurement of tophus volume: comparison with physical measurement

OBJECTIVE: Computed tomography (CT) has high accuracy for tophus detection. This study assessed reliability of CT measurement of tophus volume and compared reproducibility of CT with physical measurement of tophus size. METHODS: Forty-seven hand tophi were analyzed in 20 patients with gout. The longest tophus diameter was recorded by 2 independent observers. All patients proceeded to CT scanning of the hands on a Philips Brilliance scanner (0.8-mm slices). Two independent observers measured tophus volume using the Surface Shaded Display 3-dimensional function on the Philips CT workstation. Five patients underwent repeat physical and CT assessments within 1 week (18 observations). Inter- and intraobserver reproducibility were analyzed by limits of agreement and coefficients of variation. RESULTS: Of the 47 lesions identified as tophi on physical examination, 42 (89%) were also identified on CT. The mean (95% confidence interval [95% CI]) difference between observers for physical measurement was 0.45 mm (-4.07, 4.96) and for CT was 65.2 mm(3) (-293.0, 423.3). The mean (95% CI) difference between visits for physical measurement was -0.72 mm (-5.47, 4.03) and for CT was -13.1 mm(3) (-112.5, 86.3). There was no difference between coefficients of variation for inter- and intraobserver reproducibility for the 2 measurement techniques. For tophi identified by physical and CT assessment, there was good correlation between measurements (r = 0.91, P < 0.0001). CONCLUSION: CT assessment of tophus volume is reliable and reproducible. However, physical measurement correlates well with CT and has equivalent reproducibility. These data support the use of physical measurement as a simple and reliable method to assess tophus size.     

Validity of gout diagnoses in administrative data

OBJECTIVE: To determine the utility of using administrative data for epidemiologic studies of gout by examining the validity of gout diagnoses in claims data. METHODS: From a population of approximately 800,000 members from 4 managed care plans, we identified patients who had at least 2 ambulatory claims for a diagnosis of gout between January 1, 1999 and December 31, 2003. From this group, a random sample of 200 patients was chosen for medical record review. Trained medical record reviewers abstracted gout-related clinical, laboratory, and radiologic data from the medical records. Two rheumatologists independently evaluated the abstracted information and assessed whether the gout diagnosis was probable/definite or unlikely/insufficient information. Discordant physician ratings were adjudicated by consensus. Based on record reviews, patients were also classified according to the American College of Rheumatology (ACR), Rome, and New York gout criteria and these results were compared with the physician global assessments. RESULTS: There were 121 patients rated as having probable/definite gout by physician consensus, leading to a positive predictive value of >or=2 coded diagnoses of gout of 61% (95% confidence interval 53-67). There was low concordance between physician assessments and established gout criteria including ACR, Rome, and New York criteria (kappa = 0.17, 0.16, and 0.20, respectively). CONCLUSION: Use of administrative data alone in epidemiologic and health services research on gout may lead to misclassification. Medical record reviews for validation of claims data may provide an inadequate gold standard to confirm gout diagnoses.     

Revisión sistemática sobre el valor de la ecografía y la resonancia magnética nuclear musculoesqueléticas en la evaluación de la respuesta al tratamiento en la gota

BackgroundImaging may be useful for monitoring response to therapy. Within the OMERACT proposal for the core set domains for outcome measures in chronic gout, serum urate levels, recurrence of gouty flares, tophus regression, and joint damage imaging have been included, among other proposed issues.ObjectivesTo perform a systematic literature review of the usefulness of magnetic resonance imaging (MRI) and ultrasound (US) on assessment of treatment response in patients with gout.MethodsMEDLINE, EMBASE, Cochrane Library (up to February 2012), and abstracts presented at the 2010 and 2011 meetings of the American College of Rheumatology and European League Against Rheumatism, were searched for treatment studies of any duration and therapeutic options, examining the ability of MRI/US to assess treatment response in gouty patients. Meta-analyses, systematic reviews, randomized clinical trials, cohort and case-control studies and validation studies were included. Quality was appraised using validated scales.ResultsThere were only 3 US published studies in the literature that analysed US utility on assessment of response to treatment in patients with gout. All of them were prospective case studies with a small number of patients and they were reviewed in detailed. A total of 36 patients with gout were examined with US. All of them had a baseline serum urate > 6 mg/dL. US features of gout (double contour sign, hyperechoic spots in synovial fluid, hyperechoic cloudy areas, tophus diameter and volume) achieved significant reduction in patients who reached the objective of uricemia ≤ 6 mg/dL in all the studies; however, patients in whom levels did not drop below 6 mg/dL had no change of US features of gout. Other parameters evaluated in one study included ESR, CRP, number of tender joints (TRN), number of swollen joints, and pain score (SP). All of them decreased with uricemia reduction, but only TRN and SP were statistically significant. No data was found on the value of MRI on treatment response assessment in patients with gout.ConclusionsThe improvement in ultrasound features shows concurrent validity with uric acid reduction. According to the published evidence, US can be a useful tool for monitoring treatment of gouty patients, although more research is needed. The value of MRI on treatment response assessment in patients with gout remains to be determined.     

Performance of the Existing Classification Criteria for Gout in Thai Patients Presenting With Acute Arthritis

Currently, there are 5 existing classification criteria for gout: the Rome, New York, American Rheumatism Association (ARA), Mexico, and Netherlands criteria. This study was carried out to determine the performance of these classification criteria in Thai patients presenting with acute arthritis.All consecutive patients presenting with acute arthritis and being consulted at the Rheumatology Unit, Chiang Mai University Hospital from January 2013 to May 2015 were invited to join the study. Gout was defined by the presence of monosodium urate crystals in the synovial fluid or tissue examined by experienced rheumatologists. The 5 existing gout classification criteria were performed and evaluated in all of the patients, who were divided in subgroups of early disease (≤2 years), established disease (>2 years), and those without tophus.There were 136 gout and 97 nongout patients. Sensitivity and specificity across all criteria ranged from 75.7% to 97.1% and 68.0% to 84.5%, respectively. Overall, the Mexico criteria had the highest sensitivity (97.1%), and the ARA survey criteria the highest specificity (84.5%), whereas the Mexico criteria performed well in early disease with sensitivity and specificity of 97.1% and 81.7%, respectively. All 5 criteria showed high sensitivity (from 76.4% to 99.1%) but low specificity (from 30.8% to 65.4%) in established disease. In patients without tophus, the sensitivity and specificity ranged from 64.1% to 95.7% and 68.8% to 85.4%, respectively. The ARA survey criteria across all groups showed consistently high specificity for gout.The 5 existing classification criteria for gout had limited sensitivity and specificity in Thai patients presenting with acute arthritis. The ARA survey criteria are the most suitable for diagnosing gout in Thai people when crystal identification is not available.     

Tophaceous joint disease strongly predicts hand function in patients with gout

OBJECTIVES: The functional impact of gout is poorly understood. The aim of this study was to determine predictors of hand function in gout. METHODS: Twenty unselected patients with gout were recruited from rheumatology clinics. No patient had an acute gout flare at assessment. Participants were assessed for clinical characteristics of gout, including the site and number of tophi. Hand function was assessed by the Sollerman hand function test. Fingertip to palm (FTP) distance measurement, grip strength and the Disability Assessment of Shoulder and Hand (DASH) questionnaire scores were also recorded. Data were analysed by simple and multiple linear regression models. RESULTS: The median Sollerman score was 75.5 (range 31-80). The median hand FTP distance was 2.91 (0.88-6.69) cm, grip strength was 31 (4-71) kg, and DASH score was 28.77 (0-76.47). Of the clinical characteristics measured, the number of joints of the hand with overlying tophi (hand tophus joint count) was the strongest single predictor of the Sollerman score (r2 = 0.59), and also predicted the other measures of hand mobility and function. A multiple regression model including hand tophus joint count, sex, number of gout flares in the preceding 6 months, gout disease duration and hand tender joint count was a better predictor of the Sollerman score than hand tophus joint count alone (r2 = 0.81, F(4,14) = 3.94, P = 0.024). CONCLUSIONS: Measures of chronic and poorly controlled disease predict hand function in patients with gout. In particular, tophaceous joint disease has a major impact on functional capacity in gout.     

Ultrasonographic measurement of tophi as an outcome measure for chronic gout

OBJECTIVE: To validate the usefulness of measuring tophi with ultrasonography (US) as an outcome measure for chronic tophaceous gout. METHODS: Patients with crystal-proven gout were included. To evaluate validity, intraarticular and articular deep tophi were evaluated with both magnetic resonance imaging (MRI) and US. Tophi were punctured with US guidance to evaluate face validity. Interobserver and intraobserver measurement studies were done to evaluate reliability, and to estimate the smallest detectable difference. Sensitivity to change was evaluated with a 12-month followup observational study of urate-lowering therapy. RESULTS: US detected at least one tophus in all joints where MRI found nodules considered to be tophi. There was a good correlation, but just fair agreement between measurements with US and MRI. Puncture of nodules suspected of being tophi recovered urate crystals in 83% of the procedures. Intraobserver intraclass correlation was > 0.90 for diameters and volume, while it was 0.71 to 0.83 in the interobserver study. US was found to be sensitive to change, and there was an inverse correlation between serum urate concentrations and change from baseline measurement of tophi. CONCLUSION: US measurement of tophi fulfilled the OMERACT filter for an outcome measure, although it should be tested further in randomized clinical trials.     

Comparison of phenotype expression by mononuclear phagocytes within subcutaneous gouty tophi and rheumatoid nodules

Summary The mononuclear phagocyte infiltrate which occupies the gout tophus has been compared with that of the subcutaneous rheumatoid nodule. In the gout tophus, macrophage migration appears to be at a relatively low level and effectively terminates once these cells have been recruited into the corona. In the nodule the evidence suggests that both macrophage and granulocyte populations continuously migrate towards, and are progressively incorporated into, the necrotic centres. These observations indicate that chemotactic activity in rheumatoid nodules is at a higher level than in gout tophi, or that the rheumatoid mononuclear phagocyte is more responsive to such stimuli.     

Improvement in OMERACT domains and renal function with regular treatment for gout: a 12-month follow-up cohort study

OMERACT proposed a set of mandatory and discretionary domains to evaluate the effect of treatment in patients with gout. To determine the percentage of improvement and the effect size 6 and 12 months after starting a proper treatment in patients with gout from our cohort (GRESGO) based on the OMERACT proposal for chronic gout. GRESGO is a cohort of consecutive, new patients with gout attending either of two dedicated clinics. This report includes 141 patients evaluated at baseline and 6 months plus 101 of them completing a 12-month follow-up in 2012. Clinical data including the OMERACT domains for chronic gout were collected at baseline and every 6 months. Treatment was prescribed by their attending physician with the purpose of getting <?6 mg/dL of seric uric acid (sUA). Most patients were males (96%) with inappropriate treatment (95%); 66% had tophi, 30% metabolic syndrome, and 32% low renal function. Mean dose of allopurinol at baseline and throughout the study went from 344?±?168 mg/day to 453?±?198 at 12 months. Most OMERACT domains and renal function improved significantly; 73% improved >?20% from 6 to 12 months. Greater improvement was observed in the domains: flares, index tophus size, pain, general health assessment, and HAQ score, all of them associated to lower sUA values. Chronic gout patients improve significantly in most OMERACT domains when conventional and regular treatment is indicated. sUA <?6 mg/dL is associated with greater improvement.     

Imaging of knee osteoarthritis: data beyond the beauty

PURPOSE OF REVIEW: MRI has revolutionized osteoarthritis research by providing semi-quantitative and quantitative imaging endpoints on most articular tissues. With the first image data of the Osteoarthritis Initiative now becoming publicly available, this article reviews recent developments in quantitative imaging of osteoarthritis. RECENT FINDINGS: Although radiography remains the standard for regulatory studies on disease modifying osteoarthritis drugs, there is no consensus on the optimal positioning and acquisition protocol. With MRI, semi-quantitative scoring systems for evaluation of multiple articular tissue changes have been developed and are currently investigated in the context of correlation with symptoms and of predicting structural progression of osteoarthritis. Most efforts on quantitative measurement of imaging endpoints have focused on cartilage morphology and composition, with higher field strength (3T), newer sequences, and new measurement endpoints being a driver of current innovation. SUMMARY: The semi-quantitative and quantitative tools for analysis of articular structure are now available and permit comprehensive analysis of morphological and compositional tissue changes in osteoarthritis. These changes will need to be related to clinical outcomes (e.g. how a patient feels or functions) with current epidemiological studies, such as the Osteoarthritis Initiatives, providing the opportunity for clinical validation of these imaging biomarkers.     

Tophaceous gout: quantitative evaluation by direct physical measurement

OBJECTIVE: The absence of accepted standardized methods for monitoring tophaceous gout limits the ability to track tophus progression or regression. This multicenter study assessed intra- and interrater reproducibility of a simple and direct physical measurement. METHODS: The quantitative evaluation was the area (mm2) of each measurable tophus and was determined independently by 2 raters on 2 occasions within 10 days. Intra- and interrater reproducibilities were determined by calculating mean differences and average percentage differences (APD) in measurements of areas for the same tophus at each of 2 visits and by each rater, respectively. RESULTS: Fifty-two tophi were measured in 13 subjects: 22 on the hand/wrist, 16 on the elbow, and 14 on the foot/ankle. The mean (+/- SD) difference in tophus areas between visits was -0.2 +/- 835 mm2 (95% CI -162 to 162 mm2) and the mean (+/- SD) APD was 29% +/- 33%. The mean (+/- SD) APD between raters was 32% +/- 27%. The largest variations in measurements were noted for elbow tophi and variations were least for well demarcated tophi on the hands. CONCLUSION: This simple and reproducible method can be easily utilized in clinical trials and in practice as a measure of efficacy of urate-lowering treatment in tophaceous gout. Among factors contributing to variability in these measurements were the anatomic site of tophi and rater experience with the method. Restriction of measurements to well circumscribed hand or foot tophi could improve reliability, but major changes, as expected with effective therapy, can clearly be documented with this simple technique.     

Imaging modalities and monitoring measures of gout

PURPOSE OF REVIEW: Imaging modalities for gout have been mostly restrained to radiographs. Ultrasonography, computed tomography and magnetic resonance imaging are emerging techniques that could be used for diagnosis, evaluation, and monitoring acute and chronic gout. RECENT FINDINGS: Diagnosis of gout is based on urate crystal observation with microscopy. Recently, crystal deposition in the hyaline cartilage has been described to be different in gout from that of calcium pyrophosphate, but validation of the findings is pending. Severity of gout with simple radiographs may not disclose periarticular or intra-articular urate deposition. Ultrasonography, computed tomography and magnetic resonance imaging may improve the evaluation of tophi not apparent in clinical examination or simple radiographs. Monitoring urate deposition may be accomplished with imaging techniques. This would be of outstanding interest for clinical trials, but also for evaluating clinical response to urate-lowering therapy. Although preliminary results evaluating for validity and reliability have been very recently reported for magnetic resonance imaging, computed tomography and ultrasonography, sensitivity to change studies are still pending. Also, monitoring of chronic inflammation with imaging techniques, such as power-Doppler, deserve further studies. SUMMARY: Evidence exists regarding the usefulness of imaging techniques for diagnosis, evaluation of severity, and monitoring of gout, but further investigation is needed.     

Role of dual-energy CT in the diagnosis and follow-up of gout: systematic analysis of the literature

The aim of this systematic review was to determine the potential role of dual-energy CT in the diagnosis and follow-up of gout with regard to the Outcome Measures in Rheumatology (OMERACT) filter. A systematic analysis of the literature was conducted using the MEDLINE and Cochrane databases and published abstracts of international congresses, according to the criteria of the OMERACT filter: feasibility, reproducibility, validity versus laboratory (serum urate, MSU synovial fluid aspirate) and other imaging modalities for gout, and its sensitivity to change in patients on urate lowering therapy (ULT). Thirty-two articles were found representing a total of 1502 patients. The data on feasibility showed that the examination took little time and involved low levels of radiation but had current limited availability. Intra- and inter-observer reproducibility was excellent, with intra-class correlation coefficients >?0.9. Validity in comparison with polarized-light microscopy showed good sensitivity and specificity (>?80%). The diagnostic performance was better than that of radiography and conventional CT-scan and at least equivalent to that of ultrasonography. The sensitivity to change varied with effect sizes from 0.05 (low) to 1.24 (high) for decrease in the tophus volume following different ULT in gout patients. Dual-energy CT-scan is a reproducible and accurate imaging modality for the diagnosis of gout, particularly for tophaceous gout (intra- or extra-articular). It can become a second-line imaging modality of choice in cases of diagnostic doubt, such as ultrasonography. Its role remains uncertain in the follow-up of gout patients treated with ULT and needs further clarification.     

Preliminary criteria for the classification of the acute arthritis of primary gout

The American Rheumatism Association subcommittee on classification criteria for gout analyzed data from more than 700 patients with gout, pseudogout, rheumatoid arthritis, or septic arthritis. Criteria for classifying a patient as having gout were a) the presence of characteristic urate crystals in the joint fluid, and/or b) a tophus proved to contain urate crystals by chemical or polarized light microscopic means, and/or c) the presence of six of the twelve clinical, laboratory, and X-ray phenomena listed in Table 5.     

The OMERACT core set of outcome measures for use in clinical trials of ANCA-associated vasculitis

There has been a marked increase in the past 15 years in the number and quality of clinical trials in the idiopathic inflammatory vasculitides, especially the small-vessel vasculitides known as antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis [AAV; granulomatosis, with polyangiitis (Wegener's)]. These trials have been conducted by multicenter, international groups in Europe and the United States with financial support provided by government agencies and biopharmaceutical companies. This increased clinical trial activity in vasculitis has been accompanied by the development and validation of new outcome measures--a challenging process for these complex, multiorgan system diseases. The international OMERACT Vasculitis Working Group has developed and implemented an iterative research agenda that has utilized accumulated experience and datasets from several multicenter clinical trials and large cohort studies. This work has led to the development, evaluation, validation, and endorsement, through the OMERACT consensus and validation processes, of a "core set" of outcome measurements for use in clinical trials of AAV. The core set includes domains of disease activity, damage assessment, patient-reported outcomes, and mortality; there is at least one validated outcome measurement instrument available for each domain. This report reviews the domains of illness in AAV included in the OMERACT core set, describes the instruments validated to measure these domains, and presents the approved core set.     

Defining appropriate outcome measures in pulmonary arterial hypertension related to systemic sclerosis: a Delphi consensus study with cluster analysis

OBJECTIVE: Outcome measures for pulmonary arterial hypertension associated with systemic sclerosis (PAH-SSc) are only partially validated. The aim of the present study was to establish an expert consensus regarding which outcome measures are most appropriate for clinical trials in PAH-SSc. METHODS: Sixty-nine PAH-SSc experts (rheumatologists, cardiologists, pulmonologists) rated a list of disease domains and measurement tools in an Internet-based 3-stage Delphi consensus study. In stages 2 and 3, the medians of domains and measurement tools and frequency distributions of ratings, along with requests for re-ratings, were distributed to respondents to provide feedback. A final score of items was identified by means of cluster analysis. RESULTS: The experts judged the following domains and tools as most appropriate for randomized controlled trials in PAH-SSc: lung vascular/pulmonary arterial pressure and cardiac function both measured by right heart catheterization and echocardiography, exercise testing measured by 6-minute walking test and oxygen saturation at exercise, severity of dyspnea measured on a visual analog scale, discontinuation of treatment measured by (serious) adverse events, quality of life/activities of daily living measured by the Short Form 36 and Health Assessment Questionnaire disability index, and global state assessed by physician measured by survival. CONCLUSION: Among experts in PAH-SSc, a core set of outcome measures has been defined for clinical trials by Delphi consensus methods. Although these outcome measures are recommended by this expert group to be used as an interim tool, it will be necessary to formally validate the present measures, as well as potential research measures, in further studies.     

Rasburicase for tophaceous gout not treatable with allopurinol: an exploratory study

OBJECTIVE: To evaluate the short-term safety and outcome of 2 different experimental applications of rasburicase 0.2 mg/kg (monthly vs daily) in patients with tophaceous gout not treatable by allopurinol. Rasburicase could be useful for patients with gout that is unresponsive to allopurinol or who cannot tolerate the therapy. METHODS: Five patients received 6 monthly infusions of rasburicase (Group 1) and 5 received 5 daily infusions (Group 2). RESULTS: In Group 1, serum uric acid (SUA) level decreased significantly, from 612.6 +/- 162.4 micromol/l at baseline to 341.2 +/- 91.8 micromol/l after 6 infusions (p = 0.001). Changes in tophus area were observed in 2 patients. In Group 2, daily infusions produced a rapid, marked decrease in SUA level during treatment. Yet SUA levels measured at 1 month (511.5 +/- 128.4 micromol/l) and 2 months (572 +/- 96.2 micromol/l) after treatment were not significantly lower than at baseline (573.6 +/- 48.2 micromol/l). No patient from Group 2 showed reduced tophus size. Eight of 10 patients experienced an adverse event, the most common being gout flare despite prophylactic treatment with colchicine. CONCLUSION: Monthly infusions of rasburicase appear to be a possible therapy for severe gout not treatable by other means. Tolerance of rasburicase in gout appears to be diminished by frequent triggering of gout attacks, and hypersensitivity reactions might be an important limitation to longterm therapy.