Predictors of response to anti-tumor necrosis factor therapy in ulcerative colitis

Ulcerative colitis(UC) is an immune-mediated, chronic inflammatory disease of the large intestine. Its course is characterized by flares of acute inflammation and periods of low-grade chronic inflammatory activity or remission. Monoclonal antibodies against tumor necrosis factor(anti-TNF) are part of the therapeutic armamentarium and are used in cases of moderate to severe UC that is refractory to conventional treatment with corticosteroids and/or immunosuppressants. Therapeutic response to these agents is not uniform and a large percentage of patients either fail to improve(primary non-response) or lose response after a period of improvement(secondary non-response/loss of response). In addition, the use of anti-TNF agents has been related to uncommon but potentially serious adverse effects that preclude their administration or lead to their discontinuation. Finally, use of these medications is associated with a considerable cost for the health system. The identification of parameters thatmay predict response to anti-TNF drugs in UC would help to better select for patients with a high probability to respond and minimize risk and costs for those who will not respond. Analysis of the major clinical trials and the accumulated experience with the use of anti-TNF drugs in UC has resulted to the report of such prognostic factors. Included are clinical and epidemiological characteristics, laboratory markers, endoscopic indicators and molecular(immunological/genetic) signatures. Such predictive parameters of long-term outcomes may either be present at the commencement of treatment or determined during the early period of therapy. Validation of these prognostic markers in large cohorts of patients with variable characteristics will facilitate their introduction into clinical practice and the best selection of UC patients who will benefit from anti-TNF therapy.     

Toll-like receptor 9 gene mutations and polymorphisms in Japanese ulcerative colitis patients

Abnormal innate immune responses toward luminal bacteria play an important role in the pathogenesis of inflammatory bowel disease.It has been demonstrated that bacteria having CpG DNA ameliorate experimental colitis in mice,and Toll-like receptor 9 (TLR9) signaling mediates the anti-inflammatory effects in mouse colonic inflammation.A gene variation in NOD2/CARD15 has been reported in Crohn’s disease (CD) patients in Western countries,but this variation has not been identified in Japanese CD patients.Therefore,we hypothesized that TLR9 is a key factor in the development of ulcerative colitis (UC),and we investigated gene mutations and polymorphisms of TLR9 in Japanese UC patients.Three single nucleotide polymorphisms (SNPs) in TLR9 were identified in healthy controls,and were assessed in 48 UC patients and 47 healthy controls.Control subjects were matched for age,sex and date of blood sampling from among a subgroup of participants.We found that TLR9-1486CC,1174GG and 2848AA increase the risk of UC [odds ratio (OR) 2.64,95% confidence interval (95% CI):1.73-6.53,P=0.042],and TLR9-1486TT,1174AA and 2848GG decrease the risk of UC (OR 0.30,95% CI:0.10-0.94,P=0.039),although there were no correlations between SNPs and disease phenotype or TLR9 mRNA expression.These findings suggest that TLR9 polymorphisms are associated with increased susceptibility to UC.     

Safety of anti-tumor necrosis factor therapy during pregnancy in patients with inflammatory bowel disease

Treatment of inflammatory bowel disease has significantly improved since the introduction of biological agents, such as infliximab, adalimumab, certolizumab pegol, and golimumab. The Food and Drug Administration has classified these factors in category B, which means that they do not demonstrate a fetal risk. However, during pregnancy fetuses are exposed to high anti-tumor necrosis factor(TNF) levels that are measurable in their plasma after birth. Since antibodies can transfer through the placenta at the end of the second and during the third trimesters, it is important to know the safety profile of these drugs, particularly for the fetus, and whether maintaining relapse of the disease compensates for the potential risks of fetal exposure. The limited data available for the anti-TNF drugs to date have not demonstrated any significant adverse outcomes in the pregnant women who continued their therapy from conception to the first trimester of gestation. However, data suggest that antiTNFs should be discontinued during the third trimester, as they may affect the immunological system of the newborn baby. Each decision should be individualized, based on the distinct characteristics of the patient and her disease. Considering all the above, there is a need for more clinical studies regarding the effect of antiTNF therapeutic agents on pregnancy outcomes.     

Two-year delay in ulcerative colitis diagnosis is associated with anti-tumor necrosis factor alpha use

BACKGROUND Ulcerative colitis(UC)is an uncommon inflammatory bowel disease(IBD).However,its incidence has recently increased in South Korea.Moreover,UC diagnoses are frequently delayed,and the relationship between diagnostic delay and UC prognosis has not been extensively studied in South Korean patients.AIM To identify meaningful diagnostic delay affecting UC prognosis and to evaluate risk factors associated with diagnostic delay in South Korean patients.METHODS Medical records of 718 patients with UC who visited the outpatient clinic of six university hospitals in South Korea were reviewed;167 cases were excluded because the first symptom date was unknown.We evaluated the relationship between the prognosis and a diagnostic delay of 3,6,12,18,and 24 mo by comparing the prognostic factors[anti-tumor necrosis factor(TNF)-αuse,admission history due to acute flare-ups,frequent admission due to flare-ups,surgery associated with UC,and the clinical remission state at the latest followup]at each diagnostic interval.RESULTS The mean diagnostic interval was 223.3±483.2 d(median,69 d;75th percentile,195 d).Among the prognostic factors,anti-TNFαuse was significantly increased after a diagnostic delay of 24 mo.Clinical risk factors predictive of a 24-mo diagnostic delay were age<60 years at diagnosis[odd ratio(OR)=14.778,95%confidence interval(CI):1.731-126.121],smoking history(OR=2.688,95%CI:1.239-5.747,P=0.012),and misdiagnosis of hemorrhoids(OR=11.066,95%CI:3.596-34.053).Anti-TNFαuse was associated with extensive UC at diagnosis(OR=3.768,95%CI:1.860-7.632)and 24-mo diagnostic delay(OR=2.599,95%CI:1.006-4.916).CONCLUSION A diagnostic delay>24 mo was associated with increased anti-TNFαuse.Age<60 years at diagnosis,smoking history,and misdiagnosis of hemorrhoids were risk factors for delayed diagnosis.     

Safety of anti-tumor necrosis factor therapy in inflammatory bowel disease

Inflammatory bowel disease （IBD）, in particular Crohn＇s disease refractory to conventional therapy, fistulizing Crohn＇s disease and chronic active ulcerative colitis,generally respond well to anti-tumor necrosis factor（TNF） therapy. However, serious side effects do occur,necessitating careful monitoring of therapy. Potentialside effects of anti-TNF therapy include opportunistic infections, which show a higher incidence whenconcomitant immunosuppression is used. Furthermore,antibody formation against anti-TNF is associated with decreased efficacy and an increased frequency of infusion reactions. The hypothesis of a slightlyincreased risk of lymphomas in IBD patients treated with anti TNF-therapy is debatable, since most studieslack the specific design to properly address this issue.Alarmingly, the occurrence of hepatosplenic T-cell lymphomas coincides with combined immunosuppressive therapy. Despite the potential serious side effects, anti-TNF therapy is an effective and relatively safe treatment option for refractory IBD. Future research is needed to answer important questions, such as the long-term risk of malignancies, safety during pregnancy, when to discontinue and when to switch anti-TNF therapy, as well as to determine the balance between therapeutic and toxic effects.     

Efficacy of cytapheresis in patients with ulcerative colitis showing insufficient or lost response to biologic therapy

For the optimal management of refractory ulcerative colitis (UC), secondary loss of response (LOR) and primary non-response to biologics is a critical issue. This article aimed to summarize the current literature on the use of cytapheresis (CAP) in patients with UC showing a poor response or LOR to biologics and discuss its advantages and limitations. Further, we summarized the efficacy of CAP in patients with UC showing insufficient response to thiopurines or immunomodulators (IM). Eight studies evaluated the efficacy of CAP in patients with UC with inadequate responses to thiopurines or IM. There were no significant differences in the rate of remission and steroid-free remission between patients exposed or not exposed to thiopurines or IM. Three studies evaluated the efficacy of CAP in patients with UC showing an insufficient response to biologic therapies. Mean remission rates of biologics exposed or unexposed patients were 29.4 % and 44.2%, respectively. Fourteen studies evaluated the efficacy of CAP in combination with biologics in patients with inflammatory bowel disease showing a poor response or LOR to biologics. The rates of remission/response and steroid-free remission in patients with UC ranged 32%-69% (mean: 48.0%, median: 42.9%) and 9%-75% (mean: 40.7%, median: 38%), respectively. CAP had the same effectiveness for remission induction with or without prior failure on thiopurines or IM but showed little benefit in patients with UC refractory to biologics. Although heterogeneity existed in the efficacy of the combination therapy with CAP and biologics, these combination therapies induced clinical remission/response and steroid-free remission in more than 40% of patients with UC refractory to biologics on average. Given the excellent safety profile of CAP, this combination therapy can be an alternative therapeutic strategy for UC refractory to biologics. Extensive prospective studies are needed to understand the efficacy of combination therapy with CAP and biologics.     

Altered expression of innate immunity genes in different intestinal sites of children with ulcerative colitis

Background

Innate immunity has been very rarely investigated in ulcerative colitis and never in paediatrics. The present study was aimed at describing expression of innate immunity genes (NOD2, RIP2, α-defensins HD5 and HD6) in inflamed colon and in ileum of children with ulcerative colitis. Expression of TNFα and IL-1β was also analyzed.

Methods

15 children with ulcerative colitis (9 pancolitis, 6 left-sided colitis) and 10 control children were enrolled. mRNA and protein expressions were detected by real time PCR and western blot assays.

Results

NOD2, RIP2, IL-1β, TNFα expression levels were significantly increased in colonic mucosa of patients compared to controls (p < 0.01). These genes were also upregulated (p < 0.01) in the ileum of both pancolitis and left-sided colitis children. HD5 and HD6 were significantly upregulated (p < 0.01) in the inflamed colon of patients as well as in the ileum of those with pancolitis.

Conclusions

An increased mucosal expression of innate immunity genes was found in the inflamed colon of children with ulcerative colitis, outlining the role of the innate immune response in disease pathogenesis. Involvement of the ileum in ulcerative colitis suggests that an immune activation can also be established in intestinal sites classically uninvolved by the inflammation, carrying implications for the treatment and course of the disease.     

Effects of oral tacrolimus as a rapid induction therapy in ulcerative colitis

AIM:To determine the efficacy and safety of rapid induction therapy with oral tacrolimus without a meal in steroid-refractory ulcerative colitis(UC)patients.METHODS:This was a prospective,multicenter,observational study.Between May 2010 and August 2012,49 steroid-refractory UC patients(55 flare-ups)were consecutively enrolled.All patients were treated with oral tacrolimus without a meal at an initial dose of 0.1mg/kg per day.The dose was adjusted to maintain trough whole-blood levels of 10-15 ng/m L for the first 2 wk.Induction of remission at 2 and 4 wk after tacrolimus treatment initiation was evaluated using Lichtiger’s clinical activity index(CAI).RESULTS:The mean CAI was 12.6±3.6 at onset.Within the first 7 d,93.5%of patients maintained high trough levels(10-15 ng/m L).The CAI significantly decreased beginning 2 d after treatment initiation.At 2wk,73.1%of patients experienced clinical responses.After tacrolimus initiation,31.4%and 75.6%of patients achieved clinical remission at 2 and 4 wk,respectively.Treatment was well tolerated.CONCLUSION:Rapid induction therapy with oral tacrolimus shortened the time to achievement of appropriate trough levels and demonstrated a high remission rate 28 d after treatment initiation.Rapid induction therapy with oral tacrolimus appears to be a useful therapy for the treatment of refractory UC.     

Effectiveness of probiotic therapy for the prevention of relapse in patients with inactive ulcerative colitis

AIM: to evaluate the effectiveness of probiotic therapy for suppressing relapse in patients with inactive ulcerative colitis(UC).METHODS: Bio-Three tablets, each containing 2 mg of lactomin(Streptococcus faecalis T-110), 10 mg of Clostridium butyricum TO-A, and 10 mg of Bacillus mesentericus TO-A, were used as probiotic therapy.Sixty outpatients with UC in remission were randomly assigned to receive 9 Bio-Three tablets/day(BioThree group) or 9 placebo tablets/day(placebo group)for 12 mo in addition to their ongoing medications.Clinical symptoms were evaluated monthly or on the exacerbation of symptoms or need for additional medication. Fecal samples were collected to analyze bacterial DNA at baseline and 3-mo intervals. Terminal restriction fragment length polymorphism and cluster analyses were done to examine bacterial components of the fecal microflora.RESULTS: Forty-six patients, 23 in each group,completed the study, and 14 were excluded. The relapse rates in the Bio-Three and placebo groups were respectively 0.0% vs 17.4% at 3 mo(P = 0.036), 8.7%vs 26.1% at 6 mo(P = 0.119), and 21.7% vs 34.8%(P = 0.326) at 9 mo. At 12 mo, the remission rate was 69.5% in the Bio-Three group and 56.6% in the placebo group(P = 0.248). On cluster analysis of fecal flora, 7 patients belonged to cluster Ⅰ, 32 to cluster Ⅱ,and 7 to cluster Ⅲ.CONCLUSION: Probiotics may be effective formaintaining clinical remission in patients with quiescent UC, especially those who belong to cluster Ⅰ on fecal bacterial analysis.     

TLRs在溃疡性结肠炎小鼠结肠中的表达研究

目的 观察溃疡性结肠炎（UC）小鼠模型结肠组织中TLR2、TLR4和TLR9的表达情况,为UC发病机制的研究提供新思路.方法 将6～8周龄健康雄性BALB/c小鼠随机分为两组：正常对照组（n=10）和UC模型组（n=10）,正常对照组小鼠蒸馏水自由饮用7d.UC模型组小鼠5％ DSS溶液自由饮用7d造模.7d后处死小鼠,采用实时荧光定量PCR方法检测各组小鼠结肠黏膜组织中TLR2、TLR4和TLR9 mRNA的表达情况.结果 正常对照组结肠组织中无TLR2、TLR4和TLR9 mRNA的表达,而UC组结肠组织中TLR2、TLR4和TLR9 mRNA表达明显,两组比较差异有统计学意义（P＜0.05）.结论 TLR2、TLR4、TLR9可能参与了UC的发病过程.     

Susceptibility to ulcerative colitis in Hungarian patients determined by gene-gene interactions

AIM:To study the inflammatory bowel disease-5 locus（IBD5）and interleukin-23 receptor（IL23R）gene variants in UC patients and test for gene-gene interaction.METHODS:The study population（n=625）was comprised of 320 unrelated ulcerative colitis（UC）patients with Caucasian origin and 316 age-and gendermatched,healthy controls.Five variants in the IBD5 locus（IGR2198a₁ rs11739135,IGR2096a₁ rs12521868,IGR2230a₁ rs17622208,SLC22A4 rs1050152 and SLC22A5 rs2631367）and two of the IL23R gene（rs1004819,rs2201841）were analysed.PCR and restriction fragment length polymorphism methods were used for genotyping,the SLC22A4 rs1050152 genotypes were determined by direct sequencing.Interactions and specific genotype combinations of the seven variants were tested by binary logistic regression analysis.The IL23R genotypes were stratified by IBD5 genotypes for further interaction analyses.RESULTS:For the IL23R rs1004819 A allele we found significantly higher allele frequency（P=0.032）in UC patients compared to control subjects.The SNP rs1004819 showed significant association with UC risk for carriers（P=0.004,OR=1.606;95%CI:1.160-2.223）and the SNP rs2201841 for homozygotes（P=0.030,OR=1.983;95%CI:1.069-3.678）.Individually none of the IBD5 markers conferred risk to UC development.There was no evidence for statistical interaction either between IBD5 loci and IL23R genes using logistic regression analysis.After genotype stratification,we could detect a positive association on the background of rs1004819 A allele for SLC22A4 T,SLC22A5 C,IGR2198a₁ C or IGR2096a₁ T allele,the highest OR was calculated in the presence of SLC22A4T allele（P=0.005,OR=2.015;95%CI:1.230-3.300）.There was no association with UC for any combinations of rs1004819 and IGR2230a₁.The IL23R rs2201841homozygous genotype and IBD5 carrier status together did not confer susceptibility for UC.CONCLUSION:The present study has shown that UC susceptibility genes are likely to act in a complex interactive manner similar to CD.     

Biological therapy for ulcerative colitis: An update

Of the diverse biological agents used for patients with ulcerative colitis, the anti-tumor necrosis factor-α agents infliximab and adalimumab have been used in large-scale clinical trials and are currently widely used in the treatment of inflammatory bowel disease patients. Recent studies have indicated that golimumab, oral tofacitinib and vedolizumab reportedly achieved good clinical response and remission rates in ulcerative colitis patients. Thus, we believe that the detailed investigation of various studies on clinical trials may provide important information for the selection of appropriate biological agents, and therefore, we have extensively reviewed such trials in the present study.     

肿瘤坏死因子基因多态性与溃疡性结肠炎相关性研究

目的 检测肿瘤坏死因子（TNF）α基因多态性是否与浙江地区汉族溃疡性结肠炎（UC）患者遗传易感相关.方法 血样来自浙江地区110例UC患者及292例健康对照者.通过特定引物的聚合酶链反应（PCR-SSP）方法直接检测野生型及TNF基因的6个多态性（TNF-1031T/C,-863C/A,-857C/T,-380G/A,-308G/A,-238G/A）.结果TNF-308A与汉族UC显著相关,等位基因频率在患者中为14.6%,在健康对照者中为8.9%,两者间差异有统计学意义（P=0.02）.TNF-857T的携带率在UC患者中为17.3%,健康对照者为12.2%,两者间差异无统计学意义（P=0.06）.单倍体分型显示,6种单倍体包括H5和H3,这两种单倍体都包含TNF-308A.H5单倍体频率在患者中为12.3%,在健康对照者为7.5%,两者间差异有统计学意义（P=0.03）.我们还发现了既往在白种人中较少见的单倍体H3.单倍体H4是由TNF基因启动子区域野生型等位基因组成,它的纯合子UC患者共有27例（24.5%）,在健康对照者中有102例（34.9%）,差异有统计学意义（P＜0.05）,说明野生型等位基因可能与疾病的发生无关.结论 TNF-308A可能与汉族UC患者遗传易感相关.进一步的功能研究有助于明确突变型TNFα在UC发病过程中的作用.     

Safe and effective: anti‐tumour necrosis factor therapy use in pregnant patients with Crohn disease and ulcerative colitis

Biological therapy, particularly the anti‐tumour necrosis factor (TNF) antibodies, infliximab and adalimumab, are used for the maintenance of remission for patients with inflammatory bowel diseases (IBD). We present 21 pregnancies in IBD patients exposed to anti‐TNF agents between 2007 and 2014. Our study demonstrates that anti‐TNF therapy is safe and effective in pregnancy. Rates of foetal complications are similar to IBD cohorts from the pre anti‐TNF era.     

Autoimmune hepatitis and anti-tumor necrosis factor alpha therapy: A single center report of 8 cases

This article describes cases of anti-tumor necrosis factor (TNF)-α-induced autoimmune hepatitis and evaluates the outcome of these patients in relation to their immunosuppressive strategy. A retrospective analysis of medical records was performed in our center, in order to detect cases of autoimmune hepatitis (AIH) associated with anti-TNF biologic agents. We describe and analyze eight cases of AIH following anti-TNF therapy, 7 with infliximab and 1 with adalimumab. A distinction should be made between induction of autoimmunity and clinically evident autoimmune disease. Liver biopsy is useful in detecting the role of the TNF-α antagonist in the development of AIH. The lack of relapse after discontinuing immunosuppressive therapy favors, as in this case series, an immune-mediated drug reaction as most patients with AIH have a relapse after treatment is suspended. Although AIH related to anti-TNF therapy is rare, a baseline immunological panel along with liver function tests should be performed in all patients with autoimmune disease before starting biologics.     

溃疡性结肠炎患者血栓前状态分子标志物的变化及其临床意义

目的探讨溃疡性结肠炎（UC）患者凝血、抗凝及纤溶指标的变化与溃疡性结肠炎的活动性及病变范围的关系。方法采用ELISA法检测32例活动期UC患者,20例缓解期UC患者及45例健康对照组的血小板颗粒膜蛋白-140（GMP-140）,血管性假性血友病因子（vWF：Ag）,血栓调节蛋白（TM）,D-二聚体（DD）的含量,采用发色底物法测定抗凝血酶-Ⅲ：活性（AT-Ⅲ：A）并进行分析。结果活动期UC患者GMP-140,vWF：Ag,TM,D-D的含量均明显高于缓解期患者及对照组,缓解期UC患者血栓前状态分子标志物水平明显高于对照组,而AT-Ⅲ：A在活动期UC患者明显低于缓解期患者及对照组。不同病变部位的活动期UC患者血栓前状态标志物水平有明显差异,活动期与缓解期UC患者各指标之间呈显著相关。结论UC患者处于明显的血栓前状态,血栓前状态分子标志物水平与病变活动性及病变范围有关,持续的高凝状态可能与UC患者的临床进展有关。     

Methotrexate in ulcerative colitis: A Spanish multicentric study on clinical use and efficacy

Background

Few data are available on the efficacy of methotrexate (MTX) in ulcerative colitis (UC).

Aim

To evaluate the efficacy and safety of MTX in UC patients.

Patients and methods

UC patients who had been treated with MTX were identified from the databases of 8 Spanish IBD referral hospitals. Patients were included in the study if they received MTX for steroid dependency or steroid refractoriness. Therapeutic success was defined as the absence of UC-related symptoms, complete steroid withdrawal and no requirement of rescue therapies within the first 6 months after starting MTX.

Results

Forty patients were included, 70% treated for steroid dependency and 27% for steroid refractoriness. Thiopurines had been previously attempted in 87.5% of patients. The median dose of MTX used for induction was 25 mg (IIQ 17.5–25) weekly given parenterally in 82.5% of cases. Eighty-five percent of patients were on steroids when MTX was started. Forty-five percent of patients met criteria for therapeutic success. Initial treatment failures were mainly due to inefficacy (50%) or intolerance (36%). After a median follow-up of 28 months (IQR 22–47), 38% of patients with initial therapeutic success required new steroid courses, 22% started biological therapy, and only 1 patient required colectomy. The cumulative probability of maintaining steroid-free clinical remission was 60%, 48%, and 35% at 6, 12, and 24 months after starting MTX, respectively. Eleven patients (27.5%) experienced adverse events, leading to MTX discontinuation in only 8 of them.

Conclusions

MTX appears to be effective to maintain clinical remission in UC, at least in the short-term, with an acceptable safety profile.     

Positions of selective leukocytapheresis in the medical therapy of ulcerative colitis

INTRODUCTIONUlcerative colitis (UC) and Crohn’s disease (CD) are the major forms of idiopathic inflammatory bowel diseases (IBD) of the intestine. UC and CD are both debilitating chronic disorders that afflict millions of individuals throughout the world…     

Elevated plasma von Willebrand factor levels in patients with active ulcerative colitis reflect endothelial perturbation due to systemic inflammation

AIM: To evaluate the plasma von Willebrand factor (vWF) levels in patients with ulcerative colitis (UC) and to investigate their relationship with disease activity, systemic inflammation and coagulation activation. METHODS: In 46 patients with ulcerative colitis (active in 34 patients), clinical data were gathered and plasma vWF levels, markers of inflammation (ESR, CRP, and fibrinogen) and thrombin generation (TAT, F1+2, and D-dimers) were measured at baseline and after 12 wk of treatment. Plasma vWF levels were also determined in 52 healthy controls (HC). The relationship of plasma vWF levels with disease activity, disease extent, response to therapy, acute-phase reactants (APRs) and coagulation markers (COAGs) was assessed. RESULTS: The mean plasma vWF concentrations were significantly higher in active UC patients (143.38±63.73%) than in HC (100.75±29.65%, P = 0.001) and inactive UC patients (98.92±43.6%, P = 0.031). ESR, CRP and fibrinogen mean levels were significantly higher in active UC patients than in inactive UC patients, whereas there were no significant differences in plasma levels of D-dimers, F1+2, and TAT. UC patients with raised APRs had significantly higher mean plasma vWF levels than those with normal APRs (144.3% vs 96.2%, P = 0.019), regardless of disease activity. Although the mean plasma vWF levels were higher in UC patients with raised COAGs than in those with normal COAGs, irrespective of disease activity, the difference was not significant (141.3% vs 118.2%, P = 0.216). No correlation was noted between plasma vWF levels and disease extent. After 12 wk of treatment, significant decreases of fibrinogen, ESR, F1+2, D-dimers and vWF levels were noted only in UC patients with clinical and endoscopic improvement. CONCLUSION: Our data indicate that increased plasma vWF levels correlate with active ulcerative colitis and increased acute-phase proteins. Elevated plasma vWF levels in ulcerative colitis possibly reflect an acute-phase response of the perturbed endothelium due to inflammation. In UC patients, plasma vWF levels may be another useful marker of disease activity or response to therapy.