Current treatment approach to ANCA-associated vasculitis.

PURPOSE OF REVIEW: This review will attempt to summarize the most potentially impactful new data on the way ANCA-associated vasculitis (AAV) is diagnosed, treated, and monitored. RECENT FINDINGS: The newly developed classification criteria for AAV have serious methodological issues that need to be addressed before they are widely adopted. The newly approved drugs and studies into both achieving remission and maintaining it have added to our overall knowledge of managing AAV and should hopefully contribute to improving outcomes in AAV. SUMMARY: The diagnosis, treatment and monitoring of AAV have seen major improvements in the last two years. The remaining issues outlined in this review still need to be addressed to best serve AAV patients.

Difficult-to-treat Behçet syndrome: A therapeutic approach.

Behcet syndrome is a systemic vasculitis which can involve many different organ systems. As such, treatment decisions need to be based on organ system involved. In addition, specific patient characteristics potentially predict milder or more severe course, and all these factors need to be taken into consideration when making treatment decisions. In this paper, we review the current approaches to treating Behcet syndrome patients.

Outcome measures in Behçet syndrome.

Disease assessment has been challenging in Behçet syndrome due to the heterogeneous disease course and multiorgan involvement with variable treatment response. There have been several recent improvements regarding outcome measures including development of a Core Set of Domains for Behçet syndrome and novel instruments for assessing specific organs and overall damage. This review focuses on the current state of outcome measures in Behçet syndrome, unmet needs, and a research agenda towards the development of standardized and validated outcome measure instruments.

2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria sets for three types of antineutrophilic cytoplasmic antibody-associated vasculitis.

PURPOSE OF REVIEW: A critique of the recently published classification criteria for three main types of antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis. RECENT FINDINGS: An ACR and EULAR joint task force recently published classification criteria for three main types of ANCA-associated vasculitis. The criteria were based on patient histories and findings in nearly 7000 patients from 136 sites in 32 countries. As such the study represented hitherto the most intensive attempt to prepare classification criteria vasculitis. We propose, this truly intensive effort was, unfortunately, unsuccessful. There were two main mishaps. The first one was that the proposed criteria were not validated in an independent cohort. This is curious in that the sponsors, ACR and EULAR, require such independent cohorts for validation. The second mishap is that the concept that disease classification criteria need to be 100% sensitive and specific for a diagnosis is unrealistic. Moreover, all-purpose disease classification criteria are not respectful to scientific research and to the probabilistic nature of the art and the science of medicine. SUMMARY: The new ACR/EULAR ANCA-associated vasculitis guidelines have not been validated in independent cohorts. We propose replacing the term disease criteria with disease guidelines.

Trial of Apremilast for Oral Ulcers in Behçet's Syndrome.

BACKGROUND: The small-molecule phosphodiesterase 4 inhibitor apremilast modulates cytokines that are up-regulated in Behçet's syndrome. In a phase 2 trial involving patients with Behçet's syndrome, apremilast reduced the incidence and severity of oral ulcers. Data on the efficacy and safety of apremilast in patients with Behçet's syndrome who had active oral ulcers and had not previously received biologic agents are limited. METHODS: In a phase 3 trial, we randomly assigned, in a 1:1 ratio, patients who had Behçet's syndrome with active oral ulcers but no major organ involvement to receive either apremilast at a dose of 30 mg or placebo, administered orally, twice daily for 12 weeks, followed by a 52-week extension phase. The primary end point was the area under the curve (AUC) for the total number of oral ulcers during the 12-week placebo-controlled period (with lower values indicating fewer ulcers). There were 13 secondary end points, including complete response of oral ulcers, change from baseline in pain associated with oral ulcers, disease activity, and change from baseline in the Behçet's Disease Quality of Life score (range, 0 to 30, with higher scores indicating greater impairment in quality of life). Safety was also assessed. RESULTS: A total of 207 patients underwent randomization (104 patients to the apremilast group and 103 to the placebo group). The AUC for the number of oral ulcers was 129.5 for apremilast, as compared with 222.1 for placebo (least-squares mean difference, -92.6; 95% confidence interval [CI], -130.6 to -54.6; P<0.001). The change from baseline in the Behçet's Disease Quality of Life score was -4.3 points in the apremilast group, as compared with -1.2 points in the placebo group (least-squares mean difference, -3.1 points; 95% CI, -4.9 to -1.3). Adverse events with apremilast included diarrhea, nausea, and headache. CONCLUSIONS: In patients with oral ulcers associated with Behçet's syndrome, apremilast resulted in a greater reduction in the number of oral ulcers than placebo but was associated with adverse events, including diarrhea, nausea, and headache. (Funded by Celgene; ClinicalTrials.gov number, NCT02307513.).

Initial visit symptoms in probable Behçet's syndrome is predictive of ISG criteria fulfillment in Behçet's syndrome: data from New York and Amsterdam cohorts.

OBJECTIVES: Behçet's syndrome (BS) is a systemic vasculitis with heterogeneous clinical presentation and a relapsing disease course. The International Study Group (ISG) criteria are most often used for classification. A significant proportion of patients is classified as probable BS because they do not fulfil the criteria at initial presentation. The aim of this study is to explore clinical BS symptoms present at initial patient visit predictive of ISG criteria diagnosis during follow-up. METHODS: Patients classified as probable BS at initial visit were included. Follow-up ISG status (defined as meeting criteria ISG+ vs. not meeting criteria ISG-) was abstracted from last visit. Univariable logistic regression was used to screen initial visit clinical features and symptoms with follow-up ISG status. All variables that passed screening at p<0.10 were included in the final multivariable model, which was then used to create a probability risk score. RESULTS: 189 patients were included (169 from New York and 20 from Amsterdam). 71 (37.6%) patients were classified as ISG+ during follow-up. In the final model, presence of morning stiffness, genital ulcers, skin lesions, and eye disease were associated with increased odds of ISG+, adjusting for age, symptom duration and family history. This was used to create a probability risk score. CONCLUSIONS: Over a third of patients with suspected or probable BS developed new manifestations over time that led to classification as ISG+ BS. The presence of morning stiffness, genital ulcers, skin lesions and eye disease at initial visit were independently associated with significantly higher odds for developing ISG+ Behçet's during follow-up.

Apremilast for oral ulcers associated with active Behçet's syndrome over 68 weeks: long-term results from a phase 3 randomised clinical trial.

OBJECTIVES: This study assessed the efficacy and safety of apremilast for the oral ulcers associated with Behçet's syndrome (BS) up to 64 weeks. METHODS: The phase 3, double-blind, placebo-controlled RELIEF study randomised adult patients with active BS to placebo or apremilast 30 mg twice daily for 12 weeks, followed by an extension phase with all patients receiving apremilast through Week 64 and 4-week post-treatment follow-up (upon treatment discontinuation). The primary endpoint was area under the curve for the number of oral ulcers over 12 weeks (AUCWk0-12), reflecting the number of oral ulcers over time and accounting for their recurring-remitting course. Oral ulcer number, complete and partial responses, pain and disease activity and quality of life (QoL) were also assessed throughout the study. RESULTS: A total of 207 participants were randomised and received at least one dose of study medication; 178 entered the extension phase and 143 completed Week 64. AUCWk0-12 was significantly lower with apremilast versus placebo (p<0.0001), and oral ulcers number, pain, complete/partial responses, disease activity and QoL with apremilast versus placebo showed improvements at Week 12, which were maintained through Week 64. The most common adverse events were diarrhoea, nausea, headache and upper respiratory tract infection; no new safety concerns were observed with longer-term apremilast exposure. CONCLUSIONS: In patients with oral ulcers associated with BS, apremilast was efficacious and benefits were sustained up to 64 weeks with continued treatment. Apremilast was well tolerated, and safety was consistent with its known safety profile.

Management of Behçet syndrome.

PURPOSE OF REVIEW: New treatment options have been studied over the last several years, with a recent approval, a first for Behçet syndrome, in the United States. New management guidelines have also been published, helping with this nowadays more commonly recognized condition's management. The goal of this review is to summarize the most important and potentially clinically relevant recent developments and discuss their impact in the management of patients with Behçet syndrome. RECENT FINDINGS: Apremilast is now approved for the treatment of oral ulcer of Behçet syndrome in the United States. It's possible benefits in controlling nonoral ulcer features of the syndrome are awaited. Long-term use of tumor necrosis factor inhibitors for the treatment of especially eye disease in Behçet syndrome seems to be safe and efficacious. New treatment options such as ustekinumab, secukinumab, tocilizumab and others have early promising data but more studies are needed to better clarify their role in Behçet management. SUMMARY: The last 2 years have not only seen the approval of the first drug specifically labeled for the treatment of Behçet syndrome in the case of apremilast, many groups have also presented and published their findings on promising new therapeutic agents, which may soon be added to our tools in treating this condition. We also know more about other drugs, such as tumor necrosis factor inhibitors as many patients have been on these for long periods of time, and long-term follow-up data seem to confirm their role in Behçet treatment. Lack of placebo controlled, randomized trials, for the most part, are still outstanding issues.

Disease activity measures at baseline predict structural damage progression: data from the randomized, controlled AMPLE and AVERT trials.

OBJECTIVE: Data from two double-blind, randomized, Phase III studies were analysed to investigate the ability of Routine Assessment of Patient Index Data 3, DAS28 (CRP), modified (M)-DAS28 (CRP) and Simplified or Clinical Disease Activity Indices to predict structural damage progression in RA. METHODS: This post hoc analysis included data from the 2-year Abatacept vs adaliMumab comParison in bioLogic-naïvE RA subjects with background MTX (AMPLE) trial in biologic-naïve patients with active RA (<5 years) and an inadequate response to MTX, and the 12-month treatment period of the Assessing Very Early Rheumatoid arthritis Treatment (AVERT) trial in MTX-naïve patients with early RA (⩽2 years) and poor prognostic indicators. Adjusted logistic regression analysis assessed the relationship between baseline disease activity and structural damage progression (defined as change from baseline greater than the smallest detectable change) at 12 and 24 months in AMPLE and 6 and 12 months in AVERT. Areas under the receiver operating characteristic curves for the impact of baseline disease activity on structural damage progression were calculated. RESULTS: Adjusted logistic regression analyses included all randomized and treated patients in AMPLE (N = 646) and those who received abatacept plus MTX or MTX monotherapy in AVERT (N = 235). Baseline Routine Assessment of Patient Index Data 3, DAS28 (CRP) and M-DAS28 (CRP) scores significantly predicted structural progression at months 12 and 24 in AMPLE (P < 0.05) and months 6 and 12 in AVERT (P < 0.01), and were stronger predictors than Simplified or Clinical Disease Activity Indices. CONCLUSION: In this post hoc analysis of two patient populations with RA, Routine Assessment of Patient Index Data 3, DAS28 (CRP) and M-DAS28 (CRP) were good at predicting structural damage. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov: NCT00929864 (AMPLE); NCT01142726 (AVERT).

Osteoarthritis is as severe as rheumatoid arthritis: evidence over 40 years according to the same measure in each disease.

Osteoarthritis (OA) may be associated with substantial work disability, morbidity, costs, and increased mortality rates, often similar to rheumatoid arthritis (RA), documented in many published reports over the last 4 decades. However, OA generally has been viewed as less severe than RA. This discrepancy may be explained in part by:a) RA may have been considerably more severe in the past, prior to effective therapies.b) most older individuals have radiographic joint damage, which often is not associated with clinical symptoms.c) RA is associated with abnormal laboratory tests, which are regarded as conveying greater significance than symptoms of pain and disability according to a "biomedical model," the dominant paradigm of modern medicine.d) Most reports of OA and RA have emphasised differences between the 2 diseases even beyond laboratory abnormalities in pathogenesis, physical findings, and imaging.e) Even pain and functional disability seen in both diseases are assessed using different patient self-report questionnaires, a WOMAC (Western Ontario McMaster Universities osteoarthritis index) in OA, and HAQ (health assessment questionnaire) in RA.An identical measure is required for optimal direct comparisons, which has been used in 8 studies performed between 1979 and 2019 at 8 sites in North America, Europe, and Australia. These studies were primarily based on retrospective analyses at sites which collected a patient questionnaire in routine clinical care by all patients at all visits to inform clinical decisions. A pain visual analogue scale (VAS) was higher in OA compared to RA in 11/12 patient groups, while physical function on a HAQ (health assessment questionnaire) or derivative MDHAQ (multidimensional HAQ) and RAPID3 (routine assessment of patient index data) were slightly higher in RA before 2013 and higher in OA in later reports. Furthermore, a study of population-based data from the 1978 US Health Interview Survey indicated similar levels of disability and earnings losses according to surrogate variables for OA and RA. Therefore, at least over the last 40 years, pain and functional disability in OA have appeared to be severe and similar to RA. These observations also-illustrate the potential value of using an identical patient questionnaire in all patients at all visits in routine care settings, analogous to using the same laboratory tests such as erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) in all rheumatic diseases, and maintaining a database of the results for later analyses.

Biomarkers in vasculitis.

PURPOSE OF REVIEW: Biomarkers are considered to be helpful in diagnosing, monitoring, predicting treatment response, and prognosis in clinical practice and as outcomes in clinical trials. In this article, we review the recent literature on new biomarkers and the expanding use of older ones in vasculitic conditions. RECENT FINDINGS: In antineutrophil cytoplasmic antibody-associated vasculitis patients antineutrophil cytoplasmic antibody type may be useful as a predictor of relapse and response to rituximab. Moreover, serial measurements of proteinase-3 titer may help to predict relapse. Urinary soluble CD163 levels are promising for identifying active renal vasculitis. Imaging modalities such as positron emission tomography, computerized angiography tomography, and temporal artery ultrasound maintain their role in diagnosis and disease assessment in large vessel vasculitis. Fecal calprotectin is a useful marker of active gastrointestinal involvement in Behçet's syndrome. SUMMARY: The publications reviewed here potentially may help to move the field of biomarkers in vasculitis management. However, more work toward understanding the underlying pathophysiology and effects of an intervention on the disease process are needed before true biomarkers can be realized. Further studies with appropriate control groups, using good definitions for disease states such as activity and remission are needed to guide our use of these markers correctly in the management of our patients.

Apremilast for Behçet's syndrome--a phase 2, placebo-controlled study.

BACKGROUND: Oral ulcers, the hallmark of Behçet's syndrome, can be resistant to conventional treatment; therefore, alternative agents are needed. Apremilast is an oral phosphodiesterase-4 inhibitor that modulates several inflammatory pathways. METHODS: We conducted a phase 2, multicenter, placebo-controlled study in which 111 patients with Behçet's syndrome who had two or more oral ulcers were randomly assigned to receive 30 mg of apremilast twice daily or placebo for 12 weeks. This regimen was followed by a 12-week extension phase in which the placebo group was switched to apremilast and a 28-day post-treatment observational follow-up phase. The patients and clinicians were unaware of the study assignments throughout the trial. The primary end point was the number of oral ulcers at week 12. Secondary outcomes included pain from these ulcers (measured on a 100-mm visual-analogue scale, with higher scores indicating worse pain), the number of genital ulcers, overall disease activity, and quality of life. RESULTS: The mean (±SD) number of oral ulcers per patient at week 12 was significantly lower in the apremilast group than in the placebo group (0.5±1.0 vs. 2.1±2.6) (P<0.001). The mean decline in pain from oral ulcers from baseline to week 12 was greater with apremilast than with placebo (-44.7±24.3 mm vs. -16.0±32.5 mm) (P<0.001). Nausea, vomiting, and diarrhea were more common in the apremilast group (with 22, 9, and 12 incidents, respectively, among 55 patients) than in the placebo group (with 10, 1, and 2 incidents, respectively, among 56 patients), findings that were similar to those in previous studies of apremilast. There were two serious adverse events in patients receiving apremilast. CONCLUSIONS: Apremilast was effective in treating oral ulcers, which are the cardinal manifestation of Behçet's syndrome. This preliminary study was neither large enough nor long enough to assess long-term efficacy, the effect on other manifestations of Behçet's syndrome, or the risk of uncommon serious adverse events. (Funded by Celgene; ClinicalTrials.gov number, NCT00866359.).

Behcet's syndrome in nonendemic regions.

PURPOSE OF REVIEW: Behcet's syndrome is more common in certain geographic regions, however, can be seen outside of these areas and need to be included in the differential diagnosis of many patients, as it has overlapping features with many rheumatologic conditions. RECENT FINDINGS: Especially in regions with immigrant populations, there seem to be similarities to originating countries in Behcet's prevalence, but the syndrome is not limited to those from certain backgrounds and can be seen in others also. There is emerging evidence that even though the prevalence of Behcet's may be similar to that of endemic areas, in nonendemic regions the condition may be less severe, suggesting potential environment agents in determining the severity of the disease. In addition, women seem to be overrepresented in nonendemic areas and may explain part of the reason for less severe symptoms, as Behcet's tends to be more severe in men. SUMMARY: The somewhat different presentation of Behcet's syndrome in nonendemic areas needs to be considered when thinking about Behcet's in the differential diagnosis of patients. Research into potentially less severe form of the disease in nonendemic areas may provide new clues to the pathogenesis of this condition.

The spectrum of early rheumatoid arthritis practice across the globe: results from a multinational cross sectional survey.

OBJECTIVES: To explore patterns of real-world early RA (ERA) care across countries. METHODS: An online survey was disseminated to practising rheumatologists across Europe and the US, also made accessible on social media between April and May 2015. Survey questions (n=38) assessed the structure and setting of ERA clinics, times to diagnosis and treatment, patient monitoring, guideline use and data recording. RESULTS: A total of 212 rheumatologists from 39 countries (76% European) completed the survey. 62% had an ERA clinic based at a university hospital. Patient referral to rheumatology was mainly (78%) via primary care; 44% had an agreed ERA local referral pathway, 15% a national pathway. Only 16% had dedicated ERA clinics, the majority being practitioners in Northern Europe with access to a local or national referral pathway. Data for research were collected by 42%. Treatment guidelines were followed by the majority, especially rheumatologists practising in Europe. Variations existed in the use of initial DMARDs with treatment decisions reported to be influenced by international/national guidelines in 71%/61%. No significant relationship between country gross national income and the availability of ERA clinics was seen. CONCLUSIONS: This study provides comparative benchmark information regarding the global provision of ERA care. Substantial variations exist in referral and early assessment pathways with guidelines having a most apparent impact in Northern Europe. Provision of an ERA service does not appear to be constrained by cost, with conceptual factors, e.g. clinician engagement, perhaps playing a role. These initial insights could potentially help harmonise ERA management across countries.

Adherence to guidelines for the treatment of Behçet's syndrome in New York and Amsterdam.

OBJECTIVES: To assess adherence to published guidelines for the treatment of Behçet's syndrome (BS) in two geographic areas. METHODS: We extracted guideline statements from the 2008 EULAR recommendations. Adherence to these statements was evaluated retrospectively in both New York (USA) and Amsterdam (The Netherlands), by reviewing records from patients fulfilling the ISG criteria. We analysed data per statement and event, and divided data according to the year in which an event occurred. We compared events prior to 2009 to those after publication of the EULAR recommendations (2009 and later). RESULTS: 474 patients were evaluated, 24 of whom were from Amsterdam. Treatment adherence varied substantially across various Behçet's manifestations, ranging from 21% vs. 31% in posterior uveitis, 50% vs. 25% in arterial disease, 29% vs. 29% in arthritis and 38% vs. 55% in erythema nodosum to 65% vs. 67% in deep venous thrombosis (DVT), before and after publication of the guidelines respectively. Topical treatment of mucocutaneous disease was only 2% vs. 8%, whereas adherence in neuro-Behçet was ≥ 94% and 100% in gastrointestinal disease. CONCLUSIONS: Adherence to treatment guidelines varies substantially by Behçet's manifestation. Lack of adherence in manifestations such as eye disease and arthritis suggests that current recommendations are not sufficient or other concurrent manifestations require more aggressive treatment. The extensive use of anti-TNF agents might indicate a shift towards more aggressive treatment. Thus, our results suggest the 2008 guidelines were not in line with treatment in clinical practice over the past years and the recent revision of the recommendations was indeed needed.