We read the editorial by Filippucci et al., entitled "Ultrasound definition of enthesitis in spondyloarthritis and psoriatic arthritis: arrival or starting point?" with great interest. The authors eloquently discuss the challenges with the existing scoring methods and propose solutions (1). We would like to raise additional points that we believe are necessary to improve the assessment of enthesitis using ultrasound.

Before the introduction of ultrasound to the field, enthesitis was determined as present or absent, based on the physical exam. Therefore, only prevalence could be compared between patient groups. Ultrasound allows precise phenotyping of the entheseal changes. The ability to accurately characterize anatomical changes within the entheseal soft tissue and on the surface of the bone, detect abnormal vascularisation and further categorize the two opposite bony changes (erosion vs new bone formation) brought a different perspective on the understanding of enthesitis. Despite some similarities between psoriatic arthritis (PsA) and other spondyloarthritis (SpA) subtypes, clear distinctions also exist (2). From the enthesitis perspective, patients with PsA have larger enthesophytes (bony spurs) at the entheseal insertions than ankylosing spondylitis (AS), despite similar levels of sonographic inflammation (3). Supporting that observation, psoriasis is shown to be an independent risk factor for enthesophytes with Axial SpA (4). Similar findings have long been demonstrated in the spine, with bulkier syndesmophytes of axial PsA patients compared to AS (2). One potential explanation for these differences is the abnormal response of psoriasis patients to trauma which has been well recognized at the skin level. The exacerbated response in the deeper tissues in PsA is hypothesized to be the reflection of the same process, known as the Deep Koebner phenomenon (5, 6). Therefore, we believe that a tool to diagnose enthesitis in PsA may differ from other SpA subtypes. More specifically, when the purpose is to diagnose patients early, a scoring method that is developed to screen for enthesitis in SpA other than PsA, may not need to include the enthesophytes. However, given how the large enthesophytes differentiate PsA from other subtypes, the enthesophytes may be more valuable within a diagnostic tool developed for PsA. Although enthesophytes can separate the groups, they do not constitute an element of disease activity, whereas other lesions such as hypoechogenicity or Doppler may be used for monitoring change. Hence, there may be differences between the sonographic tools that are developed for diagnosis vs therapy monitoring. Outcome Measures in Rheumatology (OMERACT) definitions inherently are not for diagnostic use but are for longitudinal use to follow outcomes after interventions and are designed using OMERACT metrics. The authors of this manuscript suggest that a targeted data-driven approach should be undertaken in creating diagnostic ultrasound instruments. The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) / ultrasound group is currently conducting an international multicenter study (DUET) (Diagnostic Ultrasound Enthesitis Tool) to obtain a feasible, reliable and accurate tool to differentiate PsA from its mimics for earlier diagnosis (7). Using statistical modelling, the group will identify the optimal combination of entheseal sites and sonographic lesions that distinguish PsA from controls with minimal influence by confounding factors.

Another critical aspect raised by Filippucci et al. is the importance of the small entheses in SpA. Ultrasound is an operator and machine-dependent modality, and the ability of a sonographer to accurately evaluate the large entheses usually occurs earlier than the small entheses in the learning curve. Hence, the earlier studies on enthesitis focused on the large enthesis, leading to the existing scoring methods (8). We agree with Filippucci et al. that the large entheses are more exposed to the impact of biomechanical stress, leading to entheseal alterations in healthy people (9). Therefore, one may consider scanning the small entheses for being less impacted by "physiological responses" that are confounded by age, BMI, physical activity and gender. On the other hand, if SpA (especially PsA) patients respond more aggressively to the same biomechanical forces than the healthy people within the large entheses, it may be more likely to find features that can differentiate the disease state from health. Despite the relatively high prevalence of entheseal ultrasound findings in healthy people, studies found a significant difference between SpA and healthy controls at a group level, especially if matched BMI, age, and gender (10). Therefore, we may need to revisit our thresholds to determine the normal range in entheseal ultrasound and consider the patient-related factors when determining those considered "normal" (similar to the growth charts that define the "normal" with the percentiles given separately for age and sex).
On the other hand, we fully agree with Filippucci et al. that it is time to focus on the small entheses to improve our patients' care. Multiple studies published in the last five years have demonstrated the significance of not only the small entheses but also the extraarticular structures in the hands (e.g. paratenon of the extensor tendon, subcutaneous tissue, pulleys and nails). We also would like to emphasize that most of the data within the field of small enthesis are in PsA, not in other subtypes of SpA, which is likely to be due to the nature of the diseases (small joints affliction is more prevalent in PsA). Therefore, understanding the importance of small enthesis and how that can be valuable for early diagnosis requires doing research in SpA subtypes separately, without lumping them. The GRAPPA ultrasound group is also working on evaluating the musculoskeletal structures in the hands beyond the joints, including the small entheses, merging the knowledge and expertise in this area.

To conclude, we believe we are neither at the arrival nor starting point for the ultrasound of the enthesis. The progress in this field has significantly improved our understanding of the role of enthesitis in the pathogenesis of SpA. With significant efforts from the GRAPPA and OMERACT ultrasound groups, as well as individual experts running well-designed studies globally, we have reasons to be optimistic that the finish line, having standardized screening tools for enthesitis, is on the horizon.

1. Filippucci E, Smerilli G, Di Matteo A, Grassi W. Ultrasound definition of enthesitis in spondyloarthritis and psoriatic arthritis: arrival or starting point? Ann Rheum Dis. 2021.
2. Feld J, Chandran V, Haroon N, Inman R, Gladman D. Axial disease in psoriatic arthritis and ankylosing spondylitis: a critical comparison. Nat Rev Rheumatol. 2018;14(6):363-71.
3. Arslan Alhussain F, Kasapoglu Gunal E, Kurum E, Bakirci S, Ozturk AB, McGonagle D, et al. Greater magnitude of entheseal microdamage and repair in psoriatic arthritis compared with ankylosing spondylitis on ultrasound. Rheumatology (Oxford). 2019;58(2):299-303.
4. Solmaz D, Bakirci S, Jibri Z, Sampaio M, Karsh J, Aydin SZ. Psoriasis is an independent risk factor for entheseal damage in axial spondyloarthritis. Semin Arthritis Rheum. 2020;50(1):42-7.
5. Pattison E, Harrison BJ, Griffiths CE, Silman AJ, Bruce IN. Environmental risk factors for the development of psoriatic arthritis: results from a case-control study. Ann Rheum Dis. 2008;67(5):672-6.
6. Tinazzi I, McGonagle D, Aydin SZ, Chessa D, Marchetta A, Macchioni P. 'Deep Koebner' phenomenon of the flexor tendon-associated accessory pulleys as a novel factor in tenosynovitis and dactylitis in psoriatic arthritis. Ann Rheum Dis. 2018;77(6):922-5.
7. Eder L, Kaeley GS, Aydin SZ. Development and Validation of a Sonographic Enthesitis Instrument in Psoriatic Arthritis: The GRAPPA Diagnostic Ultrasound Enthesitis Tool (DUET) Project. J Rheumatol Suppl. 2020;96:50-2.
8. Elalouf O, Bakirci Ureyen S, Touma Z, Anderson M, Kaeley GS, Aydin SZ, et al. Psoriatic Arthritis Sonographic Enthesitis Instruments: A Systematic Review of the Literature. J Rheumatol. 2019;46(1):43-56.
9. Bakirci S, Solmaz D, Stephenson W, Eder L, Roth J, Aydin SZ. Entheseal Changes in Response to Age, Body Mass Index, and Physical Activity: An Ultrasound Study in Healthy People. J Rheumatol. 2020;47(7):968-72.
10. Kaeley GS. Visualization of Enthesitis by Ultrasound: a Key Diagnostic Tool in Spondyloarthropathy Diagnosis and Management. Curr Rheumatol Rep. 2020;22(9):48.

Dear Editor, with great interest we read the results of the TICOSPA study (1) in which a tight-control/treat-to-target strategy (T2T) was compared with usual care in patients with axial spondyloarthritis (axSpA). In this study which was the first ever to use a T2T strategy in axSpA a main outcome parameter was used that had never been used before: the percentage of patients with a ≥30% improvement on the ‘Assessements of spondyloarthritis international society (ASAS)-Health Index (ASAS-HI), and other conventional efficacy outcomes were also recorded (1). As recently explained, one important reasons to use the ASAS HI in TICOSPA as primary endpoint was to avoid circular reasoning, e.g. using the same items for inclusion and outcome (2).
The aim of this correspondence is not to discuss the strategy used in the trial since this has been done in a recent editorial but to discuss the use of this outcome parameter which represents a tool that has been developed over many years with > 2000 patients and a major input from patients. This is also documented by the fact that 5 items out of the 17 in the ASAS HI were proposed by patients with ankylosing spondylitis (AS) and they are not part of any other tool that has been used in axSpA (3).
The ASAS HI is a disease-specific health index designed to assess global functioning and health in patients with axSpA that had originally been started to overcome the problem to define disease severity because this domain contains many different aspects of the disease: disease activity, damage, reduced mobility, reduced physical function, reduced social participation. The impact of function and activity on the disease has recently been intensively reviewed (4). Thus, it comes close to the meaning of impact of the disease. The impact of the disease might be related to quality of life, but is even a bit broader than the subjective experience of those problems. This broader concept is included in the International Classification of Functioning, Disability and Health (ICF) which has been published by WHO in 2001. The ICF represents an universally accepted model that classifies and describes functioning, disability and health in individuals with a wide spectrum of diseases or conditions in a systematic way. The term ‘functioning’ in the context of the ICF is equated more with ‘health’ than ‘function’ as the latter term is limited to physical function and ignores the complexity of global functioning. The ASAS HI covers areas of physical, emotional, and social functioning based on categories summarized in the ASAS/World Health Organization (WHO) ICF core set for AS (5). Within the Comprehensive ICF Core Set, 80 categories were selected which describe the typical spectrum of problems related to the functioning of patients with AS in a multidisciplinary assessment, 66 items relate to functioning and 14 to environmental factors which have recently been looked at in more detail (6).
The ASAS HI is a 17-item instrument covering sum scores ranging from 0 (good health) to 17 (poor health). Each item consists of one question that the patient needs to respond to with either “I agree” (Score 1), “I do not agree” (Score 0). An improvement ≥3 from baseline in ASAS HI represent a clinically meaningful change and attaining a “good health status” is defined by score ≤5 (7). The ASAS HI has been extensively evaluated. When patients were asked to rate items the highest relative importance was assigned to pain, sleep, being exhausted, standing and motivation to do anything that requires physical effort, while the lowest was assigned to sexual relationships, toileting, contact with people, driving and washing hair (8).
There is limited information with regard to which items are best influenced by bDMARD therapy. There are two studies on treatment with r-axSpA (9) and nr-axSpA (10) with ixekizumab. The vast majority (> 95%) of bDMARD-naïve patients had an ASAS HI ≥ 3 at baseline. About 50% of r-axSpA and nr-axSpA patients on ixekizumab achieved an improvement of the ASAS HI score > 3 at weeks 16 and 52, respectively. The results at week 16 were similar for the comparator adalimumab but the placebo response rate was also quite high with 34.5% (10). Significantly more nr-axSpA patients on ixekizumab reported improvements in ASAS HI “good health status” (ASAS HI ≤ 5) at weeks 16 and 52, respectively (10). In another study evaluating the clinimetric properties of the ASAS HI a value of 4 was found to be indicate inactive disease. However, there is still need to detect the most responsive items of the ASAS HI and to clarify whether these are consistent with patients’ needs.

On this basis, what does it mean to reach a 30% reduction of ASAS HI ? In the recently published trials on ixekizumab the baseline value of the ASAS HI was between 8-10 (9,10). In TICOSPA the mean ASAS HI was 8.2 in the T2T and 9 in the control group which required statistical adjustments. Furthermore, since the ASAS HI outcome was used for the first time, the sample size calculation was not easy, and it can be calculated that, if 20 patients more in each arm would have been included the primary outcome would have been reached.
Nevertheless, the outcome 30% improvement of the ASAS HI is not yet validated, its choice was not data driven but there was reason to use it which is much appreciated. However, an evaluation should be performed and we hope that companies provide data for that. In that line, the standardized response mean (SRM) of the ASAS HI requires a cut-off of 3.0 ASAS HI scoring points (3), this should be taken into account.
In summary, we do think that the ASAS HI is a useful outcome instrument in clinical trials which, in addition to disease activity and function, is able to convince us about an improvement that made a real difference for patients.

Uta Kiltz and Jürgen Braun,
Rheumazentrum Ruhrgebiet, Ruhr Universität Bochum, Germany

References

1. Molto A, López-Medina C, Van den Bosch FE, Boonen A, Webers C, Dernis E, et al. Efficacy of a tight-control and treat-to-target strategy in axial spondyloarthritis: results of the open-label, pragmatic, cluster-randomised TICOSPA trial. Ann Rheum Dis 2021 May 6: annrheumdis-2020-219585. Epub ahead of print.
2. Kiltz U, Wendling D, Braun J. ASAS Health Index: The "All in One" for Spondyloarthritis Evaluation? J Rheumatol 2020 Oct 1; 47(10): 1457-1460.
3. Kiltz U, van der Heijde D, Boonen A, Cieza A, Stucki G, Khan MA, et al. Development of a health index in patients with ankylosing spondylitis (ASAS HI): final result of a global initiative based on the ICF guided by ASAS. Ann Rheum Dis 2015; 74(5):830-5.
4. Braun J, Baraliakos X, Kiltz U. Nature Rev Rheum 2021 July 26th online ahead of print.
5. Boonen A, Braun J, van der Horst Bruinsma IE, Huang F, Maksymowych W, Kostanjsek N, et al. ASAS/WHO ICF Core Sets for ankylosing spondylitis (AS): how to classify the impact of AS on functioning and health. Ann Rheum Dis 2010; 69(1): 102-7.
6. Kiltz U et al. Development of an environmental contextual factor item set relevant to global functioning and health in axial spondyloarthritis patients. Rheumatology 2021 in press
7. Kiltz U, van der Heijde D, Boonen A, Akkoc N, Bautista-Molano W, Burgos-Vargas R, et al. Measurement properties of the ASAS Health Index: results of a global study in patients with axial and peripheral spondyloarthritis. Ann Rheum Dis 2018; 77(9):1311-7.
8. Kiltz U, Essers I, Hiligsmann M, Braun J, Maksymowych WP, Taylor WJ, van der Heijde D, Boonen A. Which aspects of health are most important for patients with spondyloarthritis? A Best Worst Scaling based on the ASAS Health Index. Rheumatology (Oxford). 2016 Oct;55(10):1771-6. Epub 2016 Jun 21.
9. Kiltz U, Wei JC, van der Heijde D, van den Bosch F, Walsh JA, Boonen A, et al. Ixekizumab Improves Functioning and Health in the Treatment of Radiographic Axial Spondyloarthritis: Week 52 Results from 2 Pivotal Studies. J Rheumatol 2021 Feb; 48(2): 188-197. Epub 2020 Jul 15
10. Walsh JA, Magrey MN, Baraliakos X, Inui K, Weng MY, Lubrano E, et al. Ixekizumab Improves Functioning and Health in the Treatment of Active Non-Radiographic Axial Spondyloarthritis: 52-Week Results, COAST-X Trial. Arthritis Care Res (Hoboken). 2020 Oct 12. Epub ahead of print.

We have a great interest in the article published by Prendecki et al studying on immune response to SARS-CoV2 vaccination (with either BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccines) in patients receiving immunosuppression (IS) for autoimmune rheumatic and glomerular diseases.[1] They reported poor humeral and cellular responses to first-dose vaccine in IS group comparing to a cohort of healthy volunteer (HV), while the immune responses could be augmented by second dose. [1] We appreciate this important and timely study. However, we believe that some issues should be discussed in this study.
First of all, the baseline comparability between IS and HV as well as between subgroups should be balanced, not only for age, but also for interval between 2 doses and types of vaccine. According to the recommendation for use of AstraZeneca COVID-19 vaccine published by World Health Organization (WHO), they suggested an interval of 8 to 12 weeks between the two doses due to the observation that two-dose efficacy and antibody level increase with a longer inter-dose interval. [2] However, IS group patients got second-dose vaccination at a median of 30 days (IQR 28-42 days), which didn’t categorize subgroup by different types of vaccine and was much earlier than the WHO recommendation timing. Although the significantly lower seroconversion rate was noticed in patients receiving ChAdOx1 than those receiving BNT2b162, we still concerned that short interval vaccination schedule would have impacts on the result of antibody level. Nevertheless, two-dose interval in HV (median 66 days, IQR 61-69 days) was significantly longer than IS. PITCH study had showed a higher antibody titer in long dose interval group (median 10 weeks, range 6-14) than conventional group (median 3 weeks, range 2-5). [3] Therefore, the baseline comparability between IS and HV in second dose protection should be ensured.
Second, it is believed that we could do more research in determining the most appropriate timing for vaccine. Not only in Prendecki et al study, B cell depletion was also described as a strong predictor to the failed serological response in many previous publications. [4-6] As a result, suggestion about delaying vaccination until B cell reconstitution occurred seemed to play a vital role in achieving better serological immunity. Spiera et al research mentioned the similar concept, which revealed a higher rates of seropositive responses to vaccines than B cell depletion even in a weak levels of reconstitution. [6] However, the duration to the last rituximab treatment especially administration within 6 months has a strong relation with failure seroconversion as well. Besides, it would be a considerable expense if we evaluate peripheral B cell maturation for all patients who were previous treated with rituximab. Hence, to take both duration and peripheral B-cell into consideration and reduce the cost, we proposed performing further analysis on the relation between the time to last rituximab infusion and baseline B cell counts as well as seroconversion rate to find out the best cutoff of initiating vaccine.
To sum up, we believed that the protocol of AstraZeneca COVID-19 vaccine and the two-dose interval should be modified and balanced between two groups for increasing credibility about baseline comparability. At the meanwhile, we suggested for further analysis on last rituximab duration, B cell number and seroconversion rate to find the cutoff for vaccination. But for patients living in high community transmission rates regions, we still recommended to follow the current guidelines and be vaccinated as soon as possible.

1. Prendecki, M., et al., Humoral and T-cell responses to SARS-CoV-2 vaccination in patients receiving immunosuppression. Annals of the Rheumatic Diseases, 2021: p. annrheumdis-2021-220626.
2. WHO. Interim recommendations for use of the ChAdOx1-S [recombinant] vaccine against COVID-19. 30, July, 2021.
3. Payne, R.P., et al., Sustained T cell immunity, protection and boosting using extended dosing intervals of BNT162b2 mRNA vaccine.
4. Bonelli, M.M., et al., SARS-CoV-2 vaccination in rituximab-treated patients: evidence for impaired humoral but inducible cellular immune response. Annals of the Rheumatic Diseases, 2021.
5. Boyarsky, B.J., et al., Antibody response to a single dose of SARS-CoV-2 mRNA vaccine in patients with rheumatic and musculoskeletal diseases. Annals of the Rheumatic Diseases, 2021. 80: p. 1098-1099.
6. Spiera, R., S. Jinich, and D. Jannat-Khah, Rituximab, but not other antirheumatic therapies, is associated with impaired serological response to SARS-CoV-2 vaccination in patients with rheumatic diseases. Annals of the Rheumatic Diseases, 2021.