333 e-Letters

  • Anti-nuclear antibodies for SLE classification versus diagnosis: titer-specific likelihood ratios to the rescue. Response to Aringer M et al. Ann Rheum Dis. 2021 Feb 10:annrheumdis-2020-219373

    Anti-nuclear antibodies for SLE classification versus diagnosis: titer-specific likelihood ratios to the rescue. Response to Aringer M, Brinks R, Dörner T, et al. European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) SLE classification criteria item performance. Ann Rheum Dis. 2021 Feb 10:annrheumdis-2020-219373.

    Antinuclear antibodies (ANA) are important laboratory markers for the diagnosis and classification of systemic lupus erythematosus (SLE). In the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for SLE, ANA with titer ≥1:80 are an entry criterion [1].
    Even though ANA 1:80 are highly sensitive for SLE, they have a low specificity. This has recently been reinforced by Aringer et al. [2] who analyzed the performance of the individual items included in the 2019 EULAR/ACR classification criteria for SLE on a large group of SLE patients (n=1197) and non-SLE disease controls (n=1074), including patients with other connective tissue diseases (two-thirds of the controls). In this study, ANA with titer ≥1:80 were highly sensitive (99.5%), but only 19.4% specific for SLE [2]. As ANA are an entry criterion for the 2019 EULAR/ACR classification criteria, the low specificity of ANA for SLE does not affect the specificity of the 2019 SLE classification criteria. An important item that conferred specificity to the 2019 SLE classification was the attribution rule [2]. The a...

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  • SARS-CoV-2 vaccine : a trigger of rheumatoid arthritis ?


    We read with great interest the letter from M. Barbhaiya et al. on systemic rheumatic disease flares after SARS-Cov-2 vaccination.[1] Whether COVID-19 vaccines could trigger rheumatoid arthritis remains unclear. To date, only few cases have been reported on this topic.[2,3]

    We report the case of a 44-year-old man, working as a teacher, without medical history or treatment, who had arthralgia affecting the hands and feet without joint swelling since early 2020. There was no clinical synovitis and the joint ultrasound showed doppler positive bursitis of the 3rd bilateral interdigital space. Acute phase reactant (C-reactive protein and sedimentation rate) were in the normal range, rheumatoid factors and antinuclear antibodies were negative unlike anti-CCP (48 UI/ L, uppper limit of normal [ULN] 3UI/L). X-rays of the hands and forefoots were normal. Treatment with hydroxychloroquine 200 mg twice a day was started in November 2020 associated with corticosteroid injections in each bursitis with a good improvement at three months.

    In early May 2021, the patient received a first injection of the anti SARS-CoV-2 BNT162b2 vaccine (BioNTech-Pfizer). A week later, he reported a flare of rheumatoid arthritis (RA) with pain and synovitis of 2 proximal interphalangeal joints and the right wrist, and pain in both shoulders with morning stiffness. DAS28-CRP was 4.2, DAS28-ESR 3.7. No skin rash was observed. Treatment with methotrexate at a dose of 20 mg/week subcu...

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  • A closer look at the enthesis using ultrasound

    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 lo...

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  • Could discontinuing JAKi’s in the event of SARS-CoV-2 infection be harmful?

    Sparks et al. (1) are to be congratulated on an important and timely study. They found that the use of JAKi was associated with worse outcome of Covid-19 infection, and they interpret this as a harmful effect of the treatment in that particular setting. But this question deserves further consideration. Assuming that the observation is correct, what could the mechanism be? As the authors correctly point out, some JAKis did show benefits for patients with severe Covid-19 infection (2, 3). We therefore propose an alternative explanation of the observed data.

    Some guidance documents (4,5), and certainly medical practice traditions, frequently have patients discontinue immunomodulatory treatments when a potentially severe infection is diagnosed, and it seems safe to assume that the vast majority of patients in the study did, in fact, stop their treatment when they became aware of the infection. While this would of course apply to all antirheumatic therapies, there are important differences in the impact this might have. Biologicals have half-lives in the order of weeks, and the effect of stopping the treatment is therefore limited in the acute setting. For MTX, pharmacodynamic aspects also lead to a long latency in the impact of discontinuing the drug. In contrast, JAKi have short half-lives and discontinuing the treatment will almost immediately lead to the re-activation of the relevant signaling pathways.

    We therefore propose, as an alternative possible explan...

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  • Comment on Serum uric acid control for prevention of gout flare in patients with asymptomatic hyperuricaemia: a retrospective cohort study of health insurance claims and medical check-up data in Japan’

    Dear editor,
    We appreciate the article entitled ‘Serum uric acid control for prevention of gout flare in patients with asymptomatic hyperuricaemia: a retrospective cohort study of health insurance claims and medical check-up data in Japan’ written by R. Koto et al1., and read with great interest. The study reported that by using urate-lowering therapy (ULT), and maintaining the serum uric acid levels (sUA) of 6.0 mg/dl or lower, the risk of gout flare may be decreased. We congratulate the authors for the successful article, and would like to make some comments.
    Firstly, the authors introduced ULT to prevent gout flare in asymptomatic hyperuricaemia patients with sUA of 8.0 mg/dl or higher by adapting the Japanese guidelines. However, according to ACR20 guidelines2 and observational studies3, for patients with asymptomatic hyperuricemia, the development of annual incident rate of gouty arthritis was 4.9 percent in patients with sUA of 9.0 mg/dl or above. While patients with sUA of 7.0 to 8.9 mg/dl experienced such disease at an annual incident rate of 0.5 percent. Therefore, we suggest by enrolling asymptomatic hyperuricaemia patients with sUA of greater than 9.0mg/dl to the study, the potential treatment cost and risk would be more balanced.
    Secondly, we would like to emphasize the possible importance of renal protection that ULT may offer. The article showed significant results and strong evidence to support ULT in decreasing the risk of gout flare, and...

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  • Correspondence on “Anterior uveitis in patients with spondyloarthritis treated with secukinumab or tumour necrosis factor inhibitors in routine care: does the choice of biological therapy matter?” by “Ulf Lindström et al”

    We have read with great interest the work of Ulf Lindström et al studying on comparing the risk of anterior uveitis (AU) in spondyloarthritis (SpA) during treatment with secukinumab versus tumour necrosis factor inhibitors (TNFi). They concluded that secukinumab appears to be associated with a higher risk of AU, compared with the monoclonal TNFi and a similar risk compared with etanercept1. However, we believe that some concerns should be discussed in this important study.

    First of all, the recruited SpA patients starting secukinumab or a TNFi between 1 Jan 2015 and 31 December 2018 were identified and the follow-up were most at the end of study 31 December 2018. However, there would be certain bias on the comparison of the rate of AU-diagnoses between the patients during treatment with secukinumab or TNFi in the late 2018 to the patients during treatment with TNFi or secukinumab in the early 2015. It would be more proper to adjust the treatment starting time. Furthermore, subgroups for the different starting year were also recommended to analyze.

    Secondly, conventional synthetic DMARDs, such as methotrexate (MTX) and sulfasalazine (SSZ), were sometimes used together with secukinumab or a TNFi in part of the patients. For both SSZ and MTX, a reduction in the AAU flare rate and sight-threatening complications has been reported especially on the course of HLA-B27-positive anterior uveitis2-4. AS a result, concomitant csDMARDs with secukinumab or a TNFi could be...

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  • Disease, drugs or vaccine?

    Vaccinations can induce autoimmunity through mechanisms like polyclonal B cell activation, epitope spreading and molecular mimicry. [1] A theoretical risk of vaccine induced flare of rheumatic diseases exists. However, it is poorly backed by evidence. [2] Two cases of previously quiescent rheumatic diseases flaring post COVID vaccination have been reported. [3,4] Barbhaiya et al in their article on “Systemic rheumatic disease flares after SARSCoV-2 vaccination among rheumatology outpatients in New York City'' showed approximately 15% patients had flare following vaccination. [5] The potential risk of a flare was one of the main concerns in the VAXICOV study in which 45.8% of 1266 patients with autoimmune or rheumatic diseases were uncertain or unwilling to take the COVID vaccine, [6] and data from this observation by Barbhaiya et al. may add more concerns in patients planning for vaccination against COVID-19. Hence, a few issues need to be addressed to have a better idea regarding the relation and risk group of post vaccination disease flare.
    First, it would have been useful to know the baseline disease activity prior to vaccination. Were patients with poorly controlled disease more vulnerable than those in remission? Did patients with higher disease activity have flares of greater severity?
    Second, the distribution of flares according to the underlying rheumatic disease would be important to know which population was most vulnerable.
    Third, r...

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  • Correspondence on “Maintaining musculoskeletal health using a behavioural therapy approach: a population-based randomised controlled trial (the MAmMOTH Study)” by Macfarlane et al.

    We read with great interest the article by Macfarlane et al.,1 comparison of the telephone Cognitive–behavioral therapy (CBT) and usual care (UC) in the treatment of chronic widespread pain (CWP). Their reported that a short course of telephone CBT did not prevent onset of CWP in adults at high risk, but improved quality of life and was cost-effective. Although the findings of this study are relevant for clinicians, there are several limitations that prevent the study results from being generalizable and ultimately applicable to clinical practice.
    First, identifying patients who respond best to certain interventions has the potential to improve outcomes for physical therapy interventions. This is particularly the case in chronic pain, which are considered heterogeneous.2 It is unlikely that any one intervention for heterogeneous conditions will be highly effective for all patients. Some researchers have reported that interventions previously shown to have little effect when provided to heterogeneous populations can be more effective when provided to selected subgroups of patients.2 3 The baseline characteristics of both comparative groups is key that identify subgroups of patients who respond differently to a specific intervention.2 However, there is no description of the baseline characteristics between two groups in this study. Without this information, it is difficult to evaluate the prevention onset of CWP, improve quality of life, and cost-effective undergoing t...

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  • Correspondence on “Filgotinib versus placebo or adalimumab in patients with rheumatoid arthritis and inadequate response to methotrexate: a phase III randomised clinical trial” by “Combe et al.”‘.

    We read with great interest the article by Combe et at.(1) Regarding Filgotinib in Rheumatoid arthritis. We have a few points to raise. Filgotinib is a JAK inhibitor and affects the IL-6 pathway hence when taking a primary endpoint (ACR20) that is dependent on ESR/CRP with a drugs that acts on the IL-6 axis and reduces acute phase reactants more efficiently than Adalimumab, claiming superiority can be flawed. The same holds true for comparing Adalimumab and Filgotinib with respect to DAS28-CRP and trying to prove superiority or non-inferiority. We need better disease activity indicators when comparing drugs that inhibit the IL-6 pathway and hence reduce ESR/CRP more effectively than those who don’t.
    Though the authors do point out that CDAI responses were similar – that could also be due to better pain control with JAK inhibitors due to their effect on pain pathway.
    At the same time it needs to be pointed out that though both Baricitinib and Upadacitinib did prove superiority to Adalimumab at week 12 with respect to ACR20 responses in the RA-BEAM(3) (69.6 with Baricitinib vs 61.2 with Adalimumab) and SELECT-COMPARE(4) (70.5% with Upadacitinib 15mg vs 63% with Adalimumab) but similar finidng were not observed with Filgotinib 100mg. The other interesting finding was that of higher response rates compared to ORAL standard(2), RA-BEAM(3) and SELECT-COMPARE(4) trials with other JAK inhibitors in terms of ACR20 responders for Adalimumab (58-63% vs 70%) and Placebo...

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  • Response to: “SARS- CoV-2 vaccine hesitancy among patients with rheumatic and musculoskeletal diseases: a message for rheumatologists” by Priori et al. (2021).

    Sir, we read with interest the recent communication by Priori et al. (2021) reporting that patients with rheumatic musculoskeletal diseases (RMDs) in Italy are less willing to receive the COVID-19 vaccination than healthy controls and that they are more likely to perceive themselves at higher risk of becoming infected with SARS-CoV-2 and developing severe COVID-19 [1]. These data are somehow at odds with our observations from patients with RMDs from other seven European countries who took part in the REUMAVID study [2].

    REUMAVID is an international cross-sectional study using an online survey of unselected patients with 15 RMDs from seven European countries (United Kingdom, Spain, Italy, France, Portugal, Greece, and Cyprus). A total of 2,002 patients participated in the second phase between February and April 2021. At that time, the European Medicines Agency (EMA) had approved four COVID-19 vaccines: BioNTech Pfizer, Moderna, Oxford AstraZeneca, and Janssen [3]. Significant differences in the roll out speed and vaccine availability between countries contributed to global anxiety created by the rapid development of the vaccines. Like our Italian colleagues, we were keen to explore patients’ willingness to get the vaccination and factors associated with possible unwillingness to do so.

    Contrary to the report by Priori et al. (2021), our results show that the majority of survey respondents were either willing to be (82.8%, n= 1,657) or had already been vaccinat...

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