We congratulate Truong et al. for performing an RCT with long-term follow-up of patients with chronic low back pain. We do, however, have major concerns regarding significant methodological flaws in this study.
Patient selection is critical in determining outcomes after interventional pain treatments and image guidance is regarded an essential component of performing procedures for pain management. 1 This is in sharp contrast with the present study: the method used to select the target facet joints wasn’t described and patients were diagnosed with facet joint pain based on a blind injection of local anesthetic around the facet joint. This was performed by a single physician using spinous processes as landmarks. Although there is ongoing debate regarding the sensitivity and specificity of diagnostic blocks, this technique lacks validity. 2 Studies have also shown a higher predictive value when medial branch blocks (vs. facet joint blocks) are used as diagnostic tools.
As a result, the percentage of patients with a positive response after their diagnostic block was extraordinarily high, much higher than the prevalence rate as determined by high-quality studies using rigorous selection criteria. Only 14 out of 261 patients reported a negative test block.2
Furthermore, studies have shown that even small volumes (< 0.5 mL) of local anesthetic injected under fluoroscopic guidance can lead to false-positive results via the spread of the injectate into pain-generating structures such as the paraspinal muscles, intervertebral foramina and even the epidural space. 3 The volume of 2 mL used for the diagnostic injection is very high 4 and probably magnifies this risk by an order of magnitude. One study found a 30% response rate with lumbar MBB performed with saline, and procedures carrying a higher placebo effect than medications. 5
Furthermore, regarding the methodology, no method of randomization was described and no blinding of the interventionalist was performed. Pertaining to treatment, the double-needle technique for the radiofrequency ablation (RFA) has not been validated in human studies. The extraordinarily high-volume (20-30 mL) of local anesthetic used to facilitate the treatment procedure may not only have relieved back pain by itself but could have also resulted in a stronger placebo effect than the already strong effect that exists for procedural interventions. 6

Based on the issues regarding selection and the execution of the treatment, generalizing these findings based on the results of a single center study hardly seems reasonable. There is evidence of effectiveness for RFA of the lumbar facet joints for the treatment of facetogenic low back pain. Generalizing the results of this RCT could potentially result in physicians withholding a viable treatment option for patients in lieu of a non-validated therapy.
We do, however, look forward seeing RCTs with long-term follow-up performed, albeit with valid diagnostic and therapeutic methodology.

 
References

1 Rathmell JP, Manion SC.The role of image guidance in improving the safety of pain treatment.Curr Pain Headache Rep. 2012;16:9-18.10.1007/s11916-011-0241-z
2 Cohen SP, Bhaskar A, Bhatia A, et al.Consensus practice guidelines on interventions for lumbar facet joint pain from a multispecialty, international working group.Reg Anesth Pain Med. 2020;45:424-467.10.1136/rapm-2019-101243
3 Cohen SP, Strassels SA, Kurihara C, et al.Randomized study assessing the accuracy of cervical facet joint nerve (medial branch) blocks using different injectate volumes.Anesthesiology. 2010;112:144-152.10.1097/ALN.0b013e3181c38a82
4 Wahezi SE, Alexeev E, Georgy JS, et al.Lumbar Medial Branch Block Volume-Dependent Dispersion Patterns as a Predictor for Ablation Success: A Cadaveric Study.PM & R : the journal of injury, function, and rehabilitation. 2018;10:616-622.10.1016/j.pmrj.2017.11.011
5 Cohen SP, Doshi TL, Constantinescu OC, et al.Effectiveness of Lumbar Facet Joint Blocks and Predictive Value before Radiofrequency Denervation: The Facet Treatment Study (FACTS), a Randomized, Controlled Clinical Trial.Anesthesiology. 2018;129:517-535.10.1097/aln.0000000000002274
6 Imamura M, Imamura ST, Targino RA, et al.Paraspinous Lidocaine Injection for Chronic Nonspecific Low Back Pain: A Randomized Controlled Clinical Trial.J Pain. 2016;17:569-576.10.1016/j.jpain.2016.01.469

I have read with much interest the present article and there are some relevant points that I think should be clarified because they completely disagree with the most recent research regarding hand joint denervation or hand neuroanatomy in general.
Van Der Meulen C. et al don’t recommend joint denervation to treat painful OA of the hand because of a lack of proper trials and studies to support this treatment. However, in that respect, Hustedt JW et al have recently conducted a prospective study confirming that results of both trapeziectomy (suspension arthroplasty) and denervation are identical (1). This, in my opinion, invalidates the authors’ reccomendations -at least- as far as 1st CMCJ denervation is concerned.
Furthermore, another of the authors’ reccomendations would be a trial to compare surgical denervation to other interventions targeting articular sensory nerves such as radiofrequency ablation. This technique is already used for spinal facet or knee joint painful arthropathies however it is virtually impossible to be performed at hand level because of anatomical reasons. Identification of articular sensory nerves of the hand can only be achieved through accurate surgical exposure because they are very small branchlets arising from bigger sensory and motor branches. They are only visible under loupe magnification and any local radiofrequency ablation in that area would inevitably cause damage to the main nerves that give off these articular sensory fibers due to its close proximity and leading to serious motor or sensory skin deficits. In that respect it is important to keep in mind Penfield’s homunculus to compare the nerve density of the hand to that of the knee.

References
1.Hustedt JW, Deeyor ST, Hui CH, Vohra A, Llanes AC, Silvestri BL. A Prospective Clinical Trial Comparing Denervation With Suspension Arthroplasty for Treatment of Carpometacarpal Arthritis of the Thumb. J Hand Surg Am. 2023 Apr;48(4):348-353.

Dear Editor:
We read with great interest the editorial by Felson et al. on definitions of remission in rheumatoid arthritis (RA).[1] It gives a comprehensive and historical overview of the development of remission criteria, and provides a well-founded critique of remission criteria based on the 28-joint Disease Activity Score (DAS28). DAS28 has been primarily developed and validated for evaluations at the group level, i.e. for measuring effects in clinical trials. However, in almost forgotten earlier times, when patient remission was rarely achieved, there was a need for a single index, expressing disease activity of the individual patient, and the only instrument available was the 44-joint Disease Activity Score (DAS).[2] When biologicals become available, in many countries of Europe, use of DAS28 as single index of disease activity was also stimulated by health authorities and insurance companies, requiring DAS28 proof of active RA and documented previous treatment failure (or contra-indication) of conventional synthetic DMARDs, before allowing reimbursement of an (expensive) biological drug. Since then, remission has proved to be an achievable goal, and for clinical trials and for individual patients, DAS28 cut-offs have been used for this purpose, especially in Europe, although their limitations for evaluations at the individual patient level have indeed been recognised.[3]
Moreover, we agree with Felson et al. that patient global assessment (PGA) is a valuable assessment. However, we feel compelled to clarify the misunderstanding that seems to persist regarding our relatively simple proposal. We do not suggest merely eliminating PGA from the definitions of remission; we suggest that a second target, based on valid and discriminative patient-reported measures of disease impact, is adopted, in parallel but separated from the existing target for (inflammatory) disease activity, which, we believe, could be refined by the exclusion of PGA. Although Felson et al. cite our paper,[4] they do not depict our proposal for this “Dual Target Strategy” and its conceptual framework, summarized in the conclusions of that paper. Following our proposal, the patient’s perspective would become more valued, rather than being ignored.
We disagree with the interpretation of the evidence provided by Felson et al. to support the concept that PGA should be kept as a component of the ACR/EULAR definitions of remission. Although PGA and measures of clinical disease activity are correlated at high levels of disease activity, contributing to the ability of PGA to distinguish active treatment from placebo in the context of clinical trials, they are only poorly, if at all, correlated at low levels of disease activity,[5, 6] precisely when the practising clinician needs to make difficult decisions regarding escalating or maintaining immunosuppressive/immunomodulatory therapy. Thus, while the inclusion of PGA may facilitate the distinction between treatments in clinical trials, we are concerned regarding the implications of including PGA as an element of composite definitions of remission used to tailor immunosuppressive/immunomodulatory therapy in clinical practice and the potential risk of overtreatment that this entails. As many as 45 to 61% of all patients with RA (in clinical trials[4] and cohort studies,[7] respectively) who are otherwise in remission fail to meet the Boolean definition of remission, solely because of a too high PGA score. These patients, in so-called “PGA-near-remission”, are exposed to the risk of overtreatment, because their disease cannot be improved by additional immunosuppression/immunomodulation. However, they still endure significant impact of non-disease activity manifestations and outcomes of the disease,[8] which were recently touched upon in the EULAR points to consider for the management of difficult-to-treat RA.[9] The use of the ACR/EULAR remission definitions in clinical practice was explicitly predicted in the original 2011 report,[10] and has been extensively adopted as part of the Treat-to-Target strategy. Thus, the implications of these definitions are more extensive than those for clinical trials only.
The assertion that PGA reflects subclinical inflammation is, in our view, unsupported by evidence. We, and in fact, some of the authors of the editorial themselves, have shown no correlation between PGA and joint damage accrual.[11] We have also demonstrated that in patients that are in PGA-near-remission there is no evidence of inflammation in other joints or synovial structures, through extensive ultrasonography assessment.[12] It is difficult to envisage what room is left for the consideration in the editorial that “…the patient global assessment reflects components of disease activity that are otherwise not captured, …as inflammation in joints not included in a 28-joint count, such as the feet and ankles.” This is, therefore, not the reason “why high patient global assessment scores, even when 28-joint counts are low, identify patients at high risk of later functional loss.”[1] This may be simply and better explained by the fact that function is a major determinant of PGA, irrespective of (inflammatory) disease activity, as repeatedly reported.[5, 6, 8, 13] These publications are the basis of our “Dual Target Strategy” proposal, which we hypothesize, may result in more accurate and comprehensive definitions of remission. We proposed the “Dual Target” to comprise (i) biologic remission, which will be sharper and more sensitive to help guide immunosuppressive/immunomodulatory therapy in individual patients in clinical practice, and (ii) patient remission, addressing also all other important aspects of non-disease activity manifestations, outcomes of the disease, and of medication adverse effects (disease impact); thus, more informative than the current one-item PGA. Surely, this approach highlights the importance of patients’ perspective as it ensures that clinicians address both the disease activity and the disease impact aspects accordingly.
In summary, we agree with many of the points made in the editorial by Felson et al., but we feel that it distorts our proposal by omitting to mention the patient remission aspect, which is what makes it a “Dual Target”: a holistic strategy that empowers patients and promotes health by allowing patients to gain greater control over decisions and actions affecting their health, a World Health Organization recommendation, since the Ottawa conference in 1986.

References
1. Felson D, Lacaille D, LaValley MP, et al. Re-examining remission definitions in rheumatoid arthritis: considering the 28-Joint Disease Activity Score, C-reactive protein level and patient global assessment. RMD Open. 2021; dx.doi.org/10.1136/rmdopen-2021-002034.
2. van der Heijde DM, van 't Hof MA, van Riel PL, et al. Judging disease activity in clinical practice in rheumatoid arthritis: first step in the development of a disease activity score. Ann Rheum Dis. 1990;49:916-20.
3. Jacobs JW, Ten Cate DF, van Laar JM. Monitoring of rheumatoid arthritis disease activity in individual patients: still a hurdle when implementing the treat-to-target principle in daily clinical practice. Rheumatology (Oxford). 2015;54:959-61.
4. Ferreira RJO, Welsing PMJ, Jacobs JWG, et al. Revisiting the use of remission criteria for rheumatoid arthritis by excluding patient global assessment: an individual meta-analysis of 5792 patients. Ann Rheum Dis. 2020;80:293-303.
5. Ferreira RJO, Duarte C, Ndosi M, et al. Suppressing Inflammation in Rheumatoid Arthritis: Does Patient Global Assessment Blur the Target? A Practice-Based Call for a Paradigm Change. Arthritis Care Res (Hoboken). 2018;70:369-78.
6. Ferreira RJO, Carvalho PD, Ndosi M, et al. Impact of Patient's Global Assessment on Achieving Remission in Patients With Rheumatoid Arthritis: A Multinational Study Using the METEOR Database. Arthritis Care Res (Hoboken). 2019;71:1317-25.
7. Ferreira RJO, Santos E, Gossec L, et al. The patient global assessment in RA precludes the majority of patients otherwise in remission to reach this status in clinical practice. Should we continue to ignore this? Semin Arthritis Rheum. 2020;50:583-5.
8. Ferreira RJO, Dougados M, Kirwan JR, et al. Drivers of patient global assessment in patients with rheumatoid arthritis who are close to remission: an analysis of 1588 patients. Rheumatology (Oxford). 2017;56:1573-8.
9. Nagy G, Roodenrijs NMT, Welsing PMJ, et al. EULAR points to consider for the management of difficult-to-treat rheumatoid arthritis. Ann Rheum Dis. 2021;10.1136/annrheumdis-2021-220973.
10. Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis. 2011;70:404-13.
11. Studenic P, Felson D, de Wit M, et al. Testing different thresholds for patient global assessment in defining remission for rheumatoid arthritis: are the current ACR/EULAR Boolean criteria optimal? Ann Rheum Dis. 2020;10.1136/annrheumdis-2019-216529.
12. Brites L, Rovisco J, Costa F, et al. High patient global assessment scores in patients with rheumatoid arthritis otherwise in remission do not reflect subclinical inflammation. Joint Bone Spine. 2021;88:105242.
13. Craig ET, Perin J, Zeger S, et al. What Does the Patient Global Health Assessment in Rheumatoid Arthritis Really Tell Us? Contribution of Specific Dimensions of Health-Related Quality of Life. Arthritis Care Res (Hoboken). 2020;72:1571-8.

Some of the most compelling clinical questions are hardly amenable to experimentation in randomized controlled trials (RCTs). ‘Does vertebroplasty improve health-related quality of life in elderly patients with an acute osteoporotic fracture?’ is one of those questions that was nevertheless challenged in not less than four RCTs recently. The outcome of this challenge was a disappointment for believers in vertebroplasty (VP): one-to-three against VP, and the invasive intervention was discarded from guidelines, as Christian Roux and colleagues have beautifully explained in a recent opinionated review in RMDOpen. [1] Obviously, an unmet need remained and Roux et al. broke a lance for reconsidering VP as a treatment option in highly selected vertebral fracture (VF)-patients with a bad prognosis. They solicited proposals for clinical studies.
Such studies should not necessarily have an RCT-design. Indisputably, RCTs provide the most unbiased results, but always at the expense of external validity. This is why clinical epidemiologists keep recalling that the absence of evidence (that VP works) does not imply that there is evidence for the absence of efficacy (of VP).
Roux et al have a point when they claim that the trials may have focused on the wrong population, that the choice of the trials’ primary outcome was not ideal, and that the duration of follow up was too short to detect clinically meaningful effects beyond pain resolution alone. All these objections involve limitations of the rigid RCT-design template. If Roux et al’s hypothesis is right, and VP indeed reduces mortality and improves health related quality of life among these selected elderly at high risk to die, perhaps different study designs with longer follow up, in different patients and with different outcomes, should be pursued. Proponents of RCTs will immediately object that such studies cannot provide the required level of unbiasedness that RCTs may provide, eg. because of the absence of a proper control group, the likelihood of bias by indication and the room for obscuring co-interventions. But as said some clinical research questions are simply not ‘made for trials’, and sometimes the medical community should better appreciate second-best, in order to avoid throwing the child with the bathwater.
Recently, we have applied principles of causal inference to two compelling research questions that were not suited well for RCTs; the first was whether intense short-term immunosuppression reduces mortality in patients with hyperinflammatory COVID-19. In a non-randomized study with untreated historic controls, and a proper mediator variable, we have construed the evidence that immunosuppressive treatment is indeed effective, [2] half a year before the RCTs and the guideline committees arrived at the same conclusion.
Whether or not bDMARDs can inhibit syndesmophyte formation in patients with axial spondyloarthritis is a matter of endless scientific debate. RCTs are (ethically) difficult to perform because of slow progression-rates warranting long-term trials, but many non-randomized studies have been done in the past. We have tackled the issue by categorizing the available evidence in the literature according to criteria of causality proposed by Gvozdenovic et al. [3] While this exercise has not provided final evidence, it gave important direction to a question that will likely never be unequivocally answered in an RCT. [4]
We invite Roux et al. to do a similar exercise in their carefully built database of studies to the efficacy of VP. They may bring some order of causation in the existing body of literature, as we did in the example of axial SpA. By doing so, they may propose a potential mediator-variable, or perhaps an instrumental-variable, that can be used in future clinical studies and shed more light on research questions that go beyond the level of pain-resolution by VP alone.