Gout in Paleopathology: A Review with Some Etiological Considerations
Round 1
Reviewer 1 Report
I find the report interesting but if to be useful for archeological studies some more technical details on preparation and study of possibly affected bones would be greatly appreciated, if available. Keep in mind that this report may be used as a reference for paleoarcheological studies and details here are valuable. few comments follow:
Line 23: where it says “gout is an erosive arthropathy” should say: a monosodium urate crystal deposit disease resulting in inflammation and in the absence of modern treatment (that has been considered curative by dissolving the crystals) joint damage and early death (or alike) – to help not specialized readers – as archeologists - to locate where the disease stands today.
Line 54: The initial deposits of urate crystals occur on the surface of the cartilage of affected joints and also tendons. Although tophi can be found early in the disease; large tophi occur in advanced gout, and bone erosions are known to be produced by cells with osteoclastic potential in the inflammatory cell crown that surrounds the central MSU deposits, and are not produced by direct action of the crystals (Chhana A, Callon KE, Pool B, Naot D, Watson M, Gamble GD, McQueen FM, Cornish J, Dalbeth N. Monosodium urate monohydrate crystals inhibit osteoblast viability and function: implications for development of bone erosion in gout. Ann Rheum Dis. 2011 Sep;70(9):1684-91).
In section 2 (Epidemiology of gout in brief) it would be appropriate to mention that serum urate levels are very low in children that only very exceptionally get the disease (Lesch-Nyhan syndrome), rising in the puberty its values to those that will be kept along their adult life in boys (men) but showing a reduced rise in women til the menopause, when values can approximate to those of men and gout may occur in them [Mikkelsen WM. The American journal of medicine. 1965; 39:242]. That gout is rare in children and premenopausal women must be mentioned, and their lower uricemia as explanation for it mentioned.
Page 3 line 217: If referring to gout flares it should say “Acute gout flares can be polyarticular but…… “
128 . it says: predilection for the lower half of the body. Hips and lower spine are very exceptionally affected; It would be better …predilection for the lower extremities, being also the olecranon bursa and hand joints frequently affected.
Lines 143- 144 When visual observation of the bone is limited, radiographs can offer essential information (65–67). Question: the figure of page 3 shows a radiograph and a CT image showing a clear overhanging lesion. Should you expand a bit in the possible advantages of using CT imaging?
Gout in pacific islanders is genetically linked to certain urate renal transporters (ABCG2 is an important one but not the only) that result in poor renal clearance of urate and so hyperuricemia. (See Merriman T, Pacific Islanders, gout)
As a personal comment to the authors and not related to their report but to their interest in paleopathology : Through sonography and arthroscopic images we know that MSU crystal deposition occurs preferentially in the surface of the joint cartilages of affected joints, and also in the site where tendons attach to bone (and there inside the tendons) so in relatively recent skeletons and likely for quite some time is appears reasonable to search there. Remember that formalin fixation dissolves the crystals, that are preserved by frozen sectioning (as for surgical biopsies) and MSU crystals are well seen by uncompensated polarized microscopy. Good luck!!
Author Response
Response to Reviewer
RE: Manuscript entitled “Gout in Paleopathology: A Review with some Etiological Considerations”
[1]I find the report interesting but if to be useful for archeological studies some more technical details on preparation and study of possibly affected bones would be greatly appreciated, if available. Keep in mind that this report may be used as a reference for paleoarcheological studies and details here are valuable. few comments follow:
[1] We have added a paragraph of recording methods that we have integrated into our assessment of individual skeletons in archaeology in the past. These include taking a standard inventory of the bones from each individual, conducting biological sex and age estimates, and omitting bones that have had their structural integrity compromised, all of which help to increase the probability of true gout diagnosis. We have also suggested some recording methods specific for the gross observation of gouty erosive lesions on bone including taking an inventory of bone regions that are part of synovial joints and establishing a bone count threshold. A bone count threshold is introduced to present gout prevalence data by ‘individual’. An ‘individual’ is defined by a bone count threshold (e.g., a minimum of five complete metacarpals and five complete metatarsals). (Refer to Subsection 3.1)
[2]Line 23: where it says “gout is an erosive arthropathy” should say: a monosodium urate crystal deposit disease resulting in inflammation and in the absence of modern treatment (that has been considered curative by dissolving the crystals) joint damage and early death (or alike) – to help not specialized readers – as archeologists - to locate where the disease stands today.
[2] Line 23: We have added the suggested sentence to the paragraph, as a follow up to the sentence mentioned. (Refer to Section 1)
[3]Line 54: The initial deposits of urate crystals occur on the surface of the cartilage of affected joints and also tendons. Although tophi can be found early in the disease; large tophi occur in advanced gout, and bone erosions are known to be produced by cells with osteoclastic potential in the inflammatory cell crown that surrounds the central MSU deposits, and are not produced by direct action of the crystals (Chhana A, Callon KE, Pool B, Naot D, Watson M, Gamble GD, McQueen FM, Cornish J, Dalbeth N. Monosodium urate monohydrate crystals inhibit osteoblast viability and function: implications for development of bone erosion in gout. Ann Rheum Dis. 2011 Sep;70(9):1684-91).
[3] We have added the suggested information. (Refer to Section 2)
[4]In section 2 (Epidemiology of gout in brief) it would be appropriate to mention that serum urate levels are very low in children that only very exceptionally get the disease (Lesch-Nyhan syndrome), rising in the puberty its values to those that will be kept along their adult life in boys (men) but showing a reduced rise in women til the menopause, when values can approximate to those of men and gout may occur in them [Mikkelsen WM. The American journal of medicine. 1965; 39:242]. That gout is rare in children and premenopausal women must be mentioned, and their lower uricemia as explanation for it mentioned.
[4] We have added the suggested information. (Refer to Section 2)
[5]Page 3 line 217: If referring to gout flares it should say “Acute gout flares can be polyarticular but…… “
[5] We believe you were referring to Line 127. In this sentence we refer to bone affected by tophaceous gout rather than gout flares. (Refer to Section 3.1)
[6]128 . it says: predilection for the lower half of the body. Hips and lower spine are very exceptionally affected; It would be better …predilection for the lower extremities, being also the olecranon bursa and hand joints frequently affected.
[6] We have added the suggested information. (Refer to Section 3.1)
[7]Lines 143- 144 When visual observation of the bone is limited, radiographs can offer essential information (65–67). Question: the figure of page 3 shows a radiograph and a CT image showing a clear overhanging lesion. Should you expand a bit in the possible advantages of using CT imaging?
[7] It is much easier to identify small gouty erosive lesions with CT imaging than with radiographs, particularly erosive lesions from the small bones of the hands and feet. We have added this information to the paragraph. (Refer to Section 3.1)
[8]Gout in pacific islanders is genetically linked to certain urate renal transporters (ABCG2 is an important one but not the only) that result in poor renal clearance of urate and so hyperuricemia. (See Merriman T, Pacific Islanders, gout)
[8] We have added the suggested information. (Refer to Section 2)
Reviewer 2 Report
The aim of this paper was to update Buckley's review of gout in paleopathology.
The authors described cases found in Europe, outside Europe, and in the pacific region.
This is an interesting review, highlighting the difficulties of gout diagnosis for paleopathologists and discussing the etiologies of gout in past populations ; in addition to genetic predisposition and lifestyle, the authors point out that early life stress may be a contributor to gout development.
References : journal abbreviations need revision
Author Response
Thank you for the review of our manuscript entitled “Gout in Paleopathology: A Review with some Etiological Considerations”. We have applied your suggested changes and have provided a response to your comment below:
“References: journal abbreviations need revision”
We have expanded all journal abbreviations where possible to ensure clarity and consistency.
Yours sincerely,
The Authors
Reviewer 3 Report
in human populations for a long time. There are testimonies to it also in ancient writings. The authors reviewed the literature on gout and presented it in the context of an aetiology that is not entirely clear. The authors noted that the incidence of this disease entity varies in different parts of the world. Reports indicate a much higher incidence of gout in the indigenous peoples of Asia and the Pacific.
The authors noted that when it comes to palaeopathological descriptions, this problem is relatively well understood, and significantly less so when it comes to other parts of the world.
The paper is a sound, literature review that also refers to the common epidemiology of the disease and views on its aetiology. The paper is very interesting and the hypothesis presented in the 5th Conclusions is supported by an in-depth analysis. The bibliography is appropriate and also includes recent reports.
[120] in figure C the measure is blurred and out of focus - it is worth correcting this
[120] in figure D it would be good to brighten the microtomogram as it is very unclear
Author Response
Thank you for the review of our manuscript entitled “Gout in Paleopathology: A Review with some Etiological Considerations”. We have applied your suggested changes and have provided a response to your comments below:
[1] “in figure C the measure is blurred and out of focus - it is worth correcting this”
[1] Here the bone and scale are at different distances making it tricky to focus the camera on both objects. We have sharpened the scale in Figure C.
[2] “in figure D it would be good to brighten the microtomogram as it is very unclear”
[2] We have brightened Figure D.
Yours sincerely,
The Authors
Round 2
Reviewer 1 Report
Second revision
My comments are properly introduced in the text
In a second reading I still found some comments that may help the authors to further improve their report.
A key issue is that current definitive diagnosis requires monosodium urate crystal identification (Richette P, Doherty M, Pascual E et al.. 2018 Updated European League Against Rheumatism evidence-based recommendations for the diagnosis of gout. Ann Rheum Dis. 2020 Jan;79(1):31-38. doi: 10.1136/annrheumdis-2019-215315. Epub 2019 Jun 5. PMID: 31167758). This appears possible in very old remains. The authors mention the gout of Holy Roman Emperor Charles V (1516–1556 AD) 196 (number 68 of their references). In this paper its authors refer how they identified the crystals (and this appears essential in a careful report on the paleopathology of gout, since this is an unequivocal proof). Besides compensated polarized microscopy (the usual tool for crystal identification in clinic [Pascual E, Sivera F, Andrés M. Synovial fluid analysis for crystals. Curr Opin Rheumatol. 2011 Mar;23(2):161-9.) other means have been developed, such as double energy computed tomography (DECT) (Shang J, Zhou LP, Wang H, Liu B. Diagnostic Performance of Dual-energy CT Versus Ultrasonography in Gout: A Meta-analysis. Acad Radiol. 2022 Jan;29(1):56-68)., a CT modality that uses two beams of X rays and depending in the absorption by the crystal to each one of them can identify different crystals, and it can do it with MSU crystals. Also Raman spectroscopy; (Li B, Singer NG, Yeni YN, Haggins DG, Barnboym E, Oravec D, Lewis S, Akkus O. A Point-of-Care Raman Spectroscopy-Based Device for the Diagnosis of Gout and Pseudogout: Comparison With the Clinical Standard Microscopy. Arthritis Rheumatol. 2016 Jul;68(7):1751-7. PMCID: PMC4992577). Also specially through sonography, now we know that MSU crystals deposit at the surface of joint cartilages – that can be well preserved in not too old cadavers – and at the insertion of tendons in bone – like the patellar tendon at the patella or tibia. I wander whether the problem of finding MSU crystal deposits in human remains has received much attention, if not it must be stated and mentioning it may stimulate some of the readers to investigate it. Sonography is very useful in clinical practice but likely inappropriate for paleopathology unless if remains are very recent.
Author Response
Response:
The Reviewer highlights the importance of MSU crystal presence in the body for the definitive diagnosis of gout and presents a list of tools that aleopathologists may consider in identifying these crystals in archaeological individuals. These tools may be used to diagnose gout among archaeological individuals if remains are well-preserved with soft and skeletal tissues intact (e.g., state of mummification). To our knowledge, the tools (except compensated polarized microscopy) listed by the Reviewer have not been applied in an archaeological context to investigate gout. The reason for this is because palaeopathologists more often encounter skeletal remains (dry bone) with no visible evidence of MSU crystals in archaeology. Given this more common scenario, in this paper (see section 4.4) we attempted to draw attention to the potential for greater research on gouty erosive lesions which become essential features to diagnose for gout in the skeleton. We, however, do agree that the technologies listed by the Reviewer provide avenues, where possible, to further explore the condition in the past. We have acknowledged these tools in the paper and their potential in identifying MSU crystals in well-preserved human remains. However, these circumstances are not as commonly encountered in archaeology as skeletal remains (see section 4.4, highlighted in turquoise).
Round 3
Reviewer 1 Report
no further comments
