Rufus of Ephesus, On gout

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Natale Gaspare De Santo

DOI: 10.69097/43-02-2026-13

Natale Gaspare De Santo1, Luca S. De Santo2, Carmela Bisaccia3

1 Emeritus University of Campania Luigi Vanvitelli, Naples, Italy
2 Translational Medicine Department, Luigi Vanvitelli University Hospital, AO dei Colli Monaldi. Adult CardiacSurgery, Naples, Italy
3 Mazzini Institute, Naples, Italy Naples, Italy

Corresponding author:
Natale Gaspare De Santo,
salita Scudillo 20, 80131, Napoli, Italia
E-mail: gaspare.desanto@unicampania.it

 

Abstract

Aims. For a study on the timeline of gout from the Corpus Hippocraticum to the Renaissance, encompassing some 26 authors, we have focussed on a Latin manuscript – “De podagra” – of the Middle Ages (posthumous edition dated to the 7th-8th century AD) of Rufus of Ephesus (98-117 AD), during the reign of Trajan. A multipurpose study has been devised to 1) translate into English and Italian the Medieval Latin treatise of the 7th-8th century AD of Rufus of Ephesus on “De podagra”; 2) define the role of Rufus in the historical timeline of gout from the Corpus Hippocraticum to the Renaissance ; 3) analyze causes, clinical presentations and therapy of acute attacks and chronic gout; and 4) identify the plant-based remedies described therein. Neither an English nor an Italian translation of “De podagra”, nor the identification of the plants described therein, has been attempted before.
Methods. Plants were identified taking into account methods used for studies on Dioscorides and Galen.
Results. The findings highlight the originality of Rufus of Ephesus’s clinical approach to therapy and the vast knowledge of diseases treated by plants.
Conclusion. Rufus of Ephesus, the third most famous figure in medicine after Hippocrates and Galen, celebrated for his studies in obstetrics, gynecology, pediatrics, and neurology, a gouty physician, left a personal mark in the history of gout by making full use of his clinical skills that had been maximized by the severe apprenticeship in anatomy and in the Corpus Hippocraticum.

Keywords: Rufus of Ephesus, gout, nutrition, physical activity, bleeding, plant-based remedies

Introduction

Gout is the oldest non-communicable disease known in humans, with origins dating back to around 2760 BC in Egypt. It is regarded as the earliest documented form of chronic inflammatory arthritis in human history. Historically, gout has been known as podagra (meaning “foot-grabber”) from Greek stems. According to Webster’s Dictionary, it literally means foot-trap from “pous” (foot) and “agra” (catching, seizure). The term “gout” was introduced by Randolphus of Bocking (1197–1258), who connected it to the Latin word “gutta” (drop). Gout is a systemic disease caused by hyperuricemia – at or above 6.8 mg/dL – leading to the deposition of sodium monurate crystals in peripheral joints and periarticular tissues. Crystal deposition activates the NOD-like receptor protein 3 inflammasome causing – via caspase-1 – the release of the cytokine IL-1β, also known as an endogenous pyrogen, a highly inflammatory cytokine and a key mediator of the acute attack [4].

Hyperuricemia may result from renal overload, renal underexcretion, or a combination of both [1, 2]. Urate deposition causes the release of cytokine IL-1β [2], mediator of the acute attack. Gout typically begins by affecting a single joint, often the first metatarsophalangeal joint of the great toe, and is usually self-limited, resolving within two weeks. Flare-ups affect two or more joints, becoming a chronic disease characterized by tophi and joint erosion. Diagnosis is based on clinical history, symptoms, signs, polarized microscopy, or fine-needle aspiration of tophi [3].

An effective cure was introduced in the fifth century CE [4] by Theodosius, Severus Iatrosophista and Jacobus Psychrestos, who applied a plaster made from Hermodactylus, a root rich in colchicine – a compound previously used as a cathartic. It was the main drug of choice for gout until the advent of allopurinol.

We have been drawn to this disease by the history of popes [5–7], which provides all the details necessary for a comprehensive understanding of gout as the oldest lifestyle disease, a disease of distinction [8], and a man-made condition. It is explainable by the theory of epidemiological transition but also a disease amenable to prevention in individuals with a high degree of education [9, 10].

Recently, we have initiated a study dedicated to illuminating the timeline of “Gout from the Corpus Hippocraticum to the Renaissance”. Our focus has been on Hippocrates and Galen [11, 12], and we have also provided preliminary data on Alexander of Tralles [13] and Rufus of Ephesus [14, 15]. The latter is studied extensively in this context.

 

Aims

A multipurpose study has been devised to: 1) translate into English and Italian the medieval Latin of De podagra the treatise of the VII-VIII century AD,  2) define Rufus’s role within the historical timeline of gout from the Corpus Hippocraticum to the Renaissance; 3) analyze the causes, clinical presentations, and therapies of both acute attacks and chronic gout; and 4) identify the vegetable remedies described therein. Neither an English nor an Italian translation of “De Podagra”, nor the identification of the plants mentioned, has been attempted before.

 

Rufus’ short biography

Rufus of Ephesus, one of the most celebrated physicians of antiquity, probably lived in the second half of the first century and the early second century, with dates assigned by Suida between 98 and 117 CE, during the reign of Trajan [16, 17].

Details about his life are scanty and often imprecise. Rufus was born at Ephesus (Asia Minor, near modern Selçuk, Turkey) and it is believed that he studied in Ephesus and Alexandria where he learned anatomy by dissecting apes, pigs and other animals, while also acquiring medical knowledge from Hippocratic texts. Rufus practiced medicine in Egypt and various parts of Asia Minor, including Ephesus, Magnesia, and Miletus, travelling extensively. However, reliable evidence of his having been in Sicily and Rome has yet to be found.

Rufus authored numerous works, but most of his writings have been lost and the surviving material is incomplete and contains errors. Among the surviving manuscripts a special mention is due to The Naming of Parts of the Human Body, a manual of anatomy based more on animal dissection than on human; a treatise on Diseases of the kidneys and bladder and to a treatise on Purgatives. Also preserved is the already mentioned Latin manuscript from the VII-VIII Century CE on “De podagra” translated into French as Traitè de la goutte by Littré and published in Review Philologique. The list additionally includes a work on Pulses, preserved in Greek and translated into French by A. Daremberg in 1810, as well as fragments transmitted in the works of Oribase and Aetius of Amida. Rufus’ Opera omnia was published by C.H. Daremberg and É. Rouelle in 1879 [18].

He adopted the theory of the four humors and practiced a medicine based on identifying their imbalance and restoration. Rufus was more interested in clinical practice than in theoretical questions. A prolific writer, many of his works survive only in Arabic translations. His clinical method, well described in “On the Interrogation of the Patient”, was based on questions. Questions were indispensable to trace the origin of the disease, identifying the critical days, understanding the time-course, determining antecedents and assessing the humours involved thereby facilitating the decision about treatment.

He covered many topics, including anatomy and pathology, and mastered both medical and surgical illnesses. He also devoted particular effort to the study of Melancholia. In the treatise on gout – he was gouty – he reports on tophi and his experience pointing to the fact that on many occasions he saw them dissolving during treatment; however, he indicated that many physicians decided to leave them in situ after an attempt with poultices and heat. He realized that it is not a humour as cause, but a toxic substance in the organism, which can target the internal parts.

Rufus was quoted thrice with appreciation by Galen [19, 20]. The first time for his studies on melancholy and later for preservation and interpretation of Hippocrates’ manuscripts. His studies have been reported in the works of Oribasius, Aetius of Amida (De re medica libri XVI, transcribed chapter XXX and XXXI of the treatise on gout), Paul of Aegina and Rhazes. No less than 36 Arab scholars have quoted him [21]. Rufus was defined by Oribasius as “The Great” [20] and by Haller “illustris medicus et insignis scriptor” [22].

His surviving writings have been edited over the centuries.

 

Methods

We have translated into English and Italian the 37 paragraphs of “De Podagra” using the same Latin text employed by Littré for his French translation (Traité de la goutte). Their contents are summarized in Table 1 and provide the most immediate way to grasp the vast knowledge Rufus had on gout. Subsequently, we have distilled a synopsis bearing all essential elements of the disease (see Enclosure, Rufus text).

Plants used by Rufus for therapies were identified using three criteria derived from the works of Lily Y. Beck and John M. Riddle on Pedanius Dioscorides, and Nicholas Everett for The Alphabet of Galen [22–24].

ON PODAGRA
1. Prologue
2. Signs to diagnose the disease
3. On exercises
4. On frictions
5. On baths
6. On the properties of natural and mineral waters
7. On herbs useful to add to sweet waters
8. On fomentations
9. Legumes
10. On fish
11. On birds
12. On meats
12a.On bread
13. On wine
14. Nutrition of the gouty persons during the attacks of the disease
15. On salting
16. On walking after waking
17. On cathartics
18. Drugs that should not be administered to gout sufferers as purgatives
19. Purgings useful to gouty persons
20. Remedies used to induce vomiting
21. On vomiting
22. On acrid aliments, other aliments
23. Why podagra descends from colon to feet
24. On remedies removing flatulence
25. On clysters
26. On potions
27. On antidotes
28. Potions should not be removed immediately
29. Methods of treatment
30. A different cure for podagra
31. On the application of cauteries and on the production of eschars on joints
32. An additional modality to cure with liniments and poultices
33. Treatments to be followed when there are complications in the pains of rheumatic diseases
34. On cooling the joints
35. On poultices producing heat
36. Remedies for treating very humid podagra
37. Fomentations
Table 1. Contents of the Treatise on podagra by Rufus of Ephesus. In Oeuvres de Rufus d’Éphèse, Paris 1845, pp. 307-348.

 

Rufus of Ephesus on Gout (De podagra)

  1. PROLOGUE

Joint diseases can be cured, provided they are caused by congestion and excess humidity, which lead to loss of heat and dryness. Initially, even when the disease is mild, the onset of congestion warrants concern. Thus, at the beginning of attacks, the pain is not severe and causes little harm; however, if the attacks become intermittent, there is an increasing influx of humors into the joints, making healing progressively more difficult. Those who overeat, especially unhealthy foods, are prone to worsening of their condition. So, the patient begins to feel very mild pain in the joints, then very acute suffering begins. The most serious condition occurs when the congestion in the patient’s joint ceases; this is followed by another danger that threatens, then soon prevails and overwhelms the patient, such as pleuropneumonia, apoplexy, or some other acute disease. Therefore, it is important to explain everything to the patient, so that detailed remedies can be explored to determine which ones are appropriate for treating the disease.

  1. DIAGNOSIS OF THE DISEASE

If a joint is painful, the patient should be asked if he has bumped the affected area. If he denies this, he must immediately be placed on a diet, given an enema and made to undergo bloodletting (preferably near the site of the pain). Abstaining from eating reduces blood production and prevents the joints from becoming sluggish. We prescribe enemas because they help evacuate the bowel. Bloodletting is useful, but less so in the lower parts. There is a need to relax the abdomen; if there is bleeding, this will be of great help, because the disease progression will be halted. Even when the disease has completely resolved in patients, they should not be considered cured, as relapses return over time, given that this disease, like many others has its periods. Those who, by not observing their state, do not take into account what we say, expose themselves to very serious diseases. Therefore, we strongly advise them, before the second and third recurrence, not to ignore the prescribed treatments typical for such cases. Immediately after bloodletting, it is beneficial to perform a massage, dehydrate the body with strenuous exercise, consume easily digestible foods, and above all, make efforts to dry the body.

  1. ON EXERCISES

Indeed, if the joints in the hands and upper limbs are in poor condition due to nodules, the feet must be exercised by walking, running, horseback riding, massaging the thighs and lower limbs. Conversely, if the joints of the feet are affected, attention should be given to the hands by encouraging different movements and performing different tasks, as this helps dehydrate the body. When a certain area has been sufficiently exercised, it is time to start very vigorous general exercises with a desiccant effect. Gout sufferers experience the most intense nerve pain when their upper and lower joints are affected simultaneously, and therefore, require very careful treatment.

  1. ON MASSAGE

I praise massages, first dry, then with oil. They should not be very prolonged, but should last until the hands become soft to the touch without being greasy under the rubbing. Do not use new oil, but rather the oldest possible, to which drying and warming ingredients will be added, such as iris (Iris florentina, L.) or St John’s wort (Hypericum crispum, L.), or plenty of salt, or even a small amount of honey. All this is beneficial to gouty patients. An equally effective remedy is pork fat, or wild boar fat, which is even more drying. I think it is important to rub the joints with suet (because there is always some on hand), oil should be used more often than not, as well as other remedies (medicines), when available. The best is to massage the area where the pain is most intense. Furthermore, for gout and all diseases of the joints and hepatic colic as well, it is good to treat the parts (limbs) with very old pork fat. Melt it over burning coals, add equal amounts of larch (Larix decidua, Mill.) and butter, then grease the sore parts.

  1. ON BATHS

I will not mention baths, in absolute terms, as effective treatment for this disease, except in cases of fatigue, sluggish digestion, plethora, or finally, excessive dryness of the joints; in these instances, baths are very often effective. Again resort to baths when the body suffers (insistent) pain, if there are nocturnal emissions or after a venereal act. In all other circumstances, baths should be avoided by gouty sufferers.

  1. ON PROPERTIES OF NATURAL OR MEDICINAL WATERS

If you put medicinal plants in the water, and if you use natural warm waters, such as waters full of asphalt, sulfur or alum, as long as you take frequent baths, they will do no harm; and, if you take sea water baths, you will be happy. Swimming will also be good for you, as this exercise is healthy for your joints.

  1. HERBS THAT ARE GOOD TO PUT IN FRESH WATER

If the waters are not natural, the types of ingredients to put in the fresh water are the following: sage (Salvia officinalis, L.), laurel (Laurus nobilis, L.), chaste tree (Vitex agnus-castus, L.), myrtle (Myrtus communis, L.), tender willow leaves (Salix, L.), salt for making brine, especially non-sea salt. All this provides the baths with drying properties, and provides a benefit when there is an excess of humors. But baths are not helpful when they are cold, because, when the patients get accustomed to the baths that we have prescribed, cold baths taken at other times will do even more harm.

  1. ON FOMENTATION – Differences in warm applications to ease pain

I recommend the perspiration caused by a sand bath, the baths that are taken by wrapping oneself in leather or fabric, and the Laconia baths. The use of dry steam baths is effective. It is what the Greeks call the tub. As for us, with a pine cone placed in a tub, closed at its end and heated with a branch, after having removed the fire, we let patients perspire inside, taking care that the water does not spill. There is still a method of perspiration which consists of rubbing the entire body with cleansing lotions, ointments and moderate anointing with iris (Iris florentina L.) or privet (Ligustrum L.) oil. We now need to get to the foods that can be beneficial for these ailing individuals.

  1. VEGETABLES

In my opinion, vegetables do not provide any real benefit; however, we must eat some of them in order to soften the belly, others, because they are cold and moist (refreshing and humectant), some are caustic, others are acrid; and some even have diuretic properties.

  1. FISH

Suitable fish are very dry ones, such as mullet, sea scorpion, or scorpion fish, odilcon (untranslatable); as well as soft-fleshed fish: for example, brown wrasse, cichlids, parrotfish, and another species of Labrus merula. This is all good as dehydrating and easy to digest; but the best meats (in this disease) are still those of anchovies, hermit crabs, and sea prawns, which are more drying. I do not recommend young tuna, any of the meaty fish, which are fatty, indigestible, give stomach problems, cause mucus and are humectant, such as sea eels. Cartilaginous fish, and generally all freshwater fish, are equally mediocre.

  1. BIRDS

As for birds, all should be recommended, except those living in water or marshes; in fact, these do not represent a healthy nourishment (for our patients), but a humectant and aqueous one; moreover, they are difficult to digest. I recommend those which live in dry places and feed on wheat, they are at the same time digestible and nutritious.

  1. SLAUGHTER MEAT

Pork is recommended in any type of diet when it comes to strengthening; for this reason, this is the only meat given to athletes. At least, this is the case now, but not in the past. It is nutritious for everyone, provided, however, that attention is given to the condition of the abdomen; because, when this tends towards humidity, it is controlled by desiccants; if it causes inflammation, it is controlled by refreshers. However, in my opinion, pork is not effective for gouty or arthritic persons; and, more generally, for people who have nerve disease who should not eat a heavy diet, especially if it is humectant, because it soon causes some other disease. Why am I against pork? It’s because it’s humectant and bad for your gut. Kid, lamb and veal are digested much better; and, in fact, these animals digest all species of vegetables, and are not harmful (to the abdomen) like pork.

12a. BREAD

You must eat bread baked in an oven heated on all sides, so that the cooking is even, and that it is well leavened, made with a flour that is not too refined, made with three-month-old wheat.

  1. WINE

Drink red wine that is neither well aged nor too fresh. For ordinary people, I do not recommend either red wine or young wine; both are indigestible for everyone, especially for the sick we are taking care of. These are the usual foods and drinks suitable for gout sufferers.

14. NUTRITION DURING ATTACKS OF THE DISEASE

In the presence of inflammation, I recommend water rather than wine, and eggs rather than slaughtered meat. Do not administer fomentations immediately after the meal; they carry the risk of tissue contraction when the food is still raw (undigested). Does cold provide relief? So first of all we suggest drinking a cup of wine with honey, 1 cotyle, rather than just wine. This compound is both a drink and a medicine. Then possibly eat the foods mentioned before every day, taking into account the good condition of the abdomen. In fact, if it is not relaxed, it will be necessary to use all types of boiled food: and among vegetable chard (Beta vulgaris L.), mallow (Malva sylvestris, L.), dock plant (Rumex obtusifolius), male mercurial herb (Mercurialis sp. L), the soft part of the thistle (Cirsium vulgare (Savi), Ten.); drink chicken broth with sea shells. If, on the contrary, the abdomen is relaxed, these foods are not necessary; but, once the pain has calmed, bread and meat will be allowed. The best foods, in this diet as in all others, are a small quantity of bread and a moderate diet, if the aim is to regulate the status of the belly, choose among the above-mentioned things.

  1. SALTING

As for salting, adopt those of Pont or those of Cadiz. Otherwise, just salt the food in any other way.

16. WALKS AND WAKEFULNESS AFTER A MEAL

You have to walk or rest; in fact, when it comes to sleeping (immediately) after taking a meal, as for humidity, I am not in favor. After eating one has to walk or rest; after all, if one wants to take a nap, do it before the meal. This is the rule to follow for gout sufferers. We are not obliged to provide a complete detail, we should not at all blame ourselves for not having described everything about the diet and treatment. It was enough for us to remember the medical advice set out above.

17. CATHARTICS

As for cathartics, those that should be administered to gout sufferers will be identified as follows. I consider it excellent for the gouty patient to be purged twice a year. First he will purge himself at the beginning of spring, before the humors boil and pour into the joints, and the second time in autumn, at the time of the Pleiades, before the first cold temperatures cause blood to freeze. Purge with remedies that eliminate mucus and bile. These humors must therefore be eliminated with cathartics that are beneficial to gout sufferers. As for the medicines that eliminate the liquid humors in gout sufferers, immediately after use they seem to calm the patients well, but afterwards they do them more harm (than good) since they cause extreme emaciation or wasting.

18. DRUGS THAT SHOULD NOT BE ADMINISTERED TO GOUT SUFFERERS AS PURGATIVES

Scamony (Convolvulus scammonia L.), tithymallus (Euphorbia amygdaloides L.), wild vine (Vitis sylvestris Gmel.), euphorbia (Euphorbia helioscopia L.), Cnidus berry (Chrozophora tinctoria L., A. Juss.), and similar medicines.

19. USEFUL PURGATIVES FOR GOUT SUFFERERS

You will give gout sufferers especially up to two drachmas of black hellebore (Helleborus cyclophyllus R.Br.), to which you will add a light dose of salt and berries of spurge flax (Daphne gnidium L.). This medicine moderately eliminates phlegm and bile. You will also give some polypody  (Polypodium vulgare L.), a plant that moderately eliminates phlegm and bile; you will have to take a dose of 2 drachmas, because it purges very gently. If you want to make a decoction of black hellebore (Helleborus cyclophyllus R.Br.) and administer it, it will be fine, likewise the polypodium. An excellent laxative for gout sufferers is still the internal part of coliquintide (Citrullus colocynthis Schrad.), at a dosage of 4 drachmas, sprinkled with honey wine or water. This medicine eliminates acidic humors, even after their resolution. Moreover, in nervous disorders none of these remedies will be harmful.  For my part, I know an excellent recipe for gout sufferers; it is made up of internal part of the coliquintide, 20 drachmas; oyster mushroom (Pleurotus ostreatus, Jacq.) 10 drachmas; wall gemander (Teucrium chamaedrys, L.), 10 drachmas; panax (Opopanax, L.) juice, 8 drachmas; silphium (extinguished plant), 8 drachmas; asafoetida (Ferula assa-foetida, L.), 8 drachmas; wild parsley (Anthriscus sylvestris, L.) 5 drachmas; round aristolochia (Aristolochia, rotunda, L.), 5 drachmas; white pepper (Piper nigrum L.), 5 drachmas; cinnamon (Cinnamomum, sp.), 4 drachmas; spikenard (Nardostachys jatamansi DC.), 4 drachmas; myrrh (Commiphora Myrrha Engl.), 4 drachmas; saffron (Crocus sativus L.), 4 drachmas. Add enough honey, mix everything together. You must take this drug frequently. It is therefore not necessary to administer these medicines at once, but first of all take care to give them at intervals, at a maximum dose of 4 drachmas, in honey wine or water. You will add a spoonful of salt, which helps to purge better, more quickly and more easily. These are the laxatives for both gout sufferers and arthritic people.

  1. REMEDIES THAT PURIFY WITH VOMITING

The best purifier for inducing vomiting is white hellebore, but I do not think it is necessary (to use it). It must be avoided as it is extremely harmful; and, if it is necessary to take it, let it be done before the disease has fully developed. At the slightest sign of small danger, try a gentler medicine to induce vomiting, such as narcissus bulb (Narcissus poeticus L), which is completely harmless and is taken in the form of a decoction; or even staphysagria (Delphinium staphisagria L.) triturated in honey wine, in a potion at a dosage of 15 grains. Another excellent medicine is garden cucumber (Cucumis sativus L.), mixed with staphisagria (Delphinium staphysagria L.), as it slightly impedes breathing. When there is pain in the feet, and (usually) if gout mainly affects the lower limbs, purging the humors by vomiting is more effective; if it affects the upper limbs, it is better to eliminate the humors through the gut.

21. VOMITING

As with other diseases, I recommend vomiting for gouty patients, and I also recommend that they provoke it often. But in this case it must be after the meal. Give a decoction in the water in which you cook oregano (Origanum vulgare L.) at the dosage of 3 cups, mixed with oxymel. Let them drink hyssop (Satureja graeca, L.), or thyme (Euphorbia chamaesyce, L., thymus Sibthorpii (LSJ.) or horseradish (Armoracia rusticana L.), taken separately, and soaked in salted oxymel. Should one decide to vomit after a meal, when pain has almost subsided, it requires appropriate attenuation, and everything that the patient wants must be given to him before the meal, so that he can take additional foods afterwards: these are the conditions under which vomiting shall be used.

22. ON ACRID FOODS AND OTHER FOODS

One shall eat horseradish, onions, pickles, mustard and vegetables, fatty butchered meat, fatty fish, pastries made with cheese, honey and oil. Finally, poultices will be given on an empty stomach, then vomiting will be caused, so that the belly returns what it has absorbed. Whether the patient is walking or resting, one should invite him to drink a bit [a broad bean amount] of absinthe (Artemisia absinthium L.) juice in 3 cyathi of water (1 cyathus 35 ml). Why do I prescribe drinking absinthe? Because I find that this plant (wormwood) aids digestion and is a good diuretic, a double result to aim for when treating gout, because there is a close relationship between the colon and the joints.

  1. GOUT MAY ORIGINATE IN THE COLON

Many people with a deep, long-lasting articular ulcer die of diarrhea. A large number of them, who complain of pain in the intestine, experience severe pain in the joints. Therefore, do not neglect digestion, or the gas that can continually arise in this type of patient; their persistence is a danger.

24. REMEDIES SUPPRESSING FLATULENCE

It is useful, in this case, to take those (medicines) that help pass gas. These are rue (Ruta graveolens, L.), cumin (Cuminum cyminum L.), anise (Pimpinella anisum L.) and dill (Anethum graveolens, L.). These plants are taken in the form of a decoction. It is also advisable to apply oil-based lotions to the belly or to perform dry rubs with a lambskin.

25. ON CLYSTERS

I also recommend enemas for gouty people, especially those whose stools are hard. For what purpose? In order to release substances that damage the joints. We must therefore prepare enemas that have the purpose of evacuating, or some other (similar) remedy. Common enemas are simple, others are pharmacological; I especially indicate those that are related to the disease (which is in question); and in fact they are the ones that will only evacuate the feces; because other diseases require other drugs (via clysters). I think hot enemas used by ancient doctors had scarce effect. Here then are medicated enemas: water, in which a decoction of coloquintis (Citrullus colocynthis, Aschrader), black hellebore (Hellebore niger L), absinthe (Artemisia absinthium, L.), southernwood (Artemesia abrotanum, L.), centaurea (Centaurea, L.), rue (Ruta graveolens, L.), hyssop (Satureja graeca, L.), iris (Iris florentina, L.), common corn-cockle (Agrostemma githago, L.), garden cress (Lepidium sativum, L.); add more saltpeter than salt and more salt than in the other enemas and also greater amounts of honey, but smaller amounts of oil, and it should be old. However, when you deem it appropriate to use this clyster, it is necessary to precede it with a mild enema. Then you’ll have this done, which is acid. In fact, it is necessary, first of all, to take into account the strength of the patient, and an evacuation that is too abrupt is always bloody. After this the patient shall drink milk to soften the intestines affected by corrosion. Attention must be paid to the diet. These clysters always greatly relieve people whose upper joints are diseased, or who have prolonged pain in the loins, and who suffer from sciatica; but those whose gout affects the lower joints experience less relief.

26. MEDICINES ADMINISTERED ORALLY

There is also another treatment method that involves medicines taken in potions. I know, in fact, that people suffering from sciatica and gout have been relieved from gout by these potions, and that some of them have helped dissolve viscous concretions. However, one should not expect prompt or immediate relief from this treatment: these remedies act slowly because the condition is not acute and does not progress rapidly. Therefore, drunkards receive a decoction of chamomile (Matricaria chamomilla, L.), cinquefoil root (Potentilla reptans L.) or helichrysum (Helichrysum orientale L.) heads; a decoction of alpine fennel (Foeniculum vulgare Gaertn.), taken in a potion, is also effective; the same goes for St. John’s wort (Hypericum crispum, L.), nutmeg (Nigristica fragrans Houtt), and camedrio (Teucrium chamaedris, L.); the amanita (Amanita caesarea Pers.) is the most effective; drink it in the oxymel at a dose of two obols. Wild spikenard (Nardostachys jatamansi DC.), decoction offers the same benefit and increases urine output; its effect is very immediate; it consists of facilitating the disposal of dense humors that stagnate, dissolving concretions and eliminating viscous humors.

  1. COMPOSITE MEDICINES AGAINST GOUT

We find yet other composite potions. First of all is the centaury potion, which includes: centaury (Centaurea centaurium, L.), gentian (Gentiana lutea, L.), round aristolochia (Aristolochia rotunda, L.), 4 pounds of each; leek (Allium porrum, L.), wild parsley (Petroselinum hortense, Hoffm.), cumin (Cuminum cyminum, L.), scordio (Teucrium scordium, L.) or wall germander (Teucrium chamaedrys, L.), 3 pounds of each; honey, 6 pounds; prepare and use. 

Here is another one, rue, which includes: gentian, round aristolochia (Aristolochia rotunda, L.), 4 drachmas of each; centaurea (Centaurea centaurion, L.), wall germander (Teucrium chamaedrys, L.), 14 drachmas of each; wild rue (Ruta graveolens, L.) seeds, 2 ounces; honey, 5 pounds; prepare and use. 

There are still other potions recommeneded by the author of Aucistae (unknown author) who in his Medicinal Preparations writes: wall germander (Teucrium chamaedrys, L.), 10 obols; round aristolochia (Aristolochia rotunda, L.), 9 obols; gentian (Gentiana lutea, L.), 8 obols; absinthe (Artemisia absinthium, L.), 7 obols; centaury (Centaurea centaurion, L.), 1 pound; St. John’s wort (Hypericum crispum, L.), 5 obols; valerian (Valeriana celtica, L), 4 obols; alpine fennel (Foeniculum vulgare, Gaertn.), 3 obols; wild parsley (Petroselinum hortense, Hoffm.), 2 obols; agaric (Polyporus, sp.); a sufficient amount of honey. 

Other potion: germander, gentian, centaury, aristolochia, wild parsley, wild lavender (Santolina chamaecyparissus, L.), agaric (Polyporus, sp.), cyclamen (Cyclamen graecum, Link), 3 [pounds of each], cyperus (Cyperus papyrus, L.), 1 pound; flaxseed (Linum usitatissimum, L.), 5 ½ pounds; aloe, 5 ½ pounds; a sufficient amount of honey. 

Other: germander, gentian, aristolochia, centaury, rue, of equal weight; a sufficient amount of honey; to be taken at a dose of 2 drachmas. 

Other: Agaric given once a day has an excellent effect. The sacred medicine, taken once a month, purges well; or even thyme (Thymus sibthorpii) and rhubarb (Rheum ribes, L.) flower powder; give two scruples once a day in wine with honey, or in anointings, and in all the ways in which it may be suitable. 

Other: spikenard (Nardostachys jatamansi, DC), 9 scruples; rhubarb, 1 ½ servings; round aristolochia, 6 obols; gentian, 3 obols; myrrh, 6 oboles; refined bay berry (Myrica rubra, Lour.) 1 pound; dose, 2 scruples. 

Avoid anything that is not useful. Above all, it is necessary to fully understand which foods are to be prescribed. One should not abruptly give up a potion after having taken it only once; I’m not convinced that we should stop taking the diuretics we are used to take, but we must eliminate them gradually, otherwise we expose ourselves to apoplexy or some other incurable disease, as I learned what happened to a certain Clemmagniti (as in the original text and untranslatable), stricken by gout, he took the centaury potion; then, feeling relieved, he interrupted the treatment: he soon felt spasmodic pain, and ultimately succumbed to cerebral apoplexy, resulting in his passing. I also know another patient who fell victim to the same misfortune; only that, since he was moody, he purged himself often and recovered; then, having suddenly stopped the enemas, he died. It is therefore necessary to gradually eliminate the sedimented humors, for fear that these very harmful substances, remaining in the body, as a result of their accumulation, could suddenly cause the patient’s demise.

28. ONE SHOULD NOT SUDDENLY STOP TAKING POTIONS

The best thing therefore, I repeat, is not to suddenly forego the composite potions of the aforementioned medicines. But if it is believed that the patient has taken enough, assuming that it is not yet convenient to have his usual drink, it is necessary, in this case, to no longer take the same amount of potion, or to take it every day, but it is necessary to reduce the dosage systematically and not eliminate it all at once.

29. TREATMENT METHODS

Is it good to change purgatives? Should the patient be purged with stronger remedies? If there really is an excess of blood, it is necessary to bleed and induce vomiting, even when these methods do not relieve the pain; and in fact one cannot do without resorting to anointings and other treatments. Therefore, treatment methods are always harmful if the interruption of their use is too abrupt. Having made this recommendation, it is following the advice of the experts that I have indicated the treatment and diet, and, if you ask me for my opinion, (I will answer) I do not attribute the same effectiveness to all the prescriptions I have provided.

30. ANOTHER WAY TO TREAT GOUT

There are various commendable ways to cure this serious disease; we recommend them for gout in the joints of the feet; I also recommend making an incision in the vein under the sole, as when varicose veins affect the thighs or tibia. In fact, these parts can be seen to swell slightly at the beginning of the disease, then more seriously. If the vein receives a deeper incision, the blood within can no longer be renewed, because there is inflammation, especially when the gout originates from the plethora, in this case diagnosis is based on redness around the foot, formation of nodules on the same part, enlargement of the veins, inflammation of the entire foot accompanied by pain and relieved by cold compresses. When the disease affects other joints, the vein is not visible. Otherwise it must be incised.

  1. ON CAUTERS AND ULCERS TO BE CREATED BY AFFIXING THEM ON JOINTS

It is also necessary to create ulcers on the joints, especially those caused by cauteries, or, in the absence of these, by medications. It is better to use cauteries, because they burn more penetratingly and more dryly. We must ensure that the joint thus burned does not heal too quickly. In some cases, it is best not to let the sores heal.

  1. ANOTHER WAY OF HEALING WITH ANOINTINGS AND POULTICES

There is another way to cure. For gouty people, a choice must be made among drying remedies; if they are very effective, causing excessive dehydration, after having dried up the fluid humor, they give rigidity to the dense humor and produce calluses. Erasistratus prescribed bringing the activity of the humors to the joints, in order to repress the plethora. So, here are the remedies to use: there are liniments, especially those that are spread on linen and applied in this way; then all the desiccants. There is also a soothing preparation composed of sulfur and vinegar, alum, heather leaves crushed with gall, myrrh (Commiphora myrrha Engl.) and vinegar. Apply this preparation on the affected parts, i.e. the elbows, arms, knees, thighs, feet, shins and other similar parts where the pain occurs. These substances prevent congestion from affecting the joints. We also mention drying poultices, hicésium, diaitéas, and all those composed of bitumen, tar and calamine. This is sufficient on anointings and liniments. In the absence of soothing, you can resort to dry rubs and sprinkle with mustard or watercress flour; in fact these remedies are of great help, provided they are not used differently than before the depletion.This is the cure I have to prescribe for all joint affections, and I believe I can guarantee recovery to anyone who will tolerate it, and will not be stopped by weakness or negligence.

  1. TREATMENT TO BE FOLLOWED WHEN THERE ARE COMPLICATIONS OF RHEUMATIC PAIN

Now we have to talk about remedies against rheumatic pain and against inflammation of the joints. It is necessary to calm them down immediately with proper methods; indeed, for some diseases, it is enough to administer low-dose emollients. It is therefore a question of applying them to pain; but, first, an emollient enema must be carried out to empty the abdomen, then, in the first days (of treatment), abstinence from drinking and eating is prescribed. If the patient has a full stomach when the pain begins, make him vomit; if there is an observable excess of body fluid, bloodletting [is indicated]. Extreme methods decrease foot inflammation.

34. COOLING OF THE JOINTS

If the joints need to be refreshed, make a poultice of either crushed celery (Apium graveolens L.) with bread or euphorbia peplis (Euphorbia peplis L.). For this, you can also use knotweed (Polygonum aviculare, L.), poppy (Papaver somniferum L.) leaves, black-fruited nightshade (Solanum nigrum, L.), parietaria (Parietaria officinalis L) or poison nut (Strychnos nux vomica L.), cupwort or Venus navel (Omphaloides linifolia L.), henbane (Hyoscyamus, L.), plantain (Plantago, L. sp.), verbena (Verbena L.) leaves and the head of hemlock (Conium maculatum L.). All these plants must be mixed with bread, as aforementioned. However, it is better to mix the old poultices with fine flour. If you use this flour alone in vinegar, apply this mixture as a poultice. Grinding the flour with the juice of the aforementioned plants, to render it soothing is also a good prescription. We also mention the juice of saffron (Crocus sativus, L.), celery (Apium graveolens, L.), sea buckthorn (Hippophae rhamnoides L.), fleawort (Plantago psyllium L.) and other similar plants. It is not a bad idea to apply gauze soaked in rose oil and water. Do not exaggerate in cooling, because intense cooling transfers the inflammation inside, resulting in relaxation of the swollen joints, a resurgence of pain and inflammation that is localized inside. 

35. HEATING POULTICES

When the patient finds comfort in warmth, a poultice made of bread and wine with cooked honey, cooked barley (Hordeum vulgare, L.), or linseed (Linum usitatissimum L.) and fenugreek (Trigonella foenum-graecum, L.) should be applied. Even better is a fig decoction prepared with these plants. Additionally, a poultice of crushed figs (Ficus carica, L.) with wine can be used. Always prepare a good poultice using cleaned and stripped vetch in wine with cooked honey, and the same applies when using tares flour.

  1. [REMEDIES] AGAINST VERY MOIST GOUT

For those who have moist joints, use drying medicines, such as Nile grass (Cyperus L.) cooked in honey, garlic in vinegar, and bitumen cooked in barley flour. These are the most active remedies. Now here are the ones that are sweetest. Dehydration is moderated with a poultice of pan-fried lentils and flour mixed with honey; or leek (Allium porrum, L.) mixed with goat fat, applied as an emollient poultice. Make a mixture of two parts of marine heliotrope (Heliotropium curassavicum L.) and one part goat fat, and apply the poultice. If the medicine is too dry, add egg yolks. There is also a poultice composed of goat or sheep fat mixed with goat and crocodile dung.

37. FOMENTATIONS [hot moist substances to ease pain]

When the joints are relaxed and the humors are diffused, turn to astringent fomentations, such as a decoction of leaves or willow bark (Salix, L. Sp.), rush (Juncus, L.), myrtle (Mirtus communis L), cypress (Cupressus sempervirens, L.), live sulfur mixed with a quantity of mildly hot vinegar using these medications, avoid joint stiffness. For this reason I find it useful, after using fomentations, to slowly cool and apply very fatty liniments. Patients must remain completely at rest during the period of inflammation. This is the treatment for gout when there is inflammation.

 

Summing up the De podagra

Gout is a disease caused by excess humidity that can be cured. However, when it becomes chronic, healing is impossible, and the patient’s condition worsens, potentially leading to death from pleuropneumonia or apoplexy. Therefore, it is important to be aware of the clinical course of the disease so that the appropriate remedies can be identified and applied from the very beginning.

During the acute attack, when the disease affects feet and hands, individuals with gout experience the most severe nerve pain. The disease is caused by bile and phlegm, an excess of blood, and plethora.

Treatment must be immediate. Fasting is appropriate to reduce blood production. “Bleeding may be of great help”. “Strong generic exercises of desiccant nature to dehydrate the body”. “Easily digestible food” should be allowed. Massages using aged oil infused with iris or hypericum are the most appropriate. They should be applied directly to the areas where the pain is most intense. Baths do not cure the disease but may help fight fatigue. The addition of salts increases dehydration. Swimming in sea water is recommended since this exercise improves the joints. Immersion in warm water or in hot sands, the use of steam baths and rubbing the entire body with ointments containing iris or privet are beneficial since they increase perspiration.

Eating vegetables does not help except for those that soften the belly. Very dry fish as well as soft-fleshed fish are recommended. Additionally, birds are recommended, except for those that live in water or marshes. Red wine is also allowed but not indispensable. During the acute attack, water should be preferred to wine, eggs rather than meat. When cold provides relief, wine mixed with honey should be allowed.

The condition of the bowel must be checked and if not loosened, some vegetables such as card, mallow, dock plant, male mercurial herb may be used. The best nutrition is based on small quantities of bread and a moderate diet. Once pain subsides bread and meat will be allowed. Foods should be salted: any salt, but preferably, that from the Pontus or Cadiz. No sleep should be taken immediately after eating, as it increases humidity. If a nap is needed, it can be allowed before eating.

Purges are important remedies for the gouty sufferers, who should be purged in spring and autumn. Purges eliminate bile and phlegm. However, during an acute attack, their use must be limited in time since they may cause wasting. Some purgatives can harm individuals with gout, including scammony, tithymal, wild vine, euphorbia, and Cnidus berries. However, the list of useful purgatives is long and includes hellebore, polypodium, and coloquintide. Drugs causing vomiting are helpful and should preferably be used, especially those based on harmless substances like Staphysagria or Narcissus. Inducing vomiting gives excellent results in gouty patients and should be practiced frequently, preferably after meals. So, patients may eat “horseradish, onions, pickles, mustard, vegetables, fatty butchered meat, fatty fish, pastries made of cheese, or honey” and immediately afterward, induce vomiting.

In gouty persons, intestinal pain is frequent. Thus, flatulence must be suppressed by means of rue, cumin, anise and dill. Enemas are also recommended since they evacuate substances that damage the joints. Enemas may be simple or pharmacological like those containing coloquintis, hellebore, hyssop and centaurea.

Potions may be used successfully; some of them can even dissolve tophi. They generally act slowly but effectively. Many composite medicines are available for treating gout; however, one should be cautious about stopping those potions suddenly. When an excess of blood is diagnosed, bleeding and vomiting are necessary manoeuvres, even if ineffective on pain.

In some patients, cautery should be applied to the joints to create deep, dry ulcers that must persist for a long time to be effective. Anointing poultices may help in the acute attack. In case of complications, the abdomen should be emptied, no water or food should be allowed, and if the stomach is full, the patient should vomit.

The armamentarium of plant-based drugs to refresh (cool) the joints is vast, but one should not exaggerate. Heating poultices are also advisable if warming the joints relieves pain.

Very important are the remedies for very moist gout (edematous). For this purpose, astringent fomentations should be used.

 

Discussion

On humors

Rufus adopted the theory of humors and based his explanations on blood, bile, phlegm (white, thick, and salty). Bile was described as yellow, greenish-yellow, green, or black. Bile originates from the gall bladder, and phlegm from the nose.

Rufus classified bile and phlegm as “perissoma”, like mucus, saliva, urine, gas, menstrual blood, earwax, milk, and semen. It should be noted that Aristotle also classified bile and phlegm as “perissoma”, but he did not include saliva and earwax in this category; instead, he included feces and blood [20].

Humors originate from food. When humors are in good balance, health is maintained, when they are out of balance disease results. Black bile, associated with autumn, may originate from blood due to long-standing imbalance. Everything can be explained by deficiency or excess, satiety or fasting, and working in hot environments. Some foods generate specific humors. Generally speaking, an excess of food produces an excess of blood; excess cheese increases phlegm; milk contributes to phlegm and bile; and wine and pomegranate increase blood.

Black bile is a permanent presence in the liver and is drawn into the spleen. When the spleen is unable to attract it, jaundice supervenes, which is different from jaundice associated with yellow bile. Cooling the blood and overheating can generate black bile and yellow bile.

There are four qualities, namely hot, cold, dry, and moist. An excess of humidity or a lack of dryness causes an excess of bile and can lead to pain, as in the case of gout. Some fish, such as tuna and eels, cause mucus (phlegm) production. Thyme discharges bile, which, after collecting in the gallbladder, travels to the kidney and intestines, thereby coloring urine and feces.

Excess humidity and lack of dryness cause pain in gout. Therefore, exercises were recommended to dissolve the humidity, which can even result from abandoning exercise or reducing it.

Exercise has a great role in the treatment of gout. I would like to focus on the role of exercise in the therapy of gout. Arthralgia is driven by excess humidity. Thus, it is important to exercise to dissolve it and even to prevent its formation by avoiding late-night meals when fluids are attracted to the body. Rufus removes the excess of blood by venesection, combined with abstinence from food to reduce blood formation, and uses clysters to remove any additional excess fluid.

Rufus’ therapy of gout

The therapy of gout is based on bleeding, fasting, foods, exercise, baths, reducing humoral production, and removal of their excess.

To this end, Rufus makes full use of plant-based remedies (see Table 2). Nutrition during an acute attack centers on the use of chard, mallow, dock, mercurial herbs, and thistle. He uses purgatives to soften the belly, emetics before and after meals (with the latter preferred), laxatives, and enemas that may be prepared from many useful plants such as hellebore, abrotan, absinthe (which is diuretic and aids digestion), centaurea, hyssop, iris, rue, thyme, and watercress. Massages are necessary to reduce the excess humidity, complemented by walking, running, riding, exercises. Napping after a meal is discouraged since it promotes the retention of humidity. During an attack, water should be preferred to wine and fish to meat. An extensive list of plants useful for cooling joints is provided (Table 3). Rufus also suggests being careful to avoid stopping treatment too early, as the disease may recur. Venesection should be practiced near the point of pain. However, it is less effective when the foot is affected.

Concerning bleeding after the initial venesection, it should be immediate if there is an excess of blood. The procedure may be repeated annually in spring and autumn. Suggestions regarding nutrition are more qualitative than quantitative; specific recommendations are provided, but no exact quantities are given.

For the therapy of gout, Rufus also made full use of compound preparations of major use, which are described in Table 4. The list highlights the importance of their knowledge, which had passed the scrutiny of Rufus’s clinical skills.

Common Name Scientific name Use
Chard Beta vulgaris L. nutrition during attack
Mallow Malva sylvestris L. nutrition during attack
Dock plant Rumex patientia, L. nutrition during attack
Male mercurial herb Mercurialis ssp. nutrition during attack
Thistle (soft part) Cirsium vulgare (Savi), Ten. nutrition during attack
Spurge flax (berries) Daphne cnidium L. Purgative
Black Hellebore Helleborus niger L. Purgative
Polypoly Polypodium vulgare L. Purgative
Coloquintide Citrullus colocynthis Schrad Purgative
Common corn-cockle Agrostemma githago L. Purgative
Garden cress Lepidium sativum L. Purgative
Narcissus (bulb) Narcissus poeticus L. emetic
Staphysagria Delphinium staphysagria L. emetic
Cucumber Cucumis sativus L. emetic
Oregano1 Origanum vulgare L after meal emetic
Hyssop Satureja graeca, L after meal emetic
Thyme2 Thymus sibthorpii (LSJ). after meal emetic
Horseradish2 Armoracia rusticana L. after meal emetic
Absinthe Artemisia absinthium L. digestive, diuretic
Rue Ruta graveolens L. suppressing flatulence
Cumin Cuminum cyminum L. suppressing flatulence
Anise Pimpinella anisum L. suppressing flatulence
Dill Anethum graveolens L. suppressing flatulence
Chamomille Matricaria Chamomilla L. Laxative
Cinquefoil (root) Potentilla reptans L. Laxative
Helichrysum (heads) Helichrisum orientale L. Laxative
Alpine fennel Foeniculum vulgare Gaertn. Laxative
St. John’s wort Hypericum crispum  L. Laxative
Nutmeg Myristica fragrans Houtt Laxative
Camedrio Teucrium chamaedrys L. Laxative
Amanita Amanita caesarea  Pers. Laxative
Spikenard (Wild) Nardostachys jatamansi DC Laxative
Myrrh Commiphora myrrha Engl. Laxative
Hellebore (black) Hellebore niger L. for enemas
Abrotane Artemisia abrotanum L. for enemas
Absynth Artemisia absinthium L for enemas
Centaurea Centaurea L. for enemas
Hyssop Satureja graeca L. for enemas
Iris Iris florentina L. for enemas
Rue Ruta graveolens, L. for enemas
Throw Agrostemma githago L for enemas
Watercress Lepidium sativum sp. for enemas
Table 2. Plants used by Rufus of Ephesus for therapy of gout (foods, purgatives, emetics, laxatives, drugs against flatulence and for enemas). 1cooked in water associated with oxymel; 2taken separately and mixed with oxymel
Common name Scientific name Use
Iris Iris florentina L. massage
St. John’s worth Hypericum crispum L. massage
Larch (added to pork fat) Larix decidua Mill. massage
Privet Ligustrum L. massage
Chaste tree Vitex agnus-castus L. to medicate water for baths
Laurel Laurus nobilis L. to medicate water for baths
Myrtle Myrtus communis L. to medicate water for baths
Sage Salvia officinalis L. to medicate water for baths
Willow (tender leaves) Salix L. to medicate water for baths
Celery3 Apiumgraveolens L. cooling the joints
Euphorbia peplis3 Euphorbia peplis L. cooling the joints
Fleawort4 Plantago psyllium, L. cooling the joints
Nightshade(black) Solanum nigrum L. cooling the joints
Nux vomica Strychnos nux vomica L. cooling the joints
Pellitory (erect) Parietaria officinalis L. cooling the joints
Poppy (leaves) Papaver somniferum L. cooling the joints
Saffron Crocus sativus L. cooling the joints
Venus navel Omphaloides linifolia L. cooling the joints
Cperus Cyperus L. edematous gout
Garlic Allium sativum L. edematous gout
Green Heliotrope Heliotropum arborrescens L. edematous gout
Leek Allium porrum L. edematous gout
Lentil Vicia lens L. edematous gout
Cypress Cupressus sempervirens L. inflammation
Myrtle Mirtus communis L. inflammation
Willow (leaves, bark) Salix, L. inflammation
Barley (cooked) Hordeum vulgare L. heating poultice
Fig (crushed) Ficus carica L. heating poultice
Fenugreek Trigonella foenum-graecum L. heating poultice
Linseed Linum usitatissimum L. heating poultice
Myrrh Commiphora myrrha Engl. soothing poultice
Table 3. Plants used by Rufus of Ephesus for therapy of gout (for massage, to medicate water for baths, to cool and to heat joints, edematous joints, inflammation). 3used in association; 4mixed with fine flour.
Common name Scientific name
Absynth Artemisia absinthium L.
Agaric Polyporus sp.
Aristolochia (round) Aristolochia rotunda L.
Bayberry Myrica rubra Lour.
Centaury Centaurea centaurium L.
Cyclamen Cyclamen graecum Link
Ciper Cyperus papyrus L.
Cumin Cuminum cyminum L.
Fennel (alpine) Foeniculum vulgare L.
Flaxseed Linum usitasissimum L.
Gentian (lutea) Gentiana lutea L.
Gentian (purpurea) Gentiana purpurea L.
Germander Teucrium chamaedrys L.
Lavender (wild) Santolina chamaecyparissus
Leek Allium porrum L.
Parsley (wild) Petroselinum hortense Hoffm.
Rhubarb Rheum ribes L.
Rue Ruta graveolens L.
Scordio Teucrium scordium L.
Spikenard Nardostachys iatamansi DC
St. John’s wort Hypericum crispum L.
Thyme Thymus sibthorpii LSD
Table 4. Plants used by Rufus of Ephesus for compound medicines for gout.

On Hiera Rufi

In Chapter 19 of the Oeuvres de Rufus d’Éphèse,  lines 10-12 on page 325, and lines 1-9 on page 326, read:

“Maximum autem ego scio et manifestum adjuntorium ad artriticos esse quod recipit colocynthidis interiores, agarico, chamaedrys, opopanacos, opu cyrenaicu, sagapenu, petroselinu, aristolochiae rotundae, piperis alba, cinnamomu…”

“For my part, I know an excellent remedy for gout sufferers; it is made from the internal part of the coliquintide (Citrullus colocynthis L.), 20 drachmas; oyster mushroom (Pleurotus ostreatus Jacq.) 10 drachmas; wall gemander (Teucrium chamaedrys L.), 10 drachmas; panax (Opopanax L.) juice, 8 drachmas; silphium (extinguished plant), 8 drachmas; asafoetida (Ferula assa-foetida L.), 8 drachmas; wild parsley (Anthriscus sylvestris L,) 5 drachmas; round aristolochia (Aristolochia rotunda L.) 5 drachmas; white pepper (Piper Nigrum, L), 5 drachmas; cinnamon (Cinnamomum sp.), 4 drachmas; spikenard (Nardostachys jatamansi DC.), 4 drachmas; myrrh (Commiphora myrrha Engl.), 4 drachmas; saffron (Crocus sativus L.), 4 drachmas. Add enough honey, mix everything together. You must take this drug frequently. Therefore, it is not necessary to administer these medicines all at once, but primarily, ensure they are given at intervals, with a maximum dose of 4 drachmas, in honey wine or water. You will also add a spoonful of salt, which helps to purge more quickly, and easily”.

In the passage, Rufus provides remedies for treating individuals with gout and describes a complex preparation. He says “scio” that means “I know,” and describes an excellent preparation to treat gouty sufferers. He knows that it is effective but does not claim priority. However, Oribase, Aetius of Amida and Paul of Aegina refer to it as Hiera Rufi, the cathartic of Rufus of Ephesus. In particular Oribasius speaks of “Hiera of syconia taken from De podagra” (Hiera Rufi) [21].

As discussed extensively by Abou-Aly on pages 275-291 of his thesis [21] many Arab scholars including Avicenna and Al-Jazzar support the authority of Rufus and call the remedy “Hiera Rufi”. All of the discussions support the authority of Rufus. It is not surprising that as time passed this preparation was converted to pills (Pillulae Rufii) by Arabs.

On tophi

Tophi are formed in the joints by the flow of humors to the joints. The chronicity of the disease causes their thickening and transformation into concretions that may evolve from viscous to stony deposits. Tophi may also develop from the repeated use of desiccants, which over time can transform viscous material into tophi. The real concern is the formation of tophi by humors, which may be due to the desiccating properties of medicines used in the therapy of gout. The major risk resides in the use of drugs to counteract plethora.

As reported in Chapter 26, skilled physicians can assist their patients by prescribing medicines taken in potions, which, however, act slowly. “I know, in fact, that people suffering from sciatica and gout have been freed from gout by these potions, and that some of them have caused the resolution of viscous concretions. However, one should not expect prompt or immediate relief from this treatment: these remedies act slowly”.

 

Conclusion

The study shows that Rufus of Ephesus, the third most famous figure in medicine after Hippocrates and Galen, is celebrated for his contributions to obstetrics, gynecology, pediatrics, and neurology. As a gouty physician, he left a personal mark on the history of gout by making full use of his clinical skills, which were honed through a rigorous apprenticeship in anatomy and the study of the Corpus Hippocraticum.

 

Acknowledgements

We are grateful to Professor Joseph Sepe, University of Maryland Global Campus, for his editing support.

A special thanks is due to Dr. Rosaria Di Martino, Head of Centro Servizio del Sistema Bibliotecario di Ateneo Università degli Studi della Campania Luigi Vanvitelli for nurturing our interest in Rufus of Ephesus.

 

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  6. De Santo NG, Bisaccia C, De Santo LS. Gout: a papal disease-a historical review of 25 gouty popes (34-2005 AD). J Nephrol. 2021 Oct;34(5):1565-1567. https://doi.org/10.1007/s40620-021-01117-8
  7. De Santo NG, Bisaccia C, De Santo LS. High Prevalence of Kidney Stone Disease of Gouty Origin in Roman Pontiffs Reigning in the Years 537-2005. Experimental and Clinical Transplantation 2023 Jun;21(Suppl 2):91-94. https://doi.org/10.6002/ect.iahncongress.21
  8. De Santo NG, Bisaccia C, De Santo LS. Pius X (1835-1914): the last gouty pope. G Ital Nefrol. 2022 Feb 16;39(1):2022-vol1. PMID: 3519163
  9. Schwartz SA. Disease of distinction. Explore (NY). 2006 Nov-Dec;2(6):515-9. https://doi.org/10.1016/j.explore.2006.08.007
  10. Omran AR. The epidemiologic transition: a theory of the epidemiology of population change. Milbank Q. 2005;83(4):731-57. https://doi.org/10.1111/j.1468-0009.2005.00398.x
  11. McKeown R. The epidemiologic transition: changing patterns of mortality and population dynamics. Am J Lifestyle Med 2009;3(1 Suppl):19S-26S. https://doi.org/10.1177/1559827609335350
  12. De Santo NG, Bisaccia C, De Santo LS. Gout From the Corpus Hippocraticum to the Renaissance: The Role ofGalen. G Ital Nefrol. 2025 Apr 29;42(2):2025-vol2. Italian. https://doi.org/10.69097/42-02-2025-14. PMID: 40332982
  13. De Santo NG, Bisaccia C, De Santo LS. Gout in the Corpus Hippocraticum. G Ital Nefrol. 2025 Aug 29;42(4):2025-vol4. Italian. https://doi.org/10.69097/42-04-2025-10. PMID: 40923585
  14. De Santo NG, Bisaccia C, and De Santo LS. Alexander of Tralles, On Gout. In Manuscripts, Plants, Remedies inthe Mediterranean Traditions: Studies across Disciplines for Alain Towaide. Berlin, Walter De Gruyter,2025, https://doi.org/10.1515/9783110780062-010
  15. Bisaccia C, De Santo LS, De Santo NG. Timelines of the history of gout from the fifth Century BCE toRenaissance: the contributions of Rufus of Ephesus. Presented in part at the XIII Congress of the International Association for the History of Nephrology
  16. Littrè É. Traité de la goutte. In Daremberg CH et Ruelle É. Oeuvres de Rufus d’Éphèse texte collationé sur les manuscrits, traduits pour la première fois en français, avec une introduction. Paris: Imprimerie National 1879
  17. Suidae Lexicon, ed. Adler, pars IV, Leipzig, 1935, p. 301
  18. De Chambre. Rufus. Dictionnaire Encyclopedique des Sciences Medicales. Tome cinquiême, p. 587-588
  19. Daremberg CH. Ruelle É. Oevres de Rufus d’Ephèse. Paris Imprimerie Nationale 1879
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  21. Abou-Aly. The medical writings of Rufus of Ephesus. Ph.D. Thesis, University Medical College, University of London 1992. http://discovery.ucl.ac.uk (pdf)
  22. Albrecht von Hailer, Bibliotheca chirurgica qua scrita ad artem chiruraiam facientia a rerum initiis recensentur, I, p. 78
  23. Beck L:Y (2020). Pedanius Dioscorides of Anazarbus. Georg Olms Verlag: Hildesheim
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  25. Everett N. The Alphabet of Galen. Pharmacy from antiquity to Middle Ages. University of Toronto Press, 2012

Gout in the Corpus Hippocraticum

Posted on Scarica PDF

Natale Gaspare De Santo

DOI: 10.69097/42-04-2025-10

Natale G. De Santo1, Carmela Bisaccia2, Luca S. De Santo3

1 Emeritus Professor of Nephrology, University of Campania Luigi Vanvitelli
2 Istituto Mazzini
3 Division of Heart Surgery  University of Campania Luigi Vanvitelli and Monaldi Hospital, (all in Naples, Italy)

Corresponding author:
E-mail: natalegaspare.desanto@unicampania.it

 

Abstract

Gout is the oldest recorded form of inflammatory arthritis to affect humankind, with roots stretching back to 2640 BC and known in Greece by 1700 BCE. It is due to deposition of sodium monourate driven by hyperuricemia.
The association of humours with causation stems from Hippocrates (460-370 BCE). More specifically, a toxic humour was suspected by Celsus (25 BCE-50 CE) and Rufus of Ephesus (98-138 CE), and confirmed by Alfred Garrod in 1849.
Its therapy has been based on colchicine since Severus Iatrosophista, Theodosius the Philosopher, and Jacobus Psychrestos, introducing Colchicum as an innovative treatment for podagra in the early Byzantine period. A breakthrough in treatment was the introduction of allopurinol in 1966.
This study aimed to examine gout in the Corpus Hippocraticum. For Hippocrates, gout is a disease caused by bile and phlegm, not by the wrath of a god.  Gout is mentioned in the Corpus 20 times, and a total of five Aphorisms are dedicated to podagra. In Affections, “Gout is a disease that induces burning pains in the joints; it comes to paroxysms, now in one limb, now in the other, where it causes ailments of variable severity”. In Prorrhetics, it is described as a disease not amenable to cure in the elderly patients with tophi – a goal achievable in the young patient willing to adhere strictly to the therapy suggested by the physician.

Keywords: Gout, Tophi, Corpus Hippocraticum, Aphorisms, Affection, Prorrhetic II

Dedicated to the memory of Professor Simon Byl (1940-2018),

Belgian Hellenist at the Université Libre de Bruxelles.

On gout and joint diseases in the Corpus Hippocraticum

he knew and taught the most.

Introduction

“Gout (ποδάγρα/podagra): an illness which may appear in the upper limbs (cheiragra) or more commonly in the lower limbs (podagra) and is characterized by a red, hot swollen joint at the base of the big toe; it was thought to be caused mainly by an excess of yellow bile” [1].

The history of gout parallels that of the history of medicine. Gout is the oldest recorded inflammatory form of arthritis to affect humankind, with roots stretching back to 2640 BCE.  Kettridge and Downs by examining in 1957 an Egyptian mummy discovered a urinary stone dated 7000 years ago. Its nucleus was made of uric acid [2, 3].

Gout is a common, complex, systemic and well-studied form of chronic inflammatory arthritis in adults, for which many therapeutic options are now available. It is due to the deposition of sodium monourate crystals in peripheral joints and periarticular tissues driven by hyperuricemia (at or above 6.8 mg/dl). Hyperuricemias may result from: (i) renal overload (overproduction or extrarenal underexcretion due to dysfunctional variants of transporters in the gut and intestine); (ii) renal underexcretion; or (iii) a combination of both renal overload and renal underexcretion.

The kidney can be both a cause and a target of hyperuricemia (calculi, renal disease and its progression). At onset, gout affects one joint, frequently the metatarsophalangeal joint of the great toe that is self-limited, and heals in 2 weeks. Flares subsequently affect two or more joints. Gout becomes a chronic disease when tophi and joint erosions appear. Risk factors include conditions with high cell turnover, as well as a high intake of purine-rich foods (such as meat, crustaceans, alcohol, and fructose-containing syrup). Prevalence increases with age and women become hyperuricemic after menopause [4, 5].

Gout known as “the unwalkable disease” (Hippocrates), for which protection was granted by the Goddess Artemis Podagra (Clemens Alexandrinus), a disease with a heritable trait recognized by Galen, and by Aretheus. Soranus of Ephesus was the first who described tophi, later widely discussed by the Byzantine physician Alexander of Tralles (525-605 AD) who illustrated the virtues of hermodactyl. Its name derives from the Latin word gutta (meaning drop to indicate the drop of a humour in excess precipitating in the joint).

 

The goal of this study

This study aims to shed light on the contribution of Hippocrates to the knowledge of gout. It is a part of a program [6-9] on establishing the timeline of Podagra from the Corpus Hippocraticum to Renaissance, encompassing no less than 25 authors (Table 1).

Gout was present in Greece since 1700 BC [10]. Many mythological Greek heroes suffered with the gout: Priam of Troy, Achilles (as suggested by Lucian of Samosata), Bellerophon, Oedipus King of Tebe. Thus we are not surprised by its significant presence in the Corpus Hippocraticum.

Hippocrates (460–370 BCE)
Teophrastus (371-287 BCE)
Nicander (2nd century BCE)
Celsus (25 BCE–50 CE)
Aretaeus of Cappadocia (1st half, 1st century CE)
Scribonius Largus (1st century CE)
Dioscorides of Anazarbus (1st century CE)
Anonymus Parisinus (1st century CE)
Galen (c. 129–c. 216 CE)
Lucian of Samosata (c. 120–after 180 CE)
Oribasius (c. 320–400/403 CE)
Severus Iatrosophista (5th century CE)
Theodosius the Philosopher (5th century CE)
Jacobus Psychrestus (5th century CE)
Aëtius (mid-5th to mid-6th century CE)
Caelius Aurelianus (6th century CE)
Evagrius Scholasticus (6th century CE)
Paulus of Aegina (625–690 CE)
Rhazes (c. 854-925/935)
Avicenna (980–1037 CE)
Michael Psellus (1018–1078 CE)
Constantinus Africanus (floruit 1020–1087 CE)
Matthaeus Platearius (d. c. 1161 CE)
Demetrios Pepagomenos (13th century CE)
Nikolaus Myrepsos (floruit 1240–1280 CE)
John Actuarius (end of the 14th century CE)
Table 1. On the Timeline of Podagra from the Corpus Hippocraticum to the Renaissance.

 

Hippocrates’ short biography

Hippocrates (c.460-c.370), the father of medicine, was born in the age of Pericles, a bright period of prosperity, science and arts in Greece. He was born in Kos near the coast of Asia Minor. In the heart of the city, an Oriental Plane tree still stands, said to have provided shade for his public lectures.

“His contemporaries constituted perhaps the most remarkable galaxy of Genius ever known. They included Pericles, the statesman builder of Acropolis, the poets and playwrights Aeschylus, Sophocles, Euripides, Aristophanes, and Pindar, whose nephew was one of Hippocrates’ students, the philosopher Socrates with his disciples Plato and Xenophon, the venerable father of history (Herodotus) with his youthful rival Thucydides, the sculptor Phidias, and Chrysippus and Euryphon of Cnidos. Hippocrates’ writings are free of the prevailing superstitions which associated the cause of disease with divine wrath for sin, and much of contemporary therapy was magic” [11].

His grandfather (Hippocrates), and his father Heraclides – priest doctors – were descendant of Asclepius and passed down knowledge and skill to the family members, thus Hippocrates received medical training from them. Heleni Tsiompanou and Spyros Marketos [12] in a paper that appeared posthumous, after Marketos death, point out that Plato (Politics) calls him  ‘The great Hippocrates, the wise physician’,  whereas Aristotle calls ‘the famous physician of Kos’ (Protagoras).

Tsiompanou and Marketos also stress the fact that Hippocrates broke with the tradition of keeping the expertise in medicine within the family. He started the School of Kos where fellows received instruction for a fee [12]. We know very little about Hippocrates’ life. Probably he successfully diagnosed and treated, as court physician, King’s “love-sickness” in Macedonia, and cured Democritus’ madness in Abdera.

“Between 440 BC and 360 BC Hippocrates and his pupils wrote a number of medical  treatises,  only 60 treatises were saved from the fire that destroyed the Great Library at Alexandria. The surviving text were published under the title of Corpus Hippocraticum. Some of the texts may not be Hippocrates’own writings but all display his influence”. He died in Thessaly, in Larissa  [12].

He broke with the oral tradition and collected detailed reports of patients he cared for. He also introduced the need to review and analyze all pre-existing data. According to Hippocrates  ‘Full discovery will be made, if the inquirer be competent, conduct his research with knowledge of discoveries already made’ (Ancient Medicine).

 

Gout in the Corpus Hippocraticum

Simon Byl pointed out [13] that in the Corpus Hippocraticum joint diseases have been described as “arthritis, arthritika, arthron, ponoi, oidemata, and eparseis of the joints, kedmata and ischias”.

These conditions are attributed to an accumulation of phlegm linked to excessive food consumption. However, the text asserts “arthritis is not lethal” (On Diseases).

The Corpus Hippocraticum also differentiates gout from other joint diseases such as acute articular rheumatism and ankylosing spondylitis. Podagra (gout affecting the foot) was identified as the most severe form of joint disease, characterised as a chronic condition. It was noted to affect younger individuals more frequently than the elderly [13]. Gout is mentioned 20 times in the Corpus Hippocraticum, with specific references to podagra appearing 5 times. The terms podagrao and podagriao (indicating affliction with gout) are used 1 and 4 times, respectively, while podagrikos (relating to gout) appears 10 times. Additionally, Simon Byl observed that the corpus contains 314 references to the word arthron (joint). In the Corpus Hippocraticum, podagra associated with tophi is described as nearly incurable [13]. Even the most skilled physicians were unable to provide relief and cautioned against the use of drugs to relieve pain.

In Aphorisms, Hippocrates mentions gout 5 times [14].

  1. “Eunuchs do not take gout, nor become bald” (VI, 28);
  2. “A woman does not develop gout unless her menses be stopped” (VI, 29);
  3. “A youth does not get gout before sexual intercourse”(VI, 30);
  4. “In gouty affections inflammation subsides within 40 days” (VI, 49);
  5. “Gouty affections become active in Spring and Autumn” (VI, 55).

However, the importance of the seasons was rejected by many authors of antiquity including Galen, Celsus and Seneca. “Hippocrates also learned by experience that an excess of wine could exacerbate or even cause gout, as did an excess of sexual activity and that the disease was more severe in the inherited form than in those who contract it by their unsafe lifestyles” [13].

In Affections of the parts, the chapter on Stranguria, sciatica and gout reads (VIII, 32) reads:

“Gout is a disease that induces burning pains in the joints; it comes to paroxysms, now in one limb, now in the other, where it causes ailments of variable severity. Cool compresses will be applied where there is pain, the intestines will be cleansed of the materials found there by giving enemas and administering a suppository; use for drink and liquid food what seems best suited. Once the pain has calmed down, purge him and then have the cooked whey and donkey’s milk taken. Gout is caused by phlegm and moving bile, which rush over the joints”.

“It can be short, acute and is not deadly. It is more frequent in youth than in old age.

Pain in the feet [podagra] is the most violent of all, most long and resistant. It is the effect of a defect in the blood altered in the small veins by the pituitary gland and bile; the disease is all the more fixed and difficult to heal if it establishes itself in small veins and if the violence exerted on many nerves and bone parts is serious. It is treated with the same means used or joint pain. It lasts for a long time, is very painful but is not deadly. Whenever the pain fixes in the fingers, the burning fire is placed above the joint using raw flax”.

In Prognostics (Book 1, Chapter 4, 19), age and conditions required to recover from gout are discussed as for gouty persons, Hippocrates says:

“It is my opinion that the old, those who have lumps in the joints, which leads to a painful life, who are habitually constipated, all these people, I say, cannot absolutely be cured, at least with no human means that I am aware of. They feel relief from the work of the viscera when it occurs, and in general, the downward colliquation of the humours benefits them. The gouty person who is young and free from knots in the limbs, active, vigorous, whose abdominal functions are regular, capable of subjecting himself to the method prescribed by the doctor, can hope for recovery”.

“These complaints are better removed by the occurrence of dysenteries or other evacuations downwards. His principal remedies are purgatives administered by the mouth or by injection, and local applications of cooling nature, and even pouring cold water on the foot. When the pain of the gout becomes fixed in a joint, it directs us to burn it with crude flax”.

In Prorrhetic II, where tophi are described as epiporomata, we are made aware of the difficulties of healing the elderly who have lumps in the joints:

“Elderly gouty sufferers who have tophi around the joints and adopt unhealthy lifestyles and whose bellies are dry are beyond the possibility of the human art… they can’t be healed, at least not by any human means I am aware of.  They benefit from evacuations when they occur.

The young gouty sufferer free of tophi in the joints, who adopts a healthy alimentation, is vigorous and practices exercise, has regular bowel movements, and is vigorous and active and accepts to follow the prescription of the doctor, he can hope to be healed”.

 

Treatments

Treatment was based on appropriate nutrition, abstention from wine, drastic purges, preferably black hellebore (Helleborus niger L.). An attack of dysentery represented the best natural remedy for gout. Burning the area above the joints with raw flax was also a possibility.

“Both cold and hot water poured abundantly over those who have no painful ulcerative tophi are very useful”.“Cold water moderates the pain, numbing the part, since mediocre numbness is a sedative. Hot water attenuates and softens; lotions and baths are used in the case of gout” (Treatise on Liquids).Salt, the ubiquitous simple, has a crucial role in treating podagra and its pains. “Apply salt on the swollen parts, the salt having been mixed with water in a paste. The paste is left in situ for three days, and after its removal, the parts shall be rubbed with red saltpeter mixed with honey for the subsequent three days” (Disease of Women I).

The paper can be concluded with a passage from Affections (first quarter of the fourth century BCE):

 “Podagra is the fiercest, longest and most tenacious of all joint diseases; it occurs when blood present in the vein has been contaminated by bile and phlegm, and since these are the thinnest and tightest vessels of the body (the same applies to the neighboring tendons and bones), pain is thus the most intense in this area. The same cure as used for arthritis is suitable in this case; the disease is long and painful, but not lethal. If the pain does not subside in the big toes, then one will cauterize the toe’s vessels above the condyle and this cauterization will be performed with raw flax” [13].

 

Acknowledgements

We thank Dr. Rosaria Di Martino, Head of Centro Servizio del Sistema Bibliotecario di Ateneo Università degli Studi della Campania Luigi Vanvitelli and Coordinator Biblioteche di Ateneo, for her expert assistance in literature searches. We are also indebted to Professor Joseph Sepe for editing the English version of the manuscript.

 

Bibliography

    1. Petros Bouras-Vallianatos. Innovation in Byzantine Medicine, Oxford, 2020
    2. Talbot JH: Gout, ed 2. New York and London, Grune & Stratton, 1964
    3. Front Matter. Henry Ford Hospital Medical Journal 1979; 27(1): 14-17.Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol27/iss.
    4. De Santo NG, Bisaccia C, De Santo LS. High Prevalence of Kidney Stone Disease of Gouty Origin in Roman Pontiffs Reigning in the Years 537-2005. Exp Clin Transplant. 2023 Jun;21(Suppl 2):91-94. https://doi.org/10.6002/ect.IAHNCongress.21. PMID: 37496353.
    5. De Santo NG, Bisaccia C, De Santo LS. Kidney Stone Disease of Non Gouty Origin in 264 Popes (34-2005 AD): A Historical Review Clinics in Surgery 2021; 6(1): 1-10) https://doi.org/10.25107/cis-v6-id3307.
    6. De Santo NG, De Santo LS, and Bisaccia C. Timelines for the history of gout from the fifth century BCE to Renaissance. The role of Alexander of Tralles. 48th IHSM Congress, Slernoi 9-12, 2024, Joint Session of the International Association for the History of Nephrology and the International Society for the History of Medicine.
    7. Bisaccia C. Timelines for the history of gout from the fifth century BCE to the end of the fourteenthcentury CE: the contribution of Rufus of Ephesus. 48th Congress of the International Society for the History of Medicine, Salerno (Italy), October  9-12, 2024
    8. De Santo NG, De Santo LS, and Bisaccia. Gout from Corpus Hippocraticum to Renaissance. 1. Corpus Hippocraticum. XIII Congress of the International Association for the History of Nephrology, Naples, Italy, November15-17, 2024.
    9. De Santo NG, De Santo LS, and Bisaccia C. Alexander of Tralles, On Gout. In Plants, Remedies in the Mediterranean Traditions: Studies across Disciplines for Alain Touwaide. De Gruyter, Berlin 2025, in press
    10. Angel JL. The People of Lerma. Analysis of a prehistoric Aegean Population. Princeton & Washington, Smithsonian Institution Press, 1971, pp. 51, 89. 92
    11. Copeman WSC. A Short History of the Gout. Berkeley and Los Angeles: University of Californuia Presds 1964, pp.21-22
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    Gout From the Corpus Hippocraticum to the Renaissance: The Role of Galen

    Posted on Scarica PDF

    Natale Gaspare De Santo

    DOI: 10.69097/42-02-2025-14

    Natale Gaspare De Santo1, Carmela Bisaccia2 and Luca Salvatore De Santo3

    1 Emeritus Professor of Nephrology, University of Campania Luigi Vanvitelli, Naples
    2 Istituto Mazzini, Naples
    3 Division of Heart Surgery, University of Campania Luigi Vanvitelli, Naples

    Corresponding author:
    Salita Scudillo, 20, 80131, Naples, Italy
    Phone: +39 3484117376
    E-mail: natalegaspare.desanto@unicampania.it

     

    Abstract

    Gout is a common, complex, systemic and well-studied form of chronic inflammatory arthritis due to deposition of sodium monourate crystals in peripheral joints and periarticular tissues driven by hyperuricemia. Gout is the oldest recorded inflammatory arthritis to affect humankind, with roots stretching back to 2640 BCE.
    To establish the timeline of gout from the Corpus Hippocraticum to the Renaissance, this study focuses on Galen (129-c.215 CE). A princeps English edition of Galen’s works is still lacking; therefore, this paper provides a translation of the paragraph on gout from the Latin edition [12] by Carolus Gottlob Kühn (Leipzig, 1821-1833).
    Galen departs from Hippocrates and displays a vast knowledge of pathogenesis, symptomatology, clinical course, differential diagnosis, therapeutic skills and prognostication. In Galen’s view, gout is due to fluid overflow that infiltrates nerves and causes pain. Overflowing fluid may be blood, phlegm, or a mixture of bile, blood, and phlegm. The prevailing humor is crude, mucous, and thick, and by residing in the joint, causes tophi. The nature of infiltrating humor can be diagnosed through color of the joint, symptoms, effects of heat and cold, effects of drugs, and information related to age, diet, quantity and quality of exercise, attitude towards baths of the patient.
    Treatment, according to Galen, required immediate bloodletting by venesection at the elbow, which could be repeated. Purges, enemas, and/or emetics are additionally needed to evacuate the humor(s). Poultices played a role draining the humor(s) as well as for their emollient-softening properties.

    Keywords: Galen, gout, humors, venesection, purges, emetics

    Introduction

    Gout is a common, complex, systemic and well-studied form of chronic inflammatory arthritis in adults for which treatment options are now available. It is due to deposition of sodium monourate crystals in peripheral joints and periarticular tissues driven by hyperuricemia at or above 6.8 mg/dL. Hyperuricemia itself results from genetic, environmental factors as well as from urate transporter dysfunction in the gut and in the kidneys.

    Hyperuricemia may be due to either renal overload (overproduction or extrarenal underexcretion due to dysfunctional variants of transporters in the gut and intestine), or to renal underexcretion, or a combination of renal overload and renal underexcretion [1–4]. Renal overload may be due to overproduction by dietary purines, endogenous purine synthesis, purine breakdown and purine salvage (Hypoxanthine-guanine phosphoribosyltransferase deficiency and 5-phosphoribosyl-1-pyrophosphate deficiency).  Crystal deposition activates the NOD-like receptor protein 3 (NLRP3) inflammasome causing—via caspase-1 —release of the cytokine IL-1β and activates proteinase 3 and elastase. The kidney may cause hyperuricemia, but is also the target of hyperuricemia (calculi, renal disease, and its progression) [1–7].

    At onset, gout affects one joint, frequently the metatarsophalangeal joint of the great toe, which is usually self-limited and heals in two weeks. Flare-ups subsequently affect two or more joints, becoming a chronic disease when tophi and erosions of the joint appear. Risk factors are diseases with high cell turnover and high intake of purine rich foods (meat, crustaceans, alcohol, and syrup containing fructose). It increases with age and women become hyperuricemic after menopause. It affects patients with hypertension, diabetes mellitus, and chronic kidney disease.  The diagnosis is made by demonstrating sodium monourate crystals in a joint by polarization microscopy or fine needle aspiration of tophi. The prevalence is 1% in Italy and in France, 2.5% in United Kingdom, Spain, Netherland, 3.9% in the USA and 1% in China. It is rare in Portugal, Czech Republic Former Soviet Union, Turkey, Malaysia, Japan, Korea, African countries. The prevalence increases with age up to 70-80 years of age.

    Its name derives from the Latin word gutta (drop) to indicate the drop of a humour in excess precipitating in the joint. Garrod made seminal experiments on the role of uric acid (1848). Having found a cure for the disease — allopurinol, still the most used ― Gertrud B. Elion (1918-1999) and George H. Hitchings (1905-1998) received the Nobel Prize for Medicine in 1988 [8, 9].

     

    Galen of Pergamum (129-c216 CE)

    The first of doctors and unique among philosophers.
    EMPEROR MARCUS AURELIUS

    The Prince of Medicine.
    VESALIUS, Defabrica corporis humani, 1555

    Until the twentieth century he was the most influencial figure
    in western medicine and perhaps in western culture.
    SUSAN P. MATTERN, 2013 [10]

     A Thinking Doctor in Imperial Rome.
    VIVIAN NUTTON, 2020 [11]

     

    Biography

    Galen (129-c.216 CE), the Greek-Roman physician, was born in Pergamum, Mysia, Anatolia (modern-day Bergama, Turkey), situated on the river Caicus, 16 kilometers from the Aegean Sea. He was the son of Nicon, a wealthy architect and Roman citizen, who owned a house in the city and a large estate. His grandfather had been an engineer. “The city of Attalus and Asclepius, the city that had turned on its Roman inhabitants and slaughtered them by thousands on a dark day in 88 BCE and then became the light of Roman Asia, beloved by Hadrian, adorned with every architecture glory – was Galen’s city” [10].

    Between 143 and 144 CE, Galen received his primary education from his father, Aelius Nicon, at home. Initially, the education focused on meticulous skills in both oral and written Greek, as well as providing a foundation in literature, mathematics, geometry, and astronomy. In addition to this foundation, Galen also had tutors in philosophy. One of his teachers was the philosopher Eudemus. His father’s intention was to mold Galen into a rich gentleman and possibly a philosopher. His father, who carefully selected his later teachers and often accompanied him to school, guided his early education. During these formative years, Galen studied Plato, Aristotle, the Stoics, and the Epicureans with great enthusiasm.

    At the age of 17 (in 145/146 CE), however, his studies shifted to medicine after his father was told in a dream by Asclepius that his son was destined for a medical career.

    Consequently, Galen studied in Pergamum with private physicians personally selected by his father. Later, following Nicon’s death (148 CE), he studied in Smyrna (150 CE), Corinth and Alexandria (152-153 CE), as reported in Table 1.

    PERGAMUM
    Satyrus Sophist
    Aeschrion Empiricist
    Epicurus Empiricist
    Stratonicus Empiricist
    Aeficianus Pneumatist
    SMYRNA
    Albinus Platonist philosopher
    Pelops Stoic interpreter of Hippocrates
    Table 1. Galen’s teachers in medicine [11].

    In Alexandria, a city with a vibrant cultural life, Galen remained for 3-4 years. There, he learned anatomy through daily dissections [10]. In 157 CE, he returned to Pergamum and, at the young age of 28, was appointed as the doctor of the local gladiators. A man of independent ideas and means, Galen never belonged to a specific philosophical or medical sect, and he remained independent throughout his life.

     

    From Pergamum to Rome

    In 162 CE, he moved to Rome, the capital of the empire, where he cultivated a friendship with the influential senator Flavius Boethus and reunited with his former philosophy teacher, Eudemus. Both relationships opened many doors for him, particularly after Galen was able to restore Eudemus’ health, curing a disease that others had deemed fatal, and subsequently healed Boethus’ son and wife. Furthermore, his masterlful public dissections gained renown throughout the city and attracted important clients. However, this success also sparked the jealousy and resentment of local physicians, toward whom, like Pliny the Elder in the previous century, he openly expressed his disdain. His attacks were mainly directed against Methodists but also towards Erasistrateans.

    For unknown reasons, in 166 CE he left Rome and returned to Pergamum, probably the fear of plague and/or the fear of the hatred generated by the envy of his Roman colleagues [10, 11].

    He returned to Rome in 169 and was appointed physician of Marcus Aurelius, who valued his medical expertise as much as his philosophy. He was in charge of preparing theriac for the Emperor until the Emperor’s death (in 180 CE).

    His subsequent life was not without difficulties, but he safely navigated the tumultuous years of Emperor Commodus. He served in office under Emperor Septimius Severus and likely died during the reign of Caracalla (197-217 CE). According to Arabic sources, Galen died in 216 or 217 CE.

     

    Galen on health and disease

    “Health is granted by a system based on the four elements (air, water, fire and earth), four qualities, two opposed pairs namely hot-cold and dry-wet, four humors (blood, phlegm, yellow bile and black bile (melancholy)), four seasons (spring, summer, autumn, winter) and temperaments that were nine (1 for each of the 4 qualities, 1 for each possible combination of the 4 qualities and 1 ideal temperament where all temperaments are in perfect balance [10]).

    The temperaments (Figure 1) became 4 in Medieval Europe. Equilibrium between humors is associated with health, imbalance with disease. Galen attributes the humoral theory directly to Hippocrates, not to Polybus, Hippocrates’ son-in-law, as reported by Aristotle.

    The liver is central to the body’s function. It generates blood from nutrients derived from food, which then circulates to the entire organism. The heart produces the innate heat that provides the energy for physical and mental health. It diminishes with age and disappears at death. The innate heat is maintained by the nutrients going from liver to the left ventricle and is cooled during respiration. Too much nutriment overheats, too little cools. Nutrients are relevant to acquired heat. Imbalance or excess of humours can be contrasted with drugs. Health is granted also by four faculties: attraction, expulsion, digestion (assimilation) and retention that allow appropriate handling of nutrients, and are present in every living organism, including plants.”

    Humours, elemental qualities, and temperaments in Medieval Galen.
    Figure 1. Humours, elemental qualities, and temperaments in Medieval Galen. Modified from De Santo NG, Bisaccia C, and De Santo RM. The Nature of water, New York, Nova 2013.

    Between 169 and 180 CE, Galen prepared the theriac for Marcus Aurelius. It was based on that of Andronicus, made of 64 ingredients, including viper’s flesh, Cinnamomum and poppy-head juice (3.4%), equivalent to approximately 33 mg of opium per day.

     

    The author

    Galen was a prolific writer. He started as a student, authoring 3 texts respectively on the anatomy of the womb, the diagnosis of diseases of the eyes and a report on a debate between the Empiricist Philippus and the Hippocratic Pelops on the best method to meet patients’ needs.  In total, he left more than 300 books, which were revised repeatedly during his life. These works cover a wide range of subjects, including anatomy, ethics, lexicography, logic, and pharmacology. He wrote in Greek, but his thought has been preserved through translations into Arabic, Hebrew, Syriac, Armenian, and Latin.  We can say that Arabic translations played a crucial role in preserving his methods. A notable example is the Canon (Al-Quanun fi al-Tibb) of Avicenna (Abu al-Hussayn ibn Abdullah ibn Sina, 980-1037 CE). According to Vivian Nutton it can be considered an outstanding treatise of Galenic medicine [11].

     

    Galen’s success

    Galen achieved success in Rome. His prestige was immense, allowing him to care for the most important families. This enabled him to assemble an outstanding personal library in the Palatinum and to purchase a villa in Castellammare di Stabia.  Unfortunately, the library, which housed the most important copies of medical books from antiquity and his own works, was located near the Temple of Apollo on the Palatine Hill and in 192 CE caught fire and was irretrievably lost. He lost not only books in the fire but also gold, silver, and other valuables. Luckily, some of his books were housed in the Villa of Castellammare.

    Galen provided medical care free of charge, but we know that he accepted gifts – such as the 400 aurei (gold coins) from Senator Flavius Boethus following the recovery of his son and wife. The great anatomist and pharmacologist “never lost the idea that medicine is about treating patients” [8]. Until the twentieth century he was the “most influential figure in western medicine and perhaps in western culture” [10].

     

    Galen’s Text: Regarding sciatica, gout and arthritis

    “Arthritis encompasses conditions such as sciatica and gout [12]. Sciatica refers to arthritis affecting the joints connected to the hip, while gout describes arthritis near the foot. Hence, gout typically begins in a single joint and progressively spreads to others, eventually becoming chronic. These three conditions share a common feature of an excessive buildup of fluid in the affected joint. This excess fluid overflows and infects the surrounding nerves, resulting in pain. The fluid that erupts can be sanguine or more commonly phlegmatic, or even a combination of phlegm, bile, and blood. More precisely, it can be said that in arthritis the prevailing humor is not typically phlegmatic but rather the one known as raw. This thick, mucus-like humor, when it remains in the joints for long periods, not only becomes denser but also more viscous. This is the origin of what is known as concretions, and once these develop, there is no hope of restoring the joint to its original condition.

    It is evident that the differences in humor affliction can be discerned through color, symptoms, and the effects of administered drugs. Therefore, the description and diagnosis of humor color are widely known and understood. Although not everyone experiences the symptoms firsthand, they are not difficult to learn. For instance, bilious blood produces a sensation of intense heat in the patient, which worsens with the application of heat and is alleviated by cold.

    To identify the humor involved, one should consider factors such as diet, physical activities, bathing routines, quantity and quality of exercises and foods, season, climate, age, and overall physical condition. These factors, along with the body’s various faculties, can assist in the diagnosis.

    To treat the illness by removing the specific humor causing it, bloodletting is employed for plethoric bodies, followed by purgation. Subsequently, appropriate medications are administered in a specific order and timing to repel the excessive flow of humor. However, special caution is needed when treating the hip joint, as it is deep and forcing the blood out can affect nearby vessels and muscles. Initially, soothing drugs for hip pain are necessary, which neither excessively cool nor heat, as these may exacerbate the secretions.

    While the focus here is not on poultices or baths but on the preparation of medicines, it is important to mention the treatment of the hip joint. In cases of sciatica, treatment often involves lancing the veins around the calf or ankles to alleviate the condition. However, in cases where strong drugs were used without evacuating the whole body, the accumulated humor may become thick and viscous due to the heat and dryness of acidic drugs, causing increased pain. Thus, beginning with the evacuation of the entire body, starting with a blood sample from the elbow, is crucial. Vomiting is particularly helpful in treating sciatica, and moderate emetics can be used in the initial stages.

    For those who have suffered from improper obstruction of fluids caused by acidic drugs that are difficult to dissolve, enemas and potent infusions, such as coloquintid, can be more  effective.With these considerations in mind, medicines are prescribed following the methods passed down by ancient doctors. Andromachus’ writings on external medicines, specifically emollient poultices (malagma), serve as an excellent starting point, providing relief for chronic conditions including sciatica.” [12].

     

    Preparations written by Andromachus for sciatic patients in his own words, from books on external drugs

    Seeds of wild rue (Ruta graveolens L.), of silphium (the extinct plant), of laurel (Laurus nobilis L.), saltpeter, southernwood (Artemisia abrotanum L.), coloquintid (Citrullus colocynthis L.), cardamom (Elettaria cardamomum L.), ammi (Ammi visnaga L.), the eighth part of a mina (436.6 g) of green rue (Ruta graveolens L.). Some of these receive a pitch of terebenthine, resin, and the same quantity of wax and taurine fat, copper disulphate, fumes of ammonium salt, of rubber from the hogweed plant (Heracleum sphondylium L.), of native sulfur [12].

    The effectiveness and warming properties of the mentioned medicines are well documented and do not require further recent verification. Wild rue seed, silphium, laurel berries, saltpeter foam, southernwood, coloquintide, cardamom, ammi, green rue, and natural sulfur all possess strong heating properties and can draw out the afflicting humors from deep within the hip joint. The poultice containing these ingredients is composed of pitch, turpentine, resin, wax, and fat. Ammonium fumes and galbanum not only contribute to the composition but also have emollient and softening properties. The gum of the hogweed plant is of a similar nature, but with faculties that are more potent.

     

    Another remedy of Andromachus with the same effect

    Andromachus provides another preparation for sciatica [12], which includes wax, turpentine, ammonium fumes, propolis, galbanum (Ferula galbaniflua, Boiss. and Buhse), bdellium (Commiphora mukul, Engl.), saffron (Crocus sativus L.), gum from the hogweed plant, sodium carbonate foam, and crushed iris oil (Iris florentina L.).

     

    A remedy of Protas of Pelusium for hip and head pain and all chronic pain

    It was made of wax (24 drachmae), seven drachmae of ammonium fumes, seven drachmae of trebentine, eight drachmae of  thapsia (Thapsia garganica L.) juice, and 1 cyathus (1 cup, 0,046 l) of oil [12].

     

    Among emollient poultices a remedy for hip pain drawn by Andromachus from Heras of Cappadocia

    “Three heminas of liquid pitch, or two and a half, wax, pine resin, wine sulfites, each a pound, six ounces of potassium nitrate, one quart of the green root parasite plant pedicularis (Pedicularis sylvatica L.), one quart of pyrethrum, two quarts of burnt wine dregs, two heminas of cardamom (Elettaria cardamomum L.), one quart of galbanum (Ferula gummosa L.). Liquids are added to the dry component. As Heras wrote near the end of his own book: they are added not in a pitch, or two and a half, but exactly three heminas” [12]. The title is verbatim that he gave.

     

    Discussion

    This study highlights Galen’s pivotal role in the historical understanding of gout, bridging the era of the Corpus Hippocraticum  and the Renaissance period. His treatise demonstrates a profound understanding of the disease pathogenesis, symptomatology, clinical course, differential diagnosis, therapeutic skills and prognostication. Gout starts in one joint and then, progressively, spreads to other joints becoming chronic.

    In Galen’s view, gout is due to fluid overflow that infiltrates nerves and causes pain. The overflowing fluid may be blood, phlegm, or a mixture of bile blood and phlegm. The prevailing humor is crude, mucous and thick and by residing in the joint becomes thicker and thicker and causes concretions (tophi). When tophi appear, the disease cannot be cured.

    The nature of infiltrating humor can be diagnosed through color of the joint, symptoms, effects of heat and cold, effects of drugs and specific information about age, diet, quantity and quality of exercise, and bathing habits.

    Bloodletting, in Galen’s therapeutic framework, is essential for plethoric patients and should be implemented promptly. A proponent of the procedure, Galen would draw large quantities of blood, preferably overnight, until the patient fainted. To treat gout, an incision was made at the elbow. Venesection might be repeated.  Enemas and /or emetics may be needed to evacuate the humor. Poultices have not only a role in evacuating the humor(s) but may have emollient and softening properties.

    Galen starts with two medical recipes by the pharmacologist Andromachus the Elder (and probably of his like-named son), physician of Nero in the century before, followed by another Andromachus’ recipe derived from Heras of Cappadocia, himself a pharmacologist of the previous century most valued by Galen, author of Narthex a book of medical remedies.

    The subsequent recipe comes from Protas of Seleucium in Egypt, a man who is mentioned in the “litany of names of some authors or providers of drugs listed by Galen” of Vivian Nutton [13] that includes 15 men and one woman (Aquilia Secundilla).

    Of great interest are the gouty patients described by Galen. The treatise On the Mixtures and Powers of Simple Dugs reports on an old man with chronic arthritis and chalky stones (tophi) who knocked at his door for immediate help. Galen who, probably, was in the middle of a discussion with his household about the use of the rancid cheese that had accumulated in the kitchen, immediately took a piece of that rancid cheese and pounded it in a mortar along with a piece of pickled pork leg and prepared a plaster that was put on the affected part. The plaster opened the chalky stone rendering incision unnecessary [10]. Galen reported also about another patient with a milder form of gout in an ambulatory patient, who was offered a cure by a street huckster. Galen challenged the charlatan to heal the patient.  The cure was not effective, as we learn in Simp. Med 1.29 11.432-33K, as enlightened by Susan P. Mattern [10].

    Although Galen considered Hippocrates an infallible physician and cited him 2500 times [10], Galen did not swear by the Hippocratic aphorism related to the absence of gout in eunuchs. He knew by experience that at the time of Hippocrates, nutrition was more appropriate, and wine was never consumed before or at breakfast; conditions that, in his view, protected eunuchs from developing the disease. By contrast, for the eunuchs of Galen’s time, gout became a possibility due to poor nutrition and use of strong wines drank even before breakfast. Galen also observed that many patients with gout had fathers or grandfathers affected by the same disease, suggesting a possible hereditary component.

    A very recent paper has identified eight Galenic case reports on inflammatory diseases of the musculoskeletal system selected from the list of 358 cases [14], some of them identified as gouty.

    Gout is probably the first known noncommunicable disease that can be discussed in terms of Omran’s “Theory of Epidemiologic Transition” [16, 17]. Omran analyzed the changing patterns of population age distribution in relation to changes in mortality, fertility, life expectancy, and causes of death. The theory has been updated frequently, by taking into consideration poverty along with incomes and education. This made the theory suitable to explain the differences between high prevalence of gout in popes and low but slightly increasing prevalence in the general population. Gout should be discussed in terms of lifestyles, income, and education. In general, rich and educated people, when made aware of the risk, agree to modify their lifestyles, whereas people who are poor and uneducated may not. Those who do not understand the risk factors are more likely to experience higher morbidity and mortality from the disease, while those with access to education are more likely to achieve protection [18].

    The above concepts were recently applied to gout in Roman Pontiffs, and it was shown that popes reigning before 1914 had a high prevalence of gout due to lifestyles causing gout. These lifestyles were later corrected through education, and by 1914 gout had virtually disappeared among popes. In contrast, individuals with poor nutrition, mostly those with low incomes, were not prone to gout. Their diets, working conditions, and daily commute to and from work provided them with protection from gout [19–22].

    In Rome at the time of Galen, life expectancy at birth ranged between 20 and 33 years [21], and in the poorer quarters it was around 20 years. As a result, gout was primarily a disease affecting elderly aristocrats. However, some cases of gout were probably linked to a high lead concentration in water due to the lead used for water pipelines, tanks and for utensils. Studies have shown that lead content in human skeletons increased significantly between 200 BCE and 200 CE [23].

     

    Conclusion

    Galen fixed practical guidelines for the management of gout at the bedside. The goal was possible since he was a “thinker”, “observer”, “good doctor”, “healer”, “dietitian”, and a “pharmacologist going beyond empirism”[11]. Gouty patients presented Galen with opportunities to fully exercise his diagnostic, therapeutic, and prognostic skills. He achieved this through patient communication and meticulous observation during frequent visits, which sometimes occurred multiple times a day. These interactions served as occasions for Galen to critique inferior physicians and charlatans and to show his superior expertise and ingenuity, as shown by the two cases illustrated before [10].

     

    Acknowledgements

    We thank Dr. Rosaria Di Martino, Head Centro Servizio del Sistema Bibliotecario di Ateneo Università degli Studi della Campania Luigi Vanvitelli and CoordinatorE Biblioteche di Ateneo, for her expert assistance in literature searches.

    Thanks are also due to Professor Joseph Sepe for the editing of the English text.

     

    Bibliography

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    2. Ragab G, Elshahaly M, Bardin T (2017). Gout: An old disease in new perspective – A review. J Adv Res;8: 495-511. https://doi.org/10.1016/j.jare.2017.04.008. Epub 2017 May 10. PMID: 28748116; PMCID: PMC5512152.
    3. Igel TF, Krasnokutsky S, and Pillinger MH (2017). Recent advances in understanding and managing gout. F1000Res. 6: 247. https://doi.org/10.12688/f1000research.9402.1.
    4. Dalbeth N, Choi HK, Joosten LAB, Khanna PP, Matsuo H,, Fernando Perez- Ruiz F and Stamp LK (2019). Gout. Nature Reviews Disease Primers 5:69. https://doi.org/10.1038/s41572-019-0115-y.
    5. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440: 237-41. https://doi.org/10.1038/nature04516.
    6. Delbarba E, Terlizzi V, Dallera N, Claudia Izzi C, Scolari F. iperuricemia e gotta. G Ital Nefrol 2016; 33 (S68) – ISSN 1724-5590.
    7. Zacchia M, Capolongo G, Rinaldi L, Capasso G. Fisiopatologia dell’handling renale dell’acido urico [Renal handling of uric acid]. G Ital Nefrol. 2015;32 Suppl 62:gin/32.S62.4. Italian. PMID: 26005871.
    8. Fyfe J A, Keller PM, Furman PA, Miller RL, and Elion G B. Thymidine Kinase from Herpes Simplex Virus Phosphorylates the New Antiviral Compound, 9-(2-Hydroxyethoxymethyl)guanine. J Biol Chem 1978; 253, 8721– 8727.
    9. Derse D, Cheng Y C, Furman P A., St. Clair M H, and Elion GB. Inhibition of Purified Human and Herpes Simplex Virus-induced DNA Polymerases by 9-(2-Hydroxyethoxymethyl)guanine Triphosphate. Effects on Primer-Template Function. J Biol Chem 1981; 256, 11447–11451.
    10. Mattern SP. The Prince of Medicine – Galen in the Roman Empire. Oxford: University press, 2013.
    11. Nutton V. Galen: A thinking Doctor in Imperial Rome. New York, Routledge 2020.
    12. Claudii Galeni, Opera Omnia, ed Karl Gottlob Kühn, Vol. XIII. Leipzig: Car. Cnobloch; 1827. p. 331–333. (Liber X, Cap. II: De ischiade, podagra et arthritide).
    13. Nutton V. The drug trade in Antiquity. J R Soc Med 1985; 78: 138-145.
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    15. Schwartz SA. Disease of distinction. Explore (NY). 2006 Nov-Dec;2(6):515-9. https://doi.org/10.1016/j.explore.2006.08.007. PMID: 17113492.
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    Hyperuricemia in Chronic Kidney Disease: To Treat or Not to Treat?

    Posted on Scarica PDF

    Marco Manganaro

    DOI: 10.69097/41-s83-2024-05

    Marco Manganaro

    già Direttore SC Nefrologia e Dialisi, ASO “SS. Antonio e Biagio e C. Arrigo”, Alessandria.

    Corresponding author:
    Marco Manganaro,
    via Giordano Bruno 63/d, 10134 Torino (Italia).
    E-mail: giurima@alice.it

     

    Abstract

    Numerous studies have shown that hyperuricemia (HU) is an independent risk factor for the development of chronic kidney disease (CKD) and cardiovascular events. However, while some evidence suggests that uric acid (UA) may play not only a predictive but also a causal role in these conditions, a robust and definitive demonstration of this is still lacking.
    Moreover, despite what appears to be a logical rationale supporting the use of so-called ‘urate-lowering therapy’ (ULT) for nephroprotection in hyperuricemic patients with CKD, studies and meta-analyses on this topic — sometimes burdened by limitations that may have affected their results — have so far provided highly divergent outcomes, leaving uncertainty about whether drug-induced reduction of uricemia can truly slow the progression of CKD and prevent its cardiovascular complications.
    This article summarizes current knowledge on UA metabolism and the drugs that interfere with it, discusses theories on the possible multiple pathogenic mechanisms underlying HU related kidney damage, and reviews the results and limitations of the most recent studies that have supported or refuted the nephroprotective role of ULT in CKD, fueling an ongoing scientific controversy.

    Keywords: Uric Acid, Asymptomatic Hyperuricemia, Gout, Chronic Kidney Disease, Urate-Lowering Therapy

    Sorry, this entry is only available in Italiano.

    Introduzione

    I rapporti tra iperuricemia (HU) e malattia renale cronica (CKD) sono complessi e di difficoltosa interpretazione per la presenza di fattori confondenti legati alla duplice potenzialità della prima di poter essere sia conseguenza, sia causa della seconda. Da un lato infatti la riduzione del filtrato glomerulare (GFR) che si verifica nella CKD comporta una ridotta escrezione urinaria di acido urico (UA) che può innalzarne i livelli serici, il concomitante impiego di diuretici aggrava tale difetto e le principali cause di CKD, cioè diabete ed ipertensione, sono spesso già di per sé condizioni iperuricemiche(1-3). D’altra parte, ormai assodato che l’HU costituisca un fattore predittivo indipendente per lo sviluppo della CKD e di eventi cardiovascolari patologici, il suo possibile ruolo causale in tali situazioni resta incerto: in particolare, per quanto attiene quello relativo al danno renale, esso risulta meglio provato nella forma da deposito di cristalli di urato, ma meno definito, anche se con crescenti indizi a suo suffragio, nelle conseguenze ascritte all’azione dell’UA solubile. Analogamente rimane ancora controverso, a causa dei contrastanti risultati sinora forniti da studi e meta-analisi sull’argomento, il possibile ruolo nefroprotettivo dalla cosiddetta urate-lowering therapy (ULT)(4-5).
    Nella trattazione che segue esamineremo gli studi più recenti e le motivazioni che sono alla base di differenti punti di vista rispetto alle sopra descritte diatribe.

     

    Fisiologia

    L’acido urico o C5H4N4O3 o 2,6,8-triossi-1H-purina, composto organico eterociclico con massa molecolare pari a 168,11 unità di massa atomica, è un acido debole che nel comparto extracellulare, al pH fisiologico, è presente al 98-99% nella forma ionizzata di urato monosodico (MSU).
    La sintesi dell’UA, prodotto finale del catabolismo delle purine esogene (da cui derivano quotidianamente circa 100-200 mg di UA) ed endogene (da cui derivano ulteriori 600-700 mg/die di UA) avviene nel fegato ad opera dell’enzima xantina ossidoreduttasi (XOR), mentre l’eliminazione dell’UA è per 1/3 gastrointestinale, poi seguita da uricolisi batterica, e per 2/3 renale. In quest’ultima sede il 95% dell’UA viene filtrato dal glomerulo (la restante quota non filtrata è quella legata alle proteine), poi riassorbito al 99% nel tratto S1 del tubulo prossimale e successivamente secreto nel tratto S2, in entrambi i casi ad opera di trasportatori di membrana specifici per ciascuna delle due direzioni e situati in parte sul versante apicale (URAT1 o SLC22A12, OAT4 o SLC22A11, OAT10 o SLC22A13, GLUT9 o SLC2A9 deputati al riassorbimento e ABCG2, ABCC2 o MRP2, ABCC4 o MRP4, NPT1 o SLC17A1, NPT4 o SLC17A3 deputati alla secrezione) ed in parte sul versante baso-laterale (GLUT9 o SLC2A9 deputato al riassorbimento e OAT1 o SLC22A6, OAT2 o SLC22A7, OAT3 o SLC22A8 deputati alla secrezione) della cellula epiteliale del tubulo; alla fine del processo la quota di UA eliminata con le urine rappresenta circa il 10% di quella filtrata(6-10).

     

    Definizione, cause e conseguenze della HU

    Negli esseri umani i livelli plasmatici di UA sono più elevati rispetto a quelli degli animali dotati di attività uricasica che permette loro di trasformarlo in allantoina (rispettivamente 3-7 mg/dl contro 1-2 mg/dl), e sono inferiori nella donna rispetto all’uomo per effetto dell’attività uricosurica propria degli estrogeni.
    La mutazione responsabile della perdita dell’uricasi (o urato ossidasi) da parte dell’uomo e dei primati superiori sarebbe avvenuta nel Miocene, tra 25 e 12 milioni di anni fa, comportando almeno quattro rilevanti vantaggi in termini evoluzionistici: il rimpiazzo dell’attività antiossidante conseguente alla perdita della capacità di sintesi della vitamina C, importante per la longevità e la neuro-protezione; la stimolazione mentale dovuta ad analogie strutturali con la caffeina, importante per lo sviluppo dell’intelligenza; la stimolazione del sistema renina-angiotensina-aldosterone (RAAS) per il mantenimento di un adeguato regime pressorio in concomitanza con l’assunzione della stazione eretta nonostante un’alimentazione all’epoca povera di sodio; l’incremento delle capacità di accumulare grasso in risposta alla ridotta disponibilità di frutti causata dal raffreddamento della terra(7,11).
    Nella seconda metà del secolo scorso, nei paesi economicamente avanzati, i livelli medi di uricemia della popolazione sono progressivamente saliti con il progredire del benessere(12) e l’incremento dell’assunzione di cibi ricchi in purine (soprattutto proteine animali, crostacei, birra, vino, e bevande alcooliche) e fruttosio (bevande zuccherate).
    Benché da lungo tempo siano considerati valori di uricemia patologici quelli superiori a 7.0 mg/dl nell’uomo e a 6.0 mg/dl nella donna, alcuni invitano a considerare l’uricemia normale per entrambi soltanto fino a 6.0-6.4 mg/dl poiché questi sono i limiti di solubilità del MSU rispettivamente a 35° e 37°(13-14); al momento questo orientamento non sembra tuttavia trovare ancora il completo accordo di tutti gli esperti.
    Cause acquisite o congenite di aumentata introduzione (dieta iperpurinica) o di aumentata produzione di UA (malatttie mielo-linfoproliferative, neoplasie, chemioterapia, psoriasi, sindrome di Lesch-Nyhan, iperattività della fosforibosilpirofosfato sintetasi), ma soprattutto (90% dei casi) di ridotta eliminazione dell’UA (ipovolemia, CKD, farmaci, saturnismo, tubulopatia autosomica dominante uromodulina-associata) inducono HU, condizione a rischio per il successivo sviluppo di patologie. Come già anticipato in premessa, queste conseguono alla formazione di cristalli di MSU e alla loro successiva precipitazione intra- tissutale (gotta articolare, nefropatia gottosa cronica, AKI da massiva precipitazione intra- tubulare acuta) o nelle vie urinarie (calcolosi), ma potenzialmente anche ad effetti emodinamici e cellulari attribuiti alla forma solubile di UA: questi ultimi comprendono attivazione del RAAS (ipertensione arteriosa), ma anche infiammazione e stress ossidativo con risvolti sia renali (disfunzione endoteliale, glomerulosclerosi, fibrosi tubulo-interstiziale) che sistemici (danno cardiovascolare, aumentata resistenza all’insulina, sindrome metabolica)(15). Va infatti considerato il ruolo ambiguo dell’UA che ha proprietà antiossidanti quando circolante nell’ambiente idrofilo extracellulare, ma ha effetti pro- ossidanti che sarebbero alla base del danno cardio-nefro-metabolico nell’ambiente idrofobico intracellulare(16).

     

    Epidemiologia della HU e della gotta

    Nel paziente adulto con GFR normale la prevalenza di iperuricemia asintomatica (aHU) è circa del 20%, mentre quella della gotta oscilla tra lo 0.7 e il 3.9%, con trend complessivo in crescita, ampia variabilità nelle diverse aree geografiche ed etnie, e valori anche superiori nella parte più anziana della popolazione. Nel paziente affetto da CKD la prevalenza di aHU sale fino all’80% e quella della gotta fino al 32% e ciò avviene in modo direttamente proporzionale alla severità della malattia renale. Inoltre, in modo quasi speculare, anche nei pazienti iperuricemici e gottosi si osserva un incremento della prevalenza di CKD dal 6-12% fino al 50% ed al 70% rispettivamente(4,8,17).

     

    Esiste davvero il danno renale cronico da UA?

    Come già detto, la patologia da cristalli comprende, oltre al danno renale acuto (AKI) da precipitazione intra-tubulare massiva di cristalli di MSU, e alla calcolosi da precipitazione di MSU nelle vie urinarie, anche la nefropatia da deposizione intra-parenchimale cronica di MSU. Quest’ultima è istologicamente caratterizzata da deposizione focale di cristalli di MSU nei tubuli, flogosi interstiziale evolvente verso la fibrosi dell’interstizio e l’atrofia tubulare, glomerulosclerosi ed arteriolosclerosi di grado variabile, mentre si manifesta clinicamente dapprima con un deficit della capacità di concentrazione delle urine e successivamente con una graduale riduzione del GFR(6).
    Benché assai ben descritta già in un lontano passato, la reale esistenza di questa forma cronica di nefropatia è stata tuttavia rimessa in discussione verso la fine del XX secolo prima di essere nuovamente riaffermata. Come riporta un antico testo scientifico(18), infatti, già verso la metà del XIX secolo Robert Bentley Todd, irlandese divenuto professore al King’s College di Londra, descriveva il quadro del rene gottoso come caratterizzato dalla presenza di “linee bianche di materiale simile al gesso nella porzione piramidale del rene che prendono la direzione dei tubuli retti e che risultano cristallizzate in forma di prismi quando osservate al microscopio e costituite da urato di soda quando sottoposte ai test chimici”. L’identità di tale riscontro, poi confermato in ampie casistiche, autoptiche e non, della metà del XX secolo(19-20), venne successivamente confutata negli anni ottanta con la pubblicazione di alcuni articoli(21-23) che formulavano le seguenti obiezioni: il riscontro bioptico di una focale deposizione di cristalli di MSU, peraltro osservabile anche in soggetti senza malattia renale, non può spiegare la diffusa presenza di cicatrici renali; il concomitante danno vascolare renale sembra dipendere da altre più rilevanti cause di nefropatia, quali ad esempio la coesistente ipertensione arteriosa; il danno interstiziale può anche conseguire al largo impiego di antiinfiammatori non steroidei (FANS) nel paziente gottoso. Così, per un certo periodo, l’UA non venne più considerato come possibile causa di CKD e l’HU venne ritenuta piuttosto una mera conseguenza della ridotta escrezione di UA dovuta alla riduzione del GFR(2).
    Nuovi elementi a suffragio della possibilità di un nesso causale tra UA e CKD giunsero dall’evidenza che ratti con CKD, se resi iperuricemici, avevano una progressione più rapida della malattia anche in assenza di deposizione intrarenale di cristalli (24): ciò riaprì la ricerca e la discussione sul possibile ruolo nefrolesivo dell’UA non solo nella sua forma cristallina, ma anche nella sua forma solubile.
    Dopo un appello di alcuni ad adoperare maggior cautela prima di estrapolare conclusioni valide per l’uomo da studi condotti su roditori dotati di attività uricasica, cioè abituati a uricemie ben inferiori a quelle umane e resi severamente iperuricemici in via sperimentale(25), successive ricerche evidenziarono reali effetti pro-infiammatori e di immuno-attivazione dell’UA solubile nei confronti rispettivamente delle cellule dell’epitelio tubulare e delle cellule mesangiali umane(26-27).
    Nuovi studi effettuati nel corrente secolo e qui di seguito descritti, sono poi giunti a identificare la HU come fattore indipendente di rischio cardiovascolare e renale nella CKD. Nel 2012 Kanbay e coll. hanno pubblicato i risultati di uno studio condotto su 303 pazienti con CKD e follow-up medio di 39 mesi che mostravano una significativa associazione tra HU ed eventi cardiovascolari fatali e non in maniera indipendente da altri fattori di rischio(28).
    Nel 2014 Zhu e coll. hanno dimostrato, in una meta-analisi di 15 studi di coorte che avevano complessivamente arruolato oltre 99.000 individui, un’associazione positiva tra livelli di UA e sviluppo di CKD, con un rischio relativo di 1.22 per ogni mg/dl di incremento dell’uricemia e in maniera indipendente da altri fattori di rischio(29).

    Nel 2018 Srivastava e coll. hanno confermato il suddetto riscontro evidenziando una curva conformata a “J” tra livelli di uricemia e rischio di morte per ogni causa (30).
    Più recentemente i risultati del progetto URRAH, uno studio osservazionale multicentrico retrospettivo italiano su una coorte di 26.971 soggetti, hanno evidenziato un’associazione indipendente tra livelli di UA e mortalità cardiovascolare e globale, con soglie di uricemia predittive di mortalità anche inferiori a quello che viene attualmente ritenuto il cut off di normalità dell’uricemia(31), oltre che una prevalenza di HU crescente con il decrescere del GFR e maggiore nei pazienti con macroalbuminuria rispetto a quelli con micro e normoalbuminuria(17).
    Anche una meta-analisi condotta da Autori brasiliani su 24 studi osservazionali riguardanti oltre 400.000 pazienti, pubblicata nel 2022(32), ha documentato una significativa correlazione tra uricemie inferiori e minor sviluppo e progressione di CKD.
    Uno studio prospettico multicentrico osservazionale del gruppo di studio francese CKD- REIN(33), condotto su 2.781 pazienti con CKD in stadio 3-5 seguiti mediamente per oltre 3 anni, dopo aver pianificato l’esecuzione di una determinazione basale e di almeno 5 successive determinazioni dell’UA per ciascun paziente, ha confrontato in modo longitudinale il rapporto tra uricemia e rischio di insufficienza renale e di morte: ne è emerso che il rischio di insufficienza renale aumenta con il crescere dell’uricemia, con un plateau tra i 6 ed i 10 mg/dl ed un brusco incremento al di sopra degli 11 mg/dl, mentre il rischio di morte palesa una curva conformata ad “U” in cui, al di sotto dei 3 mg/dl (forse per il venir meno dell’azione anti-ossidante dell’UA) e al di sopra degli 11 mg/dl, esso è doppio rispetto a quello osservato con valori di uricemia attorno ai 5 mg/dl. Ne è altresì emerso che analoghe curve, costruite solo in funzione delle uricemie basali, non sono in grado di fornire i medesimi risultati: ciò potrebbe spiegare perché alcuni precedenti lavori non abbiano trovato correlazione tra livelli di UA e insufficienza renale.
    Schwartz e coll.(34), in uno studio longitudinale su 693 bambini o adolescenti con CKD ad eziologia glomerulare e non glomerulare, hanno trovato un’importante correlazione tra livelli di UA e rischio di progressione della nefropatia: la perdita annuale di GFR in tre fasce pre-definite (<5.5 mg/dl, 5.5-7.5 mg/dl e >7.5 mg/dl) di uricemia basale era infatti rispettivamente -1,4%, -7,7% e -14,7% nelle glomerulopatie e -1,4%, -4,1% e -8,6% nelle nefropatie ad eziologia non glomerulare. Esaminando poi la perdita di GFR osservata per ogni successivo mg/dl di incremento dell’UA nei pazienti che al controllo basale appartenevano alle prime due fasce si evinceva una significativa perdita del GFR, di -5,7% e -4,3% nelle glomerulopatie e di -5,1% e -3,3% nelle nefropatie non glomerulari.
    Assodato il ruolo dell’UA come fattore di rischio per lo sviluppo della nefropatia, sono in molti a ritenere plausibile un suo ruolo attivo e non solo predittivo in tal senso, ipotizzando differenti e coesistenti meccanismi lesivi per la sua forma cristallina e per quella solubile. Da un lato la precipitazione a livello tubulare di cristalli di MSU in grado di indurre flogosi interstiziale. Dall’altro una duplice possibilità, immunologica la prima, non immunologica la seconda, che l’UA solubile, identificato come sostanza pericolosa dai recettori dell’immunità innata, inneschi una risposta infiammatoria evolvente verso la fibrosi, ma anche che, attraverso l’attivazione del RAAS e l’avvio di stress ossidativo, induca vasocostrizione, disfunzione endoteliale e proliferazione delle cellule muscolari lisce vascolari alle quali conseguono glomerulosclerosi e fibrosi interstiziale (9,15,35,36).

    Una recente divergente osservazione sostiene invece la possibilità che la forma solubile dell’UA abbia effetti soppressivi, e non stimolanti, sull’immunità innata e che sia implicata, insieme ad altri fattori, nello sviluppo della cosiddetta immunodeficienza secondaria alla malattia renale (SIDKD), tipica dell’uremia in fase avanzata, che si caratterizza per alterate difese nei confronti dei patogeni, scarsa risposta ai vaccini e attenuazione delle patologie infiammatorie croniche non infettive(37). Questo contrasta con gli studi citati in precedenza conferendo invece all’UA solubile effetti anti-infiammatori e anti-ossidanti e avvalorando l’ipotesi che la produzione di specie reattive dell’ossigeno (ROS) e il rilascio di citochine pro-infiammatorie non derivino dalla HU, bensì dalla contestuale attivazione della XOR(5).
    Per quanto attiene invece la patologia da cristalli, i noti limiti della biopsia renale nei riguardi dell’identificazione della nefropatia gottosa, difficoltosa soprattutto nelle fasi iniziali di malattia perché il prelievo di tessuto renale avviene perlopiù in sede corticale mentre la patologia ha prevalente estrinsecazione midollare, ed anche perché alcuni fissativi causano la dissoluzione dei cristalli stessi(15), sembrano oggi superabili grazie alla Dual-energy computed tomography (DECT) e/o all’impiego combinato dell’ultrasonografia B-mode e Power Doppler-mode. La DECT è infatti in grado di fornire immagini dei depositi di MSU consentendo di applicare loro un codice colore che li distingua dalle calcificazioni, mentre con l’ultrasonografia l’iperecogenicità midollare apprezzabile in B-mode
    corrisponde alla presenza di artefatti scintillanti all’indagine in modalità Power Doppler (38- 39).

     

    Il possibile ruolo della XOR

    La XOR è un enzima del peso molecolare di 300 kDa regolato a più livelli e dotato di due forme, la xantina deidrogenasi (XDH) presente nell’ambiente intracellulare e la xantina ossidasi (XO) che deriva dalla conversione della precedente quando rilasciata a livello plasmatico. La sua struttura è composta da due sub-unità identiche, ciascuna delle quali costituita da un duplice gruppo Fe/S all’estremo N-terminale, da un cofattore flavin- adenina dinucleotide (FAD) dotato di attività NADH-ossidasica nella porzione intermedia e da un cofattore molibdopterinico all’estremo C-terminale responsabile delle attività enzimatiche xantino-deidrogenasica, xantino-ossidasica e nitrito/nitrato-reduttasica.

    La XOR provvede al catabolismo delle purine trasformando l’ipoxantina in xantina e quest’ultima in UA. Essa è inoltre in grado di interferire sullo stato ossido-riduttivo e sulla dinamica dei segnali dell’ambiente cellulare mediante la produzione di ROS e di specie reattive dell’azoto (RNS). Ne deriva che un’eventuale inadeguata attivazione della XOR possa indurre danni tissutali sia di tipo ossidativo che di tipo infiammatorio, assumendo dunque un ruolo patogenetico nelle fasi iniziali della CKD e nelle altre patologie HU- correlate (ipertensione arteriosa, obesità, resistenza all’insulina) che potrebbero quindi anche conseguire più all’iperattività della XOR che non alla HU di per sé.
    In questa differente prospettiva, il trattamento con farmaci inibitori della XOR (XORi) quali allopurinolo e febuxostat, oltre a ridurre l’uricemia prevenendo la deposizione tissutale di cristalli di MSU, ridurrebbe la produzione di ROS indotta dalla XOR prevenendo il danno ossidativo tissutale. In aggiunta, gli XORi non competitivi (febuxostat), attraverso l’azione della ipoxantina-guanina-fosforibosil-transferasi (HGPRT) del cosiddetto “purine salvage pathway”, promuoverebbero il riutilizzo dell’ipoxantina, convertita in inosin-monofosfato (IMP) utilizzabile per incrementare la produzione di ATP. Quest’ultima azione potrebbe anche spiegare gli eventi cardiaci sfavorevoli, descritti in alcuni pazienti al momento della sospensione della terapia con febuxostat, come conseguenti ad un disturbo della conduzione e della contrazione da improvvisa ridotta disponibilità di ATP(40-41).

     

    L’approccio terapeutico alla HU sintomatica nel paziente con CKD

    L’approccio terapeutico alla HU sintomatica(6,9,10,42,43) deve sempre innanzitutto prevedere l’analisi delle sue possibili cause, l’adozione di appropriate variazioni dello stile di vita e dell’alimentazione (incoraggiamento dell’attività fisica e del calo ponderale; eliminazione di birra, vino, alcoolici e bevande zuccherate; riduzione dell’apporto di proteine animali; mantenimento di un adeguato apporto di fluidi, frutta e verdura), nonché la ricerca e il governo di eventuali altri fattori di rischio concomitanti (fumo, ipertensione, iperglicemia, dislipidemia, obesità). Poiché queste prime obbligatorie misure possono non essere sufficienti, si rende spesso poi necessario anche il ricorso anche alla ULT che può contare sull’esistenza di farmaci appartenenti a tre distinte categorie: XORi, uricosurici e uricasi ricombinanti. Una recente review di Jenkins e coll.(43) ha censito l’esistenza di 36 sostanze ipouricemizzanti, 10 delle quali approvate da una o più organizzazioni nazionali di controllo del farmaco (allopurinolo, febuxostat, topiroxostat, benzbromarone, lesinurad, dotinurad, probenecid, sulfinpirazone, pegloticase, rasburicase) e 26 in studio; di particolare interesse tra queste ultime nuove forme di uricasi ricombinante a minor immunogenicità e farmaci con duplice meccanismo d’azione.
    Tra i farmaci finora approvati, gli XORi restano al momento la prima scelta per la buona efficacia nella riduzione dell’uricemia, la semplicità d’utilizzo e, nonostante tutto, la relativa buona sicurezza d’impiego se somministrati nel rispetto di alcune ben specificate cautele.
    L’allopurinolo è un analogo purinico, inibitore competitivo non specifico di XOR, che agisce tramite il suo metabolita attivo ossipurinolo ad eliminazione renale. Oltre alla nota interferenza con il metabolismo di altri farmaci (azatioprina, warfarin, diuretici), la sua complicanza più temibile è la sindrome da ipersensibilità all’allopurinolo (AHS): essa è legata alla presenza dell’allele HLA-B*58.01, peraltro più frequente nelle popolazioni asiatica e afro-americana, le sole per le quali ha indicazione il test genetico per ricercarlo, mentre si riscontra solo nello 0.7% dei soggetti di razza bianca. Anche il supposto ruolo della CKD nel favorire la AHS è oggi ridimensionato e ritenuto limitato ai casi di avvio del trattamento a dosi troppo alte, più che non alla necessità di adeguare al GFR la successiva dose di mantenimento. Nella CKD è pertanto indicato iniziare con 100 mg/die se il GFR è 30-60 ml/min e con 50 mg/die se il GFR è <30 ml/min, salendo con gradualità ogni 2-5 settimane fino alla dose che consente di raggiungere il target di uricemia <6 mg/dl, e potendo arrivare anche sino a 300 mg/die finché il GFR resta >15 ml/min. Nel paziente in trattamento sostitutivo occorre ricordare che la dialisi rimuove l’UA, ma che, mentre la dialisi peritoneale lo fa in modo continuo, l’emodialisi lo fa ad intermittenza, con una modalità che potrebbe da sola non essere sufficiente nelle forme di gotta severa; a questo proposito va quindi tenuto presente che l’eventuale assunzione dell’allopurinolo deve avvenire dopo la seduta dialitica perché l’emodialisi rimuove il suo metabolita attivo(9,10,43).

    Il febuxostat è un inibitore selettivo non purinico di XOR, più costoso dell’allopurinolo, per il quale occorre ricordare che, come quest’ultimo, interferisce con il metabolismo dell’azatioprina. Esso è anche in grado di inibire ABCG2 e di rallentare così l’eliminazione dei propri metaboliti senza tuttavia innalzare significativamente l’uricemia. Avendo un metabolismo prevalentemente epatico è utilizzabile nella CKD a 40 mg/die, ma probabilmente anche a dosi maggiori, con buon profilo di sicurezza, finché il GFR si mantiene >15 ml/min. Se l’avvio del trattamento avviene quando il paziente ha già GFR <30 ml/min, è opportuno farlo a posologia ridotta; in dialisi, pur con pochi dati al riguardo, dosi di 20-40 mg sembrano ben tollerate(9,10,43).
    Il topiroxostat è un altro inibitore selettivo non purinico di XOR, approvato solo in Giappone e con profilo di sicurezza non dissimile dai precedenti, che si somministra alla dose di mantenimento di 60-80 mg due volte al dì (9,43).
    Gli URICOSURICI sono farmaci ULT di seconda scelta che non funzionano se il GFR è inferiore a 20-30 ml/min, possono indurre nefrolitiasi e vengono generalmente impiegati, pur con tutti i limiti appena descritti, in caso di intolleranza agli XORi o in associazione a questi ultimi quando la monoterapia si rivela insufficiente.
    Il probenecid è un inibitore non selettivo di URAT1, che in minor misura agisce anche su GLUT9, OAT1 e OAT3, del quale occorre tener presente la capacità di alterare la clearance di altri farmaci quali ad esempio penicilline, furosemide e methotrexate. Si somministra a una dose variabile da 0.5 a 2 g al giorno(43).
    Il benzbromarone è un uricosurico non selettivo più potente del precedente, che agisce allo stesso modo e che può dare epatotossicità. Si somministra alla dose 50-200 mg al giorno(43).
    Il lesinurad è un inibitore selettivo di URAT1 che si somministrava alla dose di 200 mg al giorno, ma del quale l’industria farmaceutica ha recentemente cessato la produzione(9,10,43). Il dotinurad è un inibitore selettivo di URAT1 in grado di inibire anche l’inflammasoma NLRP3 che si somministra alla dose di 0.5-4 mg al giorno(43).
    Il sulfinpirazone è un altro uricosurico non selettivo in via di cessazione di produzione la cui dose quotidiana varia da 100 a 800 mg suddivisi in due somministrazioni(43).
    Le URICASI RICOMBINANTI hanno potente attività ipouricemizzante derivante dalla loro capacità di trasformare l’UA in allantoina, ma sono gravate dalla necessità di somministrazione per via endovenosa, da costi elevati e soprattutto dalla loro immunogenicità.
    La rasburicase è indicata nelle HU di origine tumorale e nella sindrome da lisi tumorale alla dose endovenosa di 2 mg/kg/die per 1-5 giorni. Non sono consigliati cicli di trattamento ripetuti in quanto può indurre sia reazioni anafilattiche, sia sviluppo di anticorpi anti-farmaco che ne compromettono l’efficacia(43).
    La pegloticase è la forma peghilata della precedente utilizzabile nella gotta severa e non responsiva ai farmaci delle categorie precedentemente illustrate. Ha lunga emivita per cui è sufficiente una somministrazione endovenosa di 8 mg ogni 2 settimane e, nel paziente con CKD, non necessita di adeguamento della dose al GFR. Suoi limiti sono rappresentati dalla necessità di infusione della durata di almeno 2 ore, dal costo elevato, dalle frequenti reazioni infusionali, dal rischio di sviluppo di anticorpi anti-farmaco che ne compromettono l’efficacia e dalla controindicazione all’impiego nei pazienti con favismo nei quali può scatenare crisi emolitiche(43).
    Occorre poi tenere presente che esistono svariati farmaci concepiti per altre scopi che possiedono anche un effetto ipouricemizzante mediato dall’inibizione di URAT1. La conoscenza di questa loro caratteristica può consentire di sfruttarli laddove, insieme alla patologia per la quale sono primariamente indicati, coesista anche una HU: tra essi il losartan, i calcio-antagonisti diidropiridinici, gli SGLT2-inibitori (soprattutto empaglifozin), il fenofibrato e l’atorvastatina, le alte dosi di aspirina, la leflunomide, alcuni FANS (indometacina e fenilbutazone), il desametasone e gli estrogeni(10,44).
    Parimenti esistono farmaci e sostanze che inducono HU, sempre mediata dell’interazione con trasportatori dell’UA della parete tubulare, effetto collaterale del quale è opportuno essere a conoscenza: i diuretici tiazidici e dell’ansa, alcuni beta-bloccanti (propranololo, atenololo, metoprololo e sotalolo), alcuni antitubercolari (pirazinamide e etambutolo), gli inibitori delle calcineurine, le basse dosi aspirina (effetto peraltro trascurabile rispetto al beneficio cardiovascolare indubbiamente offerto dal farmaco), l’insulina, il testosterone e il lattato(44).

     

    È plausibile che la somministrazione della ULT nella CKD possa esercitare anche un’azione nefroprotettiva?

    Un piccolo trial randomizzato e controllato (RCT) del 2006 condotto a Hong Kong su 54 pazienti iperuricemici con CKD(45) documentava un rallentamento del calo del GFR rispetto ai controlli dopo 12 mesi di trattamento con allopurinolo.
    Giungevano ad analoghe conclusioni, dopo 24 mesi di trattamento con allopurinolo, anche due studi spagnoli del 2010 e del 2015, peraltro non disegnati in doppio-cieco, rispettivamente su 113 e 107 pazienti con CKD(46-47).
    Lo studio RENAAL, disegnato per valutare gli effetti antiipertensivi del losartan(48-49), evidenziava anche un effetto ipouricemizzante del farmaco che determinava una riduzione del 6% del rischio di progressione della CKD per ogni 0.5 mg/dl di riduzione dell’uricemia. Le linee guida KDIGO per la gestione della CKD, la cui stesura risale peraltro ormai al 2012, riportavano tuttavia l’inesistenza di sufficienti evidenze sia per supportare, sia per controindicare l’impiego della ULT allo scopo di rallentare la progressione della nefropatia nel paziente con CKD ed HU sintomatica o asintomatica(50), lasciando del tutto all’orientamento personale di ogni medico la scelta del comportamento da adottare di fronte a ciascun singolo caso. Purtroppo, anche l’ormai lunga serie di studi al riguardo successivi a quella data ha continuato a fornire dati non univoci e spesso criticabili.
    Nel 2017 uno studio con 7 anni di follow up condotto con il criterio della randomizzazione mendeliana su 3.896 caucasici finnici affetti da diabete di tipo 1(51) concludeva che la HU è indipendentemente associata al calo del GFR, ma non con un rapporto causale.
    Anche da una revisione a ombrello di precedenti meta-analisi di Li e coll. del 2017(52) emergeva un nesso causale tra livelli di UA e sviluppo di gotta o nefrolitiasi, ma non tra livelli di UA e ipertensione o CKD, la cui semplice associazione veniva ritenuta insufficiente ad autorizzare la prescrizione della ULT a scopo nefroprotettivo.
    Un’altra meta-analisi cinese del 2017(53) su 16 RCT comprendenti 1.211 pazienti con CKD trovava invece un tasso di declino significativamente inferiore nei pazienti trattati con ULT.

    I risultati dello studio FEATHER, un RCT di confronto tra febuxostat e placebo su 443 pazienti con HU asintomatica e CKD in stadio 3, pubblicati da Kimura e coll. nel 2018(54), non mostravano differenze significative nel tasso di riduzione del GFR tra i due gruppi, anche se emergeva invece un significativo beneficio in un sottogruppo di pazienti con malattia meno avanzata, cioè senza proteinuria e con creatininemia inferiore alla media complessiva.
    Uno studio retrospettivo del 2018(55) su 12.751 pazienti con CKD stadio 2-4, confrontando quelli trattati con ULT fino a raggiungere un’uricemia inferiore a 6 mg/dl rispetto ai non trattati, concludeva che i primi avevano una significativa maggior probabilità di miglioramento del GFR, soprattutto negli stadi 2 e 3, ma non nello stadio 4.
    Kojima e coll hanno pubblicato nel 2019 i risultati dello studio FREED(56), un RCT multicentrico giapponese con 3 anni di follow up su 1.070 anziani iperuricemici con ipertensione, diabete, CKD o patologia cardiovascolare, nell’ambito del quale l’andamento del gruppo di quelli trattati con febuxostat è stato confrontato con quello dei non trattati, dimostrando che il raggiungimento di un end-point composito, costituito dal tasso di eventi cerebrali, cardiovascolari, renali o mortali, era significativamente inferiore tra i primi. Una meta-analisi di studi condotti su pazienti di origine europea eseguita con il metodo della randomizzazione mendeliana e pubblicata nel 2019(57) dimostrava invece nuovamente, pur in presenza di un nesso causale tra livelli di UA e rischio di gotta, l’assenza di un analogo nesso rispetto al rischio di riduzione del GFR per cui gli Autori giudicavano improbabile un effetto nefroprotettivo da parte della ULT.
    Due importanti studi pubblicati nel 2020(58-59), a seguito descritti, sui quali erano riposte le aspettative di molti per una definitiva dimostrazione della possibile utilità della ULT per rallentare il calo del GFR nella HU della CKD non hanno invece raggiunto questo traguardo. Lo studio PERL(58), RCT effettuato su 530 pazienti statunitensi e canadesi con diabete tipo 1 e CKD stadio 1-3a, non ha mostrato differenze significative nel tasso medio di declino del GFR tra il gruppo trattato con l’allopurinolo e quello trattato con il placebo. Lungo l’elenco delle successive osservazioni riguardanti i limiti che potrebbero aver inficiato le conclusioni di questo studio: casistica relativamente piccola, reclutamento pianificato per pazienti con uricemia >4.5 mg/dl (quindi anche con uricemia normale) ed attuato in soggetti con diabete mediamente di lunga durata, mal controllato e con nefropatia ad andamento fast- progressive(4,9,36,60).
    Lo studio australiano e neozelandese CKD-FIX(59), RCT su 363 pazienti con CKD in stadio 3- 4 senza gotta, diabetici e non, trattati in parte con allopurinolo ed in parte con placebo e seguiti per 2 anni, ha ottenuto una riduzione delle uricemie nel braccio con allopurinolo senza ottenere differenze significative nel tasso annuo di riduzione del GFR rispetto al braccio con placebo. Anche in questo caso sono stati elencati svariati limiti che potrebbero aver inficiato le conclusioni dello studio: casistica relativamente piccola e comprendente pazienti con CKD già troppo avanzata, arruolamento avvenuto in modo incompleto (solo al 60% rispetto al numero preventivamente pianificato), elevata (17-30%) percentuale di interruzione della terapia senza conseguente esclusione di questi pazienti dalla casistica, eccessiva eterogeneità delle uricemie basali per mancata adozione tra i criteri di inclusione di un range ben definito(4,9,36,60).

    Da segnalare a questo proposito anche altre non dirette e più generali osservazioni, valide per ottimizzare il disegno di eventuali futuri studi, sul fatto che i benefici del trattamento con ULT potrebbero anche variare in funzione dell’età(60), della durata(60) e della tipologia della nefropatia di base(35,61), oltre che del tipo, della dose e della durata(4) del trattamento ipouricemizzante.
    Sempre nel 2020 Chen e coll.(62) hanno effettuato una revisione sistematica con meta- analisi di 28 RCT, tra i quali erano inclusi anche gli studi FEATHER, PERL e CKD-FIX e complessivamente riguardanti 3.934 pazienti, senza trovare benefici cardio-nefroprotettivi della ULT. Anche un successivo aggiornamento di questo studio, riportato nelle linee-guida CARI messe a punto in Australia e Nuova Zelanda nel 2022(63), nel quale sono stati selezionati 17 dei 28 RCT analizzati nel lavoro precedente, nello specifico quelli nei quali almeno il 66% dei soggetti reclutati risultasse affetto da CKD, e ne sono stati aggiunti 2 con analoghe caratteristiche, pur appurando che la ULT riduce gli attacchi gotta e non è meno sicura del placebo, ha confermato l’assenza di benefici cardionefroprotettivi e la non indicazione al suo impiego con questo scopo. Costituisce tuttavia un limite di entrambi questi studi il fatto che non tutti i pazienti avessero una HU e una CKD(4).
    Nel 2022 Tien e coll. di Taiwan(64) hanno pubblicato una revisione sistematica con meta- analisi di 13 RCT riguardanti complessivamente 2.842 pazienti con aHU rilevando benefici nefroprotettivi della ULT rispetto al placebo, dove però raggiungevano la significatività quelli trattati con allopurinolo, ma non quelli trattati con febuxostat.
    Un’altra revisione sistematica con meta-analisi di Tsukamoto e coll.(65) su 10 RCT che includevano 1.480 pazienti con CKD ha documentato una significativa azione nefroprotettiva del topiroxostat e del febuxostat nei pazienti con HU, ma non dell’allopurinolo e della pegloticase.
    Al contrario, uno studio retrospettivo statunitense su 269.651 pazienti con GFR >60 ml/min e senza albuminuria non solo non mostrava benefici nefroprotettivi nell’avvio della ULT, ma addirittura rilevava un maggior rischio di insorgenza di CKD(66).
    Sempre nel 2022, il trail randomizzato ALL-HEART ha arruolato 5.721 ultrasessantenni del Regno Unito con cardiopatia ischemica e senza gotta non trovando differenze nel raggiungimento di un endpoint composito, riguardante eventi cardiovascolari sfavorevoli, tra trattati anche con allopurinolo e trattati solo con le cure usuali(67).
    Nel 2023 una meta-analisi, eseguita da Autori brasiliani(68) su 18 RCT complessivamente riguardanti 2.463 pazienti con CKD, ha documentato significativi effetti nefroprotettivi della ULT rispetto al placebo.
    Ancora nel 2023 i risultati pubblicati da Yang e coll.(69), relativi ad un RCT multicentrico cinese su 100 pazienti con CKD in stadio 3-4 seguiti per 12 mesi, mostrano un rallentamento del declino del GFR nel gruppo trattato con febuxostat rispetto a quello trattato con placebo.
    Per quanto attiene il confronto tra i diversi farmaci utilizzabili per la ULT nella CKD, sia in termini di sicurezza di impiego, sia in termini di maggior o minor efficacia cardionefroprotettiva, alcuni articoli di più recente pubblicazione forniscono indicazioni, anche anche in questo caso non tali da consentire di trarne univoche conclusioni.
    Lo studio CARES del 2018(70), un RCT su 6.190 pazienti con gotta e patologia cardiovascolare, stratificati per livelli di GFR, dimostra la non inferiorità del febuxostat rispetto all’allopurinolo per tasso di eventi cardiovascolari avversi, ma ne palesa una maggior mortalità totale e cardiovascolare. I risultati di questo studio sono stati peraltro messi in discussione per l’alto tasso di sospensione del trattamento e di perdita al follow- up, la mancanza di un gruppo di controllo con placebo e l’insufficiente associata prescrizione di farmaci cardioprotettivi nei cardiopatici arruolati per lo studio(43).
    Nel 2021 Pawar e coll., per rivalutare il problema della sicurezza cardiovascolare in un contesto reale, hanno esaminato retrospettivamente i dati relativi a 467.461 pazienti del sistema statunitense Medicare giungendo alla conclusione che il febuxostat non aumenta il rischio cardiovascolare rispetto all’allopurinolo(71).
    La già citata revisione sistematica con meta-analisi di Tsukamoto e coll. del 2022(65) su studi relativi a pazienti con CKD documenta una significativa azione nefroprotettiva del topiroxostat e del febuxostat, ma non dell’allopurinolo e della pegloticase.
    Altri 2 RCT cinesi pubblicati nel 2022 e condotti per 6 mesi rispettivamente su 100 e 120 pazienti con CKD mostrano nel primo caso(72) la superiorità del febuxostat rispetto all’allopurinolo sia come effetto nefroprotettivo, sia come sicurezza d’impiego, e nel secondo caso(73), la maggior nefroprotezione offerta delle basse dosi di febuxostat rispetto a quelle di allopurinolo (20 mg e 200 mg rispettivamente) con sicurezza d’impiego non inferiore.
    Uno studio retrospettivo del 2023 condotto da Lai e coll.(74) su 13.661 pazienti di Taiwan con aHU in trattamento con ULT evidenzia minor rischio di sviluppare CKD con il benzbromarone che non con l’allopurinolo.
    Un’analisi post-hoc del 2023 di Kohagura e coll.(75), riferita a 707 dei 1.070 pazienti dello studio FREED(56) che avevano un GFR <60 ml/min, evidenzia che il rischio relativo di sviluppo o peggioramento della macroalbuminuria era del 56% inferiore nel gruppo con febuxostat rispetto ai controlli.
    In un altro studio randomizzato di Kohagura e coll. su 95 pazienti con ipertensione, HU e CKD in stadio 3(76) non sono emerse differenze nel declino del GFR fra quelli trattati con febuxostat e quelli trattati con benzbromarone. Il declino del GFR era peraltro significativamente inferiore con febuxostat nel sottogruppo con CKD in stadio 3a, ma non in quello in stadio 3b: tutto sommato una non trascurabile conferma che, anche i farmaci che mostrano un’efficacia nefroprotettiva nelle fasi più precoci della CKD, tendono a perderla nei pazienti con CKD in stadio più avanzato.
    La già citata meta-analisi di Bignardi e coll.(68), che documenta l’utilità della ULT ai fini nefroprotettivi, non ha trovato differenze di efficacia in tal senso fra i tre XORi studiati. Va infine per completezza ricordato che, una recente ricognizione dello stato dell’arte sui rapporti tra HU e CKD anche nell’ambito del trapianto renale, riporta un analogo clima di incertezza caratterizzato dall’evidenza che la HU, presente nel 28% dei casi, costituisca un indubbio fattore di rischio indipendente per lo sviluppo di insufficienza del rene trapiantato, ma con rapporto di causalità e indicazioni all’impiego della ULT ancora oggetto di dubbi(77).
    In conclusione, come ben dimostrato non solo dall’insieme dei risultati delle ricerche sin qui citate, ma anche dall’accesa diatriba consegnata alla Letteratura(78-80) da gruppi di Autori in dissenso su quali caratteristiche conferiscano maggiore o minore attendibilità agli studi (degne di menzione, a questo proposito, anche le critiche ai lavori nei cui gruppi di controllo non era avvenuta, come lecito attendersi, una significativa progressione della nefropatia), e come ben riporta il titolo di un’ampia revisione sull’argomento recentemente pubblicata(4), probabilmente molto resta ancora da fare.

     

    Quali comportamenti clinici e quali future ricerche gli esperti suggeriscono di adottare alla luce dell’attuale stato delle conoscenze?

    Alcuni Autori(4) suggeriscono di affrontare il problema del trattamento della HU nella CKD distinguendo i comportamenti da adottare nei pazienti con gotta da quelli nei pazienti con aHU: nel primo caso la ULT, che trova comunque indicazione per ridurre il rischio di ricorrenza degli attacchi artritici e di peggioramento del danno articolare perseguendo un target di uricemia <5-6 mg/dl(81-85), ha buona probabilità di interferire favorevolmente sulla patologia da deposito di cristalli che si sviluppa anche in sede extra-articolare (renale e vascolare)(4,39); nel secondo caso, poiché i controversi risultati delle meta-analisi si spiegherebbero anche con il fatto che alcuni sottogruppi di pazienti potrebbero giovarsi più di altri della ULT, sembra trovare crescenti consensi l’idea che la ricerca venga orientata verso l’individuazione di tali sottogruppi(4,9,36,60). In particolare, secondo Johnson e coll.4), potrebbero essere da tenere in maggior considerazione quelli con patologia tissutale da cristalli ancora silente, oggi meglio identificabili con le indagini ecografiche e DECT già in precedenza citate, quelli con cristalluria ricorrente e/o nefrolitiasi uratica e quelli con aumentati livelli intracellulari di UA, questi ultimi indirettamente individuabili attraverso il rilievo di un’incrementata attività plasmatica della XOR. Altri punti fondamentali da tenere presente nel disegnare futuri studi sono rappresentati: dal momento d’inizio della ULT (4,9,36,41), che dovrebbe essere quanto mai tempestivo e precoce perché il danno renale da UA solubile, una volta avviato, progredisce poi indipendentemente dai livelli di uricemia per l’iperfiltrazione e l’ipertensione glomerulare; dalla durata del trattamento(4) che sembra possa offrire benefici maggiori se protratto per almeno due anni; dalla verifica se il target di uricemia per ottenere l’effetto nefroprotettivo può essere o meno il medesimo adottato per la prevenzione della gotta(42).
    Altri Autori(5,40,42) suggeriscono inoltre di chiarire fino a che punto gli effetti dei farmaci XORi dipendano in modo diretto dalla loro azione ipouricemizzante e non da altri effetti quali ad esempio l’azione anti-ossidante indotta dal blocco di altri substrati della XOR.

     

    Conclusioni

    E’ assodato che la HU costituisca un fattore di rischio indipendente per lo sviluppo della CKD con crescenti anche se non definitive dimostrazioni di causalità legate a possibili plurimi meccanismi patogenetici.
    In considerazione delle differenze nel metabolismo delle purine tra una specie e l’altra va ricordato che, qualunque risultato ottenuto in proposito da esperimenti su animali dotati di attività uricasica, necessita comunque di essere riconfermato nell’uomo.
    A dispetto della presenza di un logico razionale per l’impiego della ULT ai fini del rallentamento della progressione della nefropatia nei pazienti con HU e CKD, i risultati controversi e i limiti degli studi a ciò rivolti non hanno finora portato a robuste e definitive dimostrazioni di reale efficacia in tal senso.

    Poiché il danno renale UA-correlato, una volta indotto e consolidato, sembrerebbe mantenuto da meccanismi indipendenti dai livelli di uricemia, resta da confermare se un precoce avvio della ULT nelle fasi iniziali della nefropatia abbia maggiori probabilità di fornire reale nefroprotezione. Analogamente occorre appurare se esistano altri specifici sottogruppi di pazienti che per età, sesso, tipologia di danno, nefropatia di base o altre caratteristiche abbiano maggiori probabilità di potersi giovare di tale trattamento.
    Sono pertanto auspicabili futuri più ampi RCT che, adeguatamente disegnati, e dotati di criteri di inclusione tali da superare i limiti di alcuni di quelli sin qui prodotti, analizzino la risposta ai differenti farmaci somministrati in fase iniziale di malattia, per un tempo sufficiente e in dosi idonee al raggiungimento di un target di uricemia che va anch’esso meglio ridefinito.
    Nel frattempo, nella pratica clinica quotidiana, è opportuno tenere sempre presente che quella dell’utilità della ULT a scopo nefroprotettivo nella CKD rimane una questione aperta e che tale terapia, per ora non raccomandata dalle linee guida per il protrarsi della mancanza di sicure evidenze, potrebbe in realtà essere di grande utilità almeno per alcuni dei nostri pazienti.

     

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