Interview; Dr. Juan Carlos Arana

An approach to the unknown; Rheumatic Diseases explained by an expert

Dr. Juan Carlos Arana Ruiz

High Specialty Physician from the National Institute of Respiratory Diseases (INER); focused on Continuing Medical Education and Development of Clinical Research Opportunities. Currently, Doctor at the ABC Hospital and the Clinic of Excellence of Rheumatology, Mexico.

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» Some of the most enigmatic and little-known conditions of medical science in general, without a doubt, is the set of rheumatic diseases. According to the World Health Organization (WHO), musculoskeletal disorders comprise more than 150 diseases affecting the locomo-tor system, and low back pain is the most common cause of disability in 160 countries(1).

To imagine its social scope, in addition to impacting health and being one of the specialties that have experienced the greatest demand in diagnosis and treatment in recent years, rheumatic diseases are one of the main causes of early retirement, absenteeism, and job loss worldwide.

On this occasion, we have the special collaboration of Dr. Juan Carlos Arana Ruiz, who shares with us his knowledge and experience in the field to elucidate the most frequent doubts about rheumatic diseases and their particularities.

To introduce ourselves to the subject, Dr. Juan Carlos Arana, what are rheumatic diseases and what are the main conditions that make them up?

They are a large and heterogeneous group of conditions ranging from painful syndromes of degenerative origin and chronic nature, which affect various structures of the musculoskeletal system (joints and their components, bones, muscles, etc.), to diseases where the central axis is a “disorder” in the processes of inflammation or components that usually protect us from external aggressions (mainly microorganisms) and internal (cancer), that is, the immune system, which by various very complex mechanisms, lead to the self-destruction of very varied components of the organism, from various types of joints to vital organs. (3-6)

Which population is more likely to suffer from rheumatic disease?

The answer is as diverse as rheumatic diseases. Although in general, they tend to affect women much more frequently (biologically speaking), being much more prone, especially during their reproductive years (from menarche to the arrival of menopause), which we call

autoimmune. However, the tendency to suffer from autoinflammatory diseases, although usually a little more common in men (e.g. ankylosing spondylitis), evidence shows that they are rather diagnosed late in women, more frequently. (4-6)

What are the latest advances in clinical research and drug development in the area of rheumatology?

Unquestionably, Rheumatology has suffered an explosion since the 90’s, with the advent of disease-modifying drugs (DMARDs) of a biological type, which are strategically designed against molecules responsible for triggering and perpetuating self-injurious inflammatory processes, such as TNF inhibitors (one of the most important molecules responsible for inflammation), also called anti-TNF, to mention some of the many examples now available, even for pathologies that were previously conside-red practically untreatable, when there was no response to traditional synthetic DMARDs (such as methotrexate, leflunomide, etc.) or the most toxic immunosuppressants (cyclosporine, azathioprine, etc.).

Such is the case of spondyloarthropathies, for which there is now a wide therapeutic weapon with efficacy that had never before been seen in problems such as psoriasis or ankylosing spondylitis (anti-IL17A, anti-IL12/23, etc.). However, the new revolution is made up of small molecules (JAK-STAT inhibitors), which make it possible to treat even as monotherapy, for conditions that have not responded to more economically accessible drugs. There are still multiple investigational drugs that have at least high biological plausibility, however, that will be defined by the future to come. (7)

On this subject, I would like to comment that there are now techniques that combine nanotechnology and bioengineering with molecular biology and immunology, at a level that seems like science fiction, such as CAR-T cells, which literally allow editing “at ease”, according to the most plausible target molecule, to achieve remission in conditions that were previously considered untreatable or that lose any response to available treatments.

Today, this is even achieved in people with lupus. Stem cell transplantation is also promising new possibilities every day in diseases as difficult to treat and as aggressive as systemic sclerosis. (7-11)

» In this same atmosphere of advances in the area, people with rheumatic diseases have benefited through innovative and patient-centered research, from basic research using disease models to clinical research that explains new tests or treatments. Based on this, what advantages could a person with a rheumatic disease obtain by entering a clinical research protocol?

It is precisely the research protocols (clinical trials) that have allowed revolutions in treatment. It is important for patients to know that when they are suggested to participate in a protocol, it is because their chances of response have been diminished and are a biologically very plausible option, that is, they have already been tested extensively and meticulously in cellular media, in animal models, and in healthy patients, to know their safe dose. Depending on the phase of the protocol, efficacy will be investigated and this is where many patients could benefit from less toxic and more potent alternatives when what is currently available on the market is not enough. (6-12)

How frequent is counterfeiting of medicines against rheumatic diseases and what are the consequences of their consumption?

Unfortunately, malicious people are not uncommon, so you must be very careful that any drug, even the one that “promises” to be of natural origin (in fact this is usually an alarm when they claim to be 100% natural since nothing encapsulated is 100% natural by its very essence), since its origin is dirty money, in addition to having another interest than economic gain, at the expense of people’s suffering. They must always make sure to use and consume drugs purchased in legally established places and certified by the corresponding Health Authority.

Never consume anything that has violations in their seal or does not follow the extremely strict standards of quality. Consequences, when there are any, the least serious, is simply the lack or loss of effectiveness, but we have even come to see contamination by carcinogens and infectious agents, the latter, with sometimes catastrophic consequences such as the loss of an organ due to infection. (17)

» Although at least five million people worldwide have a form of Systemic Lupus Erythematosus(2), it is currently a very poorly understood pathology compared to other diseases due to the complexity of its symptoms and treatments. As for this disease, what do you think are the best treatment options and management strategies for people with Lupus?

The first and most important strategy is proper and early diagnosis. At least 70% of patients who come to my office with a suspected diagnosis of lupus do not actually have lupus. This is a disease that became fashionable because it was suffered by a famous person, but it is fortunately rare, affecting less than 0.05 to 0.1% of the world’s population, especially in its most severe forms. In this regard it is important to note that each patient with lupus is very particular, I have never seen two patients exactly alike, even though there are classification criteria that have become ostensibly easier to use for diagnosis; a rheumatologist is required to certify the diagnosis, often in a joint effort with other specialists. The treatment should always be orchestrated by a specialist in Rheumatology,

since it is complex, still poorly distinguishable, except for the most severe forms, and in continuous evolution. Today we have two approved biologics, belimumab and anifrolumab which, however, are not useful for any patient. As well as an old acquaintance, rituximab, although it does not have the approval, has been used in an artisanal way, although it is also not effective in all patients, so a treatment directed by objectives is recommended where some glucocorticoid is used as little time as possible (as bridge therapy), which allows improving the quality of life of the affected person, as well as ensuring complete remission (ideally) of the disease. (12-13)

What is drug-induced lupus?

Excellent and accurate question, given that precisely many patients who experience this problem, is simply due to some drug that generates a disordered immune response and its interruption alone is enough to end the problem in at least 90% of those who suffer from it. The most common in favoring it are some antiarrhythmics such as amiodarone or propafenone, as well as antihypertensives such as alphamethyldopa or hydralazine.

But even in TNF inhibitors it has been described, by the way, that rarely this type of lupus affects beyond skin, joints and if anything, blood cells, but in the case of the latter, up to 8% come to have kidney involvement. It should be noted that the chance of a person developing this type of disordered response is very low, so they should not panic if they are told and do not have any autoimmune diseases in the family. As I said, it usually remits in the vast majority, with simply stopping the drug and strangely it is serious. (15-16)

Finally, dear Dr. Arana, what is the role of genetics in rheumatic diseases?

Excellent question, although its answer is extremely heterogeneous, as heterogeneous are autoimmune diseases (where there is a large number of genes involved, and will depend on the presence of one or more of these, as well as polymorphisms in these genes, eg, in lupus only more than 30 genes have been described, and the agreement in identical twins is 24% - 35%) and autoinflammatory (these with greater genetic predisposition, for example, those of Norse ancestry with the presence of HLA-B27). Genetic penetrance is higher in chronic-degenerative diseases, such as osteoarthritis of the hands, where the risk is as high as 87% of suffering from it in identical twins. (12-14)

Clinical Research Insider Editorial

References

1. World Health Organization (WHO) 8 February 2021. Musculoskeletaldisorders . Accessed December 15, 2022. Retrieved from: https://www.who.int/es/ news-room/fact-sheets/detail/musculoskeletal-conditions

2. Fundación Lupus de América. Last updated: February 23, 2022. Hechosyestadísticassobrelupus.Accessed December 15, 2022. Retrieved from: https:// www.lupus.org/es/resources/hechos-y-estadisticas-sobre-lupus

3. Lin, C.M.A., Cooles, F.A.H. & Isaacs, J.D. Precision medicine: the precision gap in rheumatic disease. NatRevRheumatol18 , 725–733 (2022). https://doi. org/10.1038/s41584-022-00845-w

4. Stovall, R., van der Horst-Bruinsma, I.E., Liu, SH. et al. Sexual dimorphism in the prevalence, manifestation and outcomes of axial spondyloarthritis. Nat RevRheumatol18,657–669 (2022). https://doi.org/10.1038/s41584-022-00833-0

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9. Volkmann, E.R., Varga, J. Emerging targets of disease-modifying therapy for systemic sclerosis. NatRevRheumatol15,208–224 (2019). https://doi. org/10.1038/s41584-019-0184-z

10. Bruner V, Atteno M, Spanò A, Scarpa R, Peluso R. Biological therapies for spondyloarthritis. TherAdvMusculoskeletDis.2014 Jun; 6(3):92-101. doi: 10.1177/1759720X14535512. PMID: 24891880; PMCID: PMC4040940.

11. Mackensen, A., Müller, F., Mougiakakos, D. et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. NatMed28,2124–2132 (2022). https://doi.org/10.1038/s41591-022-02017-5

12. Samotij D, Reich A. Biologics in the Treatment of Lupus Erythematosus: A Critical Literature Review. BiomedResInt.2019 Jul 18; 2019:8142368. doi: 10.1155/2019/8142368. PMID: 31396534; PMCID: PMC6668536.

13. Guerra SG, Vyse TJ, Cunninghame Graham DS. The genetics of lupus: a functional perspective. ArthritisResTher.2012 May 29; 14(3):211. doi: 10.1186/ ar3844. PMID: 22640752; PMCID: PMC3446495.

14. Magnusson K, Turkiewicz A, Haugen IK, Englund M. The genetic contribution to hand osteoarthritis. OsteoarthritisCartilage.2022 Oct;30(10):1385-1389. doi: 10.1016/j.joca.2022.06.011. Epub 2022 Jul 14. PMID: 35843480.

15. He Y, Sawalha AH. Drug-induced lupus erythematosus: an update on drugs and mechanisms. CurrOpinRheumatol.2018 Sep; 30(5):490-497. doi: 10.1097/BOR.0000000000000522. PMID: 29870500; PMCID: PMC7299070.

16. Solhjoo M, Goyal A, Chauhan K. Drug-Induced Lupus Erythematosus. [Updated 2022 Apr 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441889/

17. Palacios García, SA. (2020). La otra pandemia. RevistadelaOFIL,30(3), 178. Epub 05 de abril de 2021. https://dx.doi.org/10.4321/s1699714x2020000300004