a case study rheumatoid arthritis

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• Published: 26 April 2024

Bispecific T cell engager therapy for refractory rheumatoid arthritis

• Laura Bucci 1 , 2   na1 ,
• Melanie Hagen 1 , 2   na1 ,
• Tobias Rothe 1 , 2 ,
• Maria Gabriella Raimondo 1 , 2 ,
• Filippo Fagni 1 , 2 ,
• Carlo Tur 1 , 3 ,
• Andreas Wirsching 1 , 2 ,
• Jochen Wacker 1 , 2 ,
• Artur Wilhelm 1 , 4 ,
• Jean-Philippe Auger 1 , 2 ,
• Milena Pachowsky   ORCID: orcid.org/0000-0002-3729-9566 1 , 2 ,
• Markus Eckstein   ORCID: orcid.org/0000-0001-5418-3349 5 ,
• Stefano Alivernini   ORCID: orcid.org/0000-0002-7383-4212 3 ,
• Angelo Zoli 3 ,
• Gerhard Krönke 1 , 4 ,
• Stefan Uderhardt 1 , 2 ,
• Aline Bozec 1 , 2 ,
• Maria-Antonietta D’Agostino   ORCID: orcid.org/0000-0002-5347-0060 3 ,
• Georg Schett   ORCID: orcid.org/0000-0001-8740-9615 1 , 2 , 3 , 6   na2 &
• Ricardo Grieshaber-Bouyer   ORCID: orcid.org/0000-0002-2873-5135 1 , 2   na2  

Nature Medicine ( 2024 ) Cite this article

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• Immunotherapy
• Rheumatoid arthritis

Bispecific T cell engagers (BiTEs) kill B cells by engaging T cells. BiTEs are highly effective in acute lymphoblastic leukemia. Here we treated six patients with multidrug-resistant rheumatoid arthritis (RA) with the CD19xCD3 BiTE blinatumomab under compassionate use. Low doses of blinatumomab led to B cell depletion and concomitant decrease of T cells, documenting their engager function. Treatment was safe, with brief increase in body temperature and acute phase proteins during first infusion but no signs of clinically relevant cytokine-release syndrome. Blinatumomab led to a rapid decline in RA clinical disease activity in all patients, improved synovitis in ultrasound and FAPI-PET-CT and reduced autoantibodies. High-dimensional flow cytometry analysis of B cells documented an immune reset with depletion of activated memory B cells, which were replaced by nonclass-switched IgD-positive naïve B cells. Together, these data suggest the feasibility and potential for BiTEs to treat RA. This approach warrants further exploration on other B-cell-mediated autoimmune diseases.

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Data availability.

All numerical data in this paper can be obtained from the corresponding author within 4 weeks upon request via email to [email protected]. Patient data can be shared only in pseudonymized form. Otherwise, there are no restrictions to data access. All data graphs in the figures (Figs. 1b–f , 2a,e–g , 3a–e,i and 4a–i and Extended Data Figs. 1 , 2a–g and 3a–m ) show raw data and depict individual values. Source data are provided with this paper.

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Acknowledgements

We thank J. Verhagen and A. Wegner for performing tissue imaging, H. Bang (Orgentec) for performing antimodified peptide autoantibody measurements and T. Winkler for helpful discussions. This study was supported by the Deutsche Forschungsgemeinschaft (DFG) through the Leibniz Award (G.S.), GR 5979/2-1 (R.G.-B.), the research group FOR2886 and the CRC1181, CRC1483, CRC/TRR305 and CRC/TRR221, the Else Kröner-Fresenius-Stiftung through 2022_EKEA.72 (to R.G.-B.) and the IZKF Erlangen (grant N10, to R.G.-B.). Further funding has been obtained from the Bundesministerium für Bildung und Forschung through the MASCARA project and the European Union (ERC Synergy grant 4D Nanoscope). We also acknowledge funding from Staedtler Stiftung.

Author information

These authors contributed equally: Laura Bucci, Melanie Hagen.

These authors jointly supervised this work: Georg Schett, Ricardo Grieshaber-Bouyer.

Authors and Affiliations

Department of Internal Medicine 3—Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany

Laura Bucci, Melanie Hagen, Tobias Rothe, Maria Gabriella Raimondo, Filippo Fagni, Carlo Tur, Andreas Wirsching, Jochen Wacker, Artur Wilhelm, Jean-Philippe Auger, Milena Pachowsky, Gerhard Krönke, Stefan Uderhardt, Aline Bozec, Georg Schett & Ricardo Grieshaber-Bouyer

Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany

Laura Bucci, Melanie Hagen, Tobias Rothe, Maria Gabriella Raimondo, Filippo Fagni, Andreas Wirsching, Jochen Wacker, Jean-Philippe Auger, Milena Pachowsky, Stefan Uderhardt, Aline Bozec, Georg Schett & Ricardo Grieshaber-Bouyer

Department of Rheumatology, Fondazione Policlinico Universitario A Gemelli, IRCSS, Catholic University of Sacred Heart, Rome, Italy

Carlo Tur, Stefano Alivernini, Angelo Zoli, Maria-Antonietta D’Agostino & Georg Schett

Department of Rheumatology, Charite, Berlin, Germany

Artur Wilhelm & Gerhard Krönke

Department of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany

Markus Eckstein

Karolinska Institutet, Stockholm, Sweden

Georg Schett

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Contributions

L.B., M.H., G.S. and R.G.-B. conceived the study and contributed to the study design. L.B., M.H., G.S. and R.G.-B. performed clinical and experimental data generation and statistical analysis. T.R., M.G.R., F.F., C.T., A. Wirsching, J.W., A. Wilhelm, J.-P.A., M.P., M.E., S.A., A.Z., G.K., S.U., A.B. and M.-A.D’A. contributed to clinical data generation, data analysis, interpretation and writing. All authors contributed to data interpretation and edited the paper.

Corresponding author

Correspondence to Georg Schett .

Ethics declarations

Competing interests.

There are no conflicts of interest related to this study. The study received no commercial funding. M.-A.D.’A. has received speaker honoraria from Abbvie, Novartis and Janssen, which were not related to this study. G.S. has received speaker honoraria from Janssen and Novartis, which were not related to this study. The other authors declare no competing interests.

Peer review

Peer review information.

Nature Medicine thanks Lihua Budde, David Fox and Deepak Rao for their contribution to the peer review of this work. Primary Handling Editor: Saheli Sadanand, in collaboration with the Nature Medicine team.

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Extended data

Extended data fig. 1 acute phase cytokines by individual patient..

Serum cytokines were analyzed by Luminex assay (N = 6 for time points T0, T2, T3, T5 and N = 4 for time points T1, T4).

Extended Data Fig. 2 T cell subsets after blinatumomab treatment in RA.

Effects of blinatumomab on ( a ) CD4+ and CD8 + T cells, ( b ) the CD4/CD8 ratio, ( c ) the proportion of naïve, effector memory (EM) and central memory (CM) CD4 + T cells, ( d ) the proportion of naïve, effector memory (EM) and central memory (CM) CD8 + T cells, ( e ) terminally differentiated effector memory CD4+ cells re-expressing CD45RA (TEMRA) ( f ) Foxp3+ regulatory T cells, ( g ) terminally differentiated effector memory CD8+ cells re-expressing CD45RA (TEMRA), ( h ) RORgt+ Th17 cells. N = 5 individual patients. Dark line depicts the median.

Extended Data Fig. 3 24 week follow-up after blinatumomab therapy during abatacept maintenance.

( a ) tender joint count, ( b ) swollen joint count, ( c ) patient global disease activity (visual analogue scale; 0–100) and ( d ) disease activity score 28 (DAS28). Hatched lines show cut-off for remission (2.6). ( e ) rheumatoid factor, ( f ) anti-cyclic citrullinated peptide (CCP)-2 autoantibodies, ( g ) anti-citrullinated, ( h ) anti-carbamylated, ( i ) anti-acetylated vimentin autoantibodies and (j) non-modified vimentin autoantibodies (control) ( k ) immunoglobulin G, ( l ) immunoglobulin A and ( m ) immunoglobulin M levels. N = 6 individual patients. Dark line depicts the median.

Supplementary information

Reporting summary, supplementary data 1.

Source data for Extended Data Fig. 1.

Supplementary Data 2

Source data for Extended Data Fig. 2.

Supplementary Data 3

Source data for Extended Data Fig. 3.

Source data

Source data fig. 1.

Source data for Fig. 1.

Source Data Fig. 2

Source data for Fig. 2.

Source Data Fig. 3

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Bucci, L., Hagen, M., Rothe, T. et al. Bispecific T cell engager therapy for refractory rheumatoid arthritis. Nat Med (2024). https://doi.org/10.1038/s41591-024-02964-1

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Published : 26 April 2024

DOI : https://doi.org/10.1038/s41591-024-02964-1

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Case Study: 106-Year-Old Woman Suddenly Develops Rheumatoid Arthritis

— diagnosis was challenging, but treatment was ultimately successful, authors related.

by Kate Kneisel , Contributing Writer, MedPage Today

"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

This month: A noteworthy case study

What to do for a 106-year-old woman who suddenly lost her mobility over the course of a few months, after being able to walk unassisted and live independently in her own home? That's what Ahmed Dheyaa Al-Obaidi, MBChB, of the University of Baghdad in Iraq, and colleagues had to figure out, as they recounted in Clinical Case Reports .

The patient noted that she had recently consulted a general practitioner but had been misdiagnosed with osteomalacia, after which she had been started on a regimen of vitamin D and calcium supplements.

She told clinicians that she had a relative who had been diagnosed with rheumatoid arthritis (RA) that had been treated with methotrexate and rituximab for 5 years.

Physical examination found her vital signs to be within normal ranges. Clinicians noted that she had significant inflammation and tenderness in her hands and feet, which presented as bilateral swelling in her wrists, metacarpophalangeal (MCP) joints, and proximal interphalangeal (PIP) joints. The metatarsophalangeal joints of both feet were similarly swollen and painful, to the extent that she had been unable to stand on her feet for the previous 3 months.

She did not smoke, and had long-standing, although well-controlled, hypertension of 20+ years.

Clinicians considered several differential diagnoses, including inflammatory arthritis, crystal arthritis, and degenerative arthritis, and also wondered if her symptoms were related to dysfunction of the endocrine system or perhaps reflected cancer-related musculoskeletal symptoms.

Lab tests showed that her hemoglobin was 10 g/dL, erythrocyte sedimentation rate (ESR) was 65 mm/h, and C-reactive protein and rheumatoid factor were both positive. Serum uric acid, liver function, renal function, and thyroid function were all within normal ranges, and screening tests for viral infections were negative.

Chest x-ray and abdominal ultrasound findings were both unremarkable, and x-rays of the hands revealed bilateral osteopenia and erosion at the wrists, and MCP and PIP joints. Hand deformities included ulnar deviation, Z-shaped deformity of both thumbs and wrists, and swelling of the MCP joints.

Imaging and blood tests confirmed the diagnosis of rheumatoid arthritis, and the patient was started on methotrexate 7.5 mg weekly and folic acid 5.0 mg weekly. To help address the side effects of nonsteroidal anti-inflammatory drugs, clinicians also prescribed paracetamol for pain.

When the patient returned for follow-up, she reported that her pain levels had gradually diminished so that she was able to walk again without help, and her appetite had improved.

Follow-up testing showed that her ESR value had decreased to 40 mm/h and there was no change in liver function. She continued with treatment, and was scheduled for regular follow-up assessments.

Al-Obaidi and co-authors called the case "extremely rare" and said that by reporting the case, believed to be the first in the literature in a patient of this age, they hoped "to encourage medical professionals to concentrate on diagnosing old patients with unusual presentation of rheumatoid arthritis."

RA is a chronic, progressive multisystemic inflammatory disease characterized by damaging synovitis, which ultimately destroys the joints, resulting in loss of function and disability. The condition is associated with decreased quality of life and increased morbidity and mortality. RA can affect any joint, but "is most often associated with erosive alterations in the tiny joints of the hand and foot," the case authors explained.

Although the incidence of RA is considered to peak from ages 30-50, recent data suggest an increasing number of cases (approximately 2%) that develop in people in their late 60s -- so-called elderly-onset rheumatoid arthritis (EORA), the team noted.

Several clinical characteristics have been identified that distinguish EORA from young (earlier)-onset RA. Al-Obaidi and colleagues cited a paper suggesting that EORA has a "more equal gender distribution, a higher frequency of acute onset with constitutional symptoms," and that patients are less likely to be positive for rheumatoid factor (RF) or anti-cyclic citrullinated peptide antibody.

EORA has three different clinical presentations, Al-Obaidi and colleagues said. The first type, which accounts for about 70% of EORA cases, is more likely to be RF-positive and involve joint erosions; this type has a comparatively worse prognosis than young-onset rheumatoid arthritis.

"The second variant (25%) is a polymyalgia rheumatica (PMR)-like form with involvement of the proximal limb joints," the authors noted. This type tends to be negative for RF, to develop more rapidly, generally does not involve joint erosions, and has a more favorable prognosis. "Asymmetric nonerosive polyarthritis may develop in 25% of PMR patients; hence, a differential diagnosis is important to be excluded," the team wrote.

The third type of EORA is similar to remitting seronegative symmetrical synovitis with pitting edema in terms of both its clinical pattern and prognosis, the case authors noted, explaining that the literature is conflicting as to whether the outcomes of EORA patients are better or worse compared with those with earlier-onset RA.

This lack of a predictable prognosis makes it challenging to advise patients. However, recent data to help guide treatment decisions, including from a 2022 study suggested that the time to remission is similar in the two RA groups.

Those researchers speculated that because of the older age of EORA patients, they are more likely to be fragile, to have co-existing comorbidities, and to have a greater risk of disease-modifying antirheumatic drug (DMARD) related toxicity .

Given the case report patient's age of 106, treatment decisions were complicated by the presence of comorbidities, even though her condition showed significant improvement using DMARDs, Al-Obaidi and co-authors added.

Read previous installments of this series:

Part 1: RA Beginnings: Before the Painful Joints

Part 2: RA: Still a Clinical Diagnosis

Part 3: RA: Choosing Initial Treatment

Kate Kneisel is a freelance medical journalist based in Belleville, Ontario.

Disclosures

The authors reported no conflicts of interest.

Primary Source

Clinical Case Reports

Source Reference: ALQazzaz A, et al "Unusual presentation of rheumatoid arthritis in a 106-year-old woman: A rare case report" Clin Case Rep 2023; DOI:10.1002/ccr3.7120.

Rheumatoid arthritis: Differentiating between forms of crippling arthritis

Emma, a 32-year-old with existing foot and hand pain, visits her healthcare provider after hand pain, neck stiffness, and worsening fatigue over the last three months.

Emma’s healthcare provider conducts a full clinical history and physical examination and decides to test for rheumatoid arthritis.  

Emma is experiencing joint pain and fatigue. See how serological testing can help confirm a diagnosis of rheumatoid arthritis.

Patient History

Family history.

• Mother has unknown form of crippling arthritis.

Emma's Personal History

• Localized pain in knuckles of hand and pads of feet.
• Ibuprofen helps some, and acetaminophen does not.
• Imaging: Marginal erosions were detected on radiographs.
• Physical examination: Normal with the exception of the hands, which were tender when palpated over the second and third proximal interphalangeal joints.

Emma’s  Test Results

These results together with this patient's case history and symptoms, help confirm the diagnosis.  

Differential Diagnosis

REFINED DIAGNOSIS

• Inflammatory arthritis, rheumatoid.

HEALTHCARE PROVIDER MANAGEMENT PLAN

• Steroids and methotrexate initially.
• Biologics or triple therapy if inadequate response.
• Follow up every eight to 12 weeks in the beginning to assess therapies and monitor lab work.
• Healthcare provider visits may extend to every three to six months if well controlled.

The people, places, and events depicted in these case studies and photographs do not represent actual patients, nor are they affiliated in any way with Thermo Fisher Scientific.

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Effect of Humor on Pain and Anxiety in Patients With Rheumatoid Arthritis: A Prospective, Randomized Controlled Study

Affiliation.

• 1 Author Affiliations: Department of Radiotherapy, Hannover Medical School, Hannover, Germany. (Dr Babadağ Savaş); Department of Internal Medicine Nursing, Faculty of Health Science (Dr Balcı Alparslan), Department of Biostatistics, Faculty of Medicine (Dr Çolak), and Department of Internal Medicine and Rheumatology, School of Medicine (Mrs Orlu [retired] and Dr Korkmaz), Eskisehir Osmangazi University, Eskisehir, Turkey.
• PMID: 38709128
• DOI: 10.1097/HNP.0000000000000645

Humor can contribute to nursing practices for relieving pain and anxiety in patients with rheumatoid arthritis (RA) during intravenous (IV) biologic treatment. This study used a prospective, randomized controlled study design to investigate the effect of humor on pain and state anxiety in patients with RA receiving IV infusion therapy. Two sample groups were formed: the intervention group (watching a comedy movie) (n = 18) and the control group (usual care) (n = 18). Both groups received IV biologic therapy. A significant difference was found between the groups' pain mean scores, but the effect size was small (P < .001, η² = 0.032). The mean visual analog scale scores decreased in both groups after the treatment; however, it decreased more in the intervention group (P < .001, Md = 2.44) than in the control group (P = .017, Md = 0.83). No significant difference was found between the groups' mean state anxiety scores, and the effect size was irrelevant (P > .05, η² = 0.001). There was a significant decrease in the anxiety levels of both groups (P < .001). During IV biologic infusion therapy, watching comedy movies is recommended as a nursing care intervention for reducing pain in patients with RA in cooperation with other health professionals.

Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.

Publication types

• Randomized Controlled Trial
• Anxiety* / etiology
• Anxiety* / psychology
• Anxiety* / therapy
• Arthritis, Rheumatoid* / complications
• Arthritis, Rheumatoid* / psychology
• Arthritis, Rheumatoid* / therapy
• Middle Aged
• Pain / etiology
• Pain / psychology
• Pain Management* / methods
• Pain Management* / standards
• Pain Management* / statistics & numerical data
• Pain Measurement / methods
• Pain Measurement / statistics & numerical data
• Prospective Studies
• Wit and Humor as Topic / psychology

Case study: management and counselling of a patient with rheumatoid arthritis

Exploring questions to be considered when managing a patient with rheumatoid arthritis.

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Case scenario

Mrs PJ is a 67-year-old woman with rheumatoid arthritis. Her current prescription includes:

• Salazopyrin EN 500mg twice a day;
• Diclofenac 50mg three times a day;
• Paracetamol 1g up to four times a day when required.

She collected her first prescription for sulfasalazine two weeks ago. She has returned to the pharmacy and asks to speak to you. She has several problems with her medication which she wishes to discuss. First, she complains that her medication is not working properly and she tells you that she has not noticed any benefit from it. She asks you whether you think she should make an appointment with her GP to discuss this.

Case discussion

Pharmacy Case Studies by Soraya Dhillon and Rebekah Raymond. Pp 471 £29.99. London: Pharmaceutical Press; 2009. ISBN 978 0 85369 724 4

This discussion, adapted from Pharmacy Case Studies [1]   published by Pharmaceutical Press, highlights the main questions to be considered in managing Mrs PJ’s case. 

How is the dose of sulfasalazine normally initiated and titrated?

The patient should start with one tablet daily, increasing their dosage by a tablet a day each week until one tablet four times a day, or two tablets three times a day are reached, according to tolerance and response.

Why is the dose increased gradually?

Nausea may be a problem for some patients, hence the dose is titrated up gradually to avoid this.

What advice would you give Mrs PJ in answer to her question? 

Mrs PJ should be informed that the onset of effect of sulfasalazine is slow and an initial benefit may not be seen for 4–16 weeks. It would be useful to check what instructions Mrs PJ has been given regarding the titration of her medication. She is currently on a dose at the lower end of the titration scale.

You could ask Mrs PJ when her follow-up appointment with the prescribing doctor is due. If she has an appointment in the very near future, her dose may be increased at that consultation. 

If Mrs PJ has not been given a titrating dose, it may be worth suggesting that she contacts her prescribing doctor to confirm the instructions given to her at the initial appointment. It is important to reiterate that the onset of action of the sulfasalazine is slow.

Mrs PJ also mentions that she has to go to her practice nurse for some blood tests but she’s not sure why. The British National Formulary recommends that liver function tests, full blood counts and renal function tests are carried out regularly.

How often should the above tests be performed?

Close monitoring of the full blood count and liver function tests is necessary initially and then at monthly intervals for at least the first three months of treatment. Renal function tests may be performed periodic­ally, as recommended by the manufacturers.

Why should these tests be performed?

Side effects of sulfasalazine include blood dyscrasias which usually occur in the first 3–6 months of treatment. The full blood count should be checked regularly so that any haematological abnormalities can be ­identified at an early stage. 

There have been reports of hepatitis and renal dysfunction in patients taking sulfasalazine, therefore liver function tests and renal function tests should be performed at regular intervals.

In the course of the conversation, Mrs PJ tells you that since she has started taking her new medication, she has been experiencing stomach discomfort about half an hour after she has taken her tablets. 

What do you think could be the cause of this problem?

As the symptoms initially appear to be related to her medication she may be experiencing gastric irritation as a result of her diclofenac or she may be suffering from nausea due to the sulfasalazine. Ask Mrs PJ whether she is suffering from any alarm symptoms like gastrointestinal bleeding, unintentional weight loss, difficulty swallowing, abdominal swelling or persistent vomiting. If Mrs PJ is experiencing any of these symptoms, she should be referred to her GP urgently.

What suggestions could you offer Mrs PJ to help resolve this problem?

With further questioning, it may be possible to clarify the symptoms and to ascertain whether one of the drugs is likely to be causing the problem. You should check that Mrs PJ is taking her diclofenac with food so as to reduce the risk of gastric irritation. If you decide that the problem is likely to be dyspepsia, in most cases an antacid may help. In this case, however, an antacid could not be taken at the same time as either sulfasalazine or diclofenac. This is because both are enteric-coated tablets and the presence of an antacid may lead to the premature dissolution of the coating due to the presence of an alkaline pH. Therefore, the use of an antacid would not be a suitable suggestion.

As this is a suspected adverse drug reaction, it would be prudent to suggest to Mrs PJ that she returns to her GP to discuss this issue with them.

What alternative medication might a doctor prescribe to help Mrs PJ with her upset stomach?  

If the doctor decided that the cause of Mrs PJ’s upset stomach may be non-steroidal anti-inflammatory drug (NSAID)-induced dyspepsia, it would be usual to stop NSAID treatment. However in the case of Mrs PJ, this might not be possible due to her concurrent medical history of rheumatoid arthritis. 

The doctor may decide to stop the NSAID and see how Mrs PJ ­manages without the diclofenac or may consider adding in a proton pump inhibitor, in line with Clinical Knowledge Summaries guidance [2] , to manage the incid­ence of NSAID-induced dyspepsia. If it is felt that the problem is related to the sulfasalazine and the nausea does not abate, the doctor may try an alternative treatment. As Mrs PJ is currently only on a low dose of sulfasalazine it would not really be possible to reduce the dose and still maintain efficacy.

Four months later, Mrs PJ returns to your pharmacy. She says that she still has not had much benefit from her sulfasalazine despite the fact that her dose has been titrated to an appropriate level.

What are the goals of therapy when treating rheumatoid arthritis?

When treating rheumatoid arthritis, the goals of therapy are to reduce the symptoms of the disease, slow progression of the disease and limit the amount of joint deformation, while improving the patient’s quality of life.

Please list the alternative treatments that may be used in the management of rheumatoid arthritis and briefly discuss when an alternative treatment would be tried.

When a drug has been titrated to the maximum dose that can be tolerated and the level of disease control is still unacceptable, therapy may be switched to an alternative agent or another drug may be added in. Other treatments available for managing rheumatoid arthritis include:

• methotrexate
• gold injections
• antimalarials
• leflunomide
• penicillamine
• ciclosporin
• azathioprine
• cyclophosphamide
• cytokine modulators
• corticosteroids

Nicola Parr , BPharm (Hons), MSc, MRPharmS is senior pharmacist, Addenbrooke’s Hospital, Cambridge and Tracy Garnier , BSc (Hons), PhD, PgCert, MRPharmS is principal lecturer in pharmaceutics, School of Pharmacy, University of Hertfordshire.

[1]   Pharmacy Case Studies by Soraya Dhillon and Rebekah Raymond. Pp 471 £29.99. London: Pharmaceutical Press; 2009. ISBN 978 0 85369 724 4

[2]  Clinical Knowledge Summaries (2015) Dyspepsia. Available at:  http://cks.nice.org.uk/dyspepsia-unidentified-cause#!scenario:2

General reference

Bryant DM & Alldred A. Rheumatoid arthritis and osteoarthritis (2007). In: Walker R and Whittlesea C (Eds)  Clinical Pharmacy and Therapeutics , 4th edn. Edinburgh: Churchill Livingstone.

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Article Contents

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Treatment response in rheumatoid arthritis is predicted by the microbiome: a large observational study in UK DMARD-naive patients

N.P.D. and M.B.F. contributed equally.

• Article contents
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Nathan P Danckert, Maxim B Freidin, Isabelle Granville Smith, Philippa M Wells, Maryam Kazemi Naeini, Alessia Visconti, Roger Compte, Alexander MacGregor, Frances M K Williams, Treatment response in rheumatoid arthritis is predicted by the microbiome: a large observational study in UK DMARD-naive patients, Rheumatology , 2024;, keae045, https://doi.org/10.1093/rheumatology/keae045

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Disease-modifying antirheumatic drugs (DMARDs) are a first-line treatment in rheumatoid arthritis (RA). Treatment response to DMARDs is patient-specific, dose efficacy is difficult to predict and long-term results are variable. The gut microbiota are known to play a pivotal role in prodromal and early-disease RA, manifested by Prevotella spp. enrichment. The clinical response to therapy may be mediated by microbiota, and large-scale studies assessing the microbiome are few. This study assessed whether microbiome signals were associated with, and predictive of, patient response to DMARD treatment. Accurate early identification of those who will respond poorly to DMARD therapy would allow selection of alternative treatment (e.g. biologic therapy) and potentially improve patient outcome.

A multicentre, longitudinal, observational study of stool- and saliva microbiome was performed in DMARD-naive, newly diagnosed RA patients during introduction of DMARD treatment. Clinical data and samples were collected at baseline ( n  = 144) in DMARD-naive patients and at six weeks ( n  = 117) and 12 weeks ( n  = 95) into DMARD therapy. Samples collected ( n  = 365 stool, n  = 365 saliva) underwent shotgun sequencing. Disease activity measures were collected at each timepoint and minimal clinically important improvement determined.

In total, 26 stool microbes were found to decrease in those manifesting a minimal clinically important improvement. Prevotella spp. and Streptococcus spp. were the predominant taxa to decline following six weeks and 12 weeks of DMARDs, respectively. Furthermore, baseline microbiota of DMARD-naive patients were indicative of future response.

DMARDs appear to restore a perturbed microbiome to a eubiotic state. Moreover, microbiome status can be used to predict likelihood of patient response to DMARD.

• rheumatoid arthritis
• antirheumatic drugs, disease-modifying

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Patients with rheumatoid arthritis have unique and complex autoantibody patterns, study reveals

by Utrecht University

Patients with rheumatoid arthritis (RA) all have a unique and diverse set of antibodies that are involved in the development of the disease. Researchers at Utrecht University unveiled the complexity of these antibodies using powerful lab tools capable of analyzing our immune system at molecular levels. Their discovery suggests that current assumptions about the origin of RA are too simple. Their findings may point towards improved diagnostics.

Rheumatoid arthritis is a chronic autoimmune disease that primarily affects the joints, causing pain, stiffness, and swelling. It arises when the immune system mistakenly attacks the body's own tissues, leading to inflammation in the joints and potentially other organs.

The exact cause of RA remains unknown, but a crucial role is played by antibodies, special proteins made by the immune system to help fight off infections. They recognize and attack specific targets, like viruses or bacteria. Some antibodies are wrongly produced, causing them to attack our own body. Normally, our body's immune system is equipped with a 'filter' that cleans up these so-called autoantibodies. Researchers believe that this mechanism is malfunctioning in RA patients.

The extend to which this filter is malfunctioning, now appears to be much greater than expected. Research by Albert Bondt and colleagues from Utrecht University and Leiden University Medical Center (LUMC), published in Nature Communications , reveals that it's not just a handful of different RA-associated autoantibodies that evade the filter. On the contrary, the researchers found an extremely broad variety of these antibodies.

The team used novel mass spectrometry tools that profile specific antibodies typically seen in the blood of RA patients, which are called anti-citrullinated protein antibodies (ACPAs). They discovered that each RA patient possesses a unique and diverse set of ACPAs.

Their findings challenge previous assumptions about the backgrounds of RA, that overlooked the antibodies' diversity and complexity. "This shows that RA is not just a disease occurring due to small errors, but a big structural problem in the immune system," says Bondt.

The study also revealed that these ACPAs are extensively modified with sugar molecules, known as Fab glycans. Intriguingly, some antibodies had multiple sugar molecules attached. This is much more then researchers normally observe in antibody profiles.

Having extra glycans aboard, may help the ACPA antibodies pass the filter of the immune system, says Bondt. The immune system uses several very strict checks during antibody production, to make sure all antibodies are correct. Wrongly produced antibodies are then detected and removed. Bondt suspects that glycans could help ACPAs trick the control system, allowing ACPAs to pass through the filter and form the onset of RA.

Current efforts to develop treatments for RA are mainly geared towards eliminating autoantibodies directly. This strategy may not be effective, says Bondt. "When you realize that there is such an extreme diversity in RA-related autoantibodies, it seems virtually impossible to eliminate them. A better approach may be to intervene earlier in the disease process, by targeting the malfunctioning filtering mechanism that allows autoantibodies to pass through."

Understanding these unique proteins is important, as it could ultimately also help doctors diagnose RA better. "When more molecular details about RA-related antibodies are uncovered, the disease may be diagnosed in an earlier stage," says Bondt. "Even though RA remains an incurable disease, with an earlier diagnosis you can take better measures to control its progression."

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• Is tooth extraction as proxy for periodontal disease related to the development of RA? Lessons from a longitudinal study in the at-risk stage of clinically suspect arthralgia
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• http://orcid.org/0000-0001-5953-6844 Sarah J H Khidir 1 ,
• http://orcid.org/0000-0002-9618-6414 René E M Toes 1 ,
• http://orcid.org/0000-0003-1900-790X Elise van Mulligen 1 , 2 ,
• http://orcid.org/0000-0001-8572-1437 Annette H M van der Helm-van Mil 1 , 2
• 1 Rheumatology , Leiden University Medical Center , Leiden , The Netherlands
• 2 Rheumatology , Erasmus Medical Center , Rotterdam , The Netherlands
• Correspondence to Sarah J H Khidir, Leiden University Medical Center, Leiden, The Netherlands; s.j.h.khidir{at}lumc.nl

https://doi.org/10.1136/ard-2024-225688

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• Anti-Citrullinated Protein Antibodies
• Arthritis, Rheumatoid
• Autoimmunity

Emerging evidence points to the involvement of periodontal disease (PD) in the pathogenesis of rheumatoid arthritis (RA), especially in anti-citrullinated protein antibodies (ACPA)-positive RA. The bacteria Porphyromonas gingivalis , involved in oral mucosal inflammation and PD, can citrullinate proteins via prokaryotic peptidylarginine deiminase. 1 Systemic translocation of oral bacteria has been found in RA-patients with PD. These bacterial translocations have been implicated in the generation of anti-modified protein antibodies (AMPAs) as ACPA can also recognise modified bacterial proteins. 2 Nevertheless, the ‘cause-consequence’ relation between PD and RA remains debatable as PD may be a risk factor (PD→RA; scenario 1; figure 1A ) but also a consequence of RA (RA→PD; scenario 2). 3 Additionally, the relation PD→RA may be confounded by related factors (eg, body mass index (BMI), smoking or other factors related to socioeconomic status (SES); scenario 3). Increased prevalence of periodontitis and P. gingivalis were reported in ACPA-positive/autoantibody-positive at-risk individuals in case–control/cross-sectional studies. 4 5 Longitudinal studies on PD in at-risk individuals could elucidate temporal relationships and provide further insight into the relation of PD in RA-development. Therefore, we longitudinally analysed the relation between tooth loss as proxy for (preceding) PD and progression to clinically apparent inflammatory arthritis (IA) and RA in patients with clinically suspect arthralgia (CSA). We also studied whether this relation is independent of SES and SES-related factors.

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Conceptual framework of hypotheses on periodontal disease and RA (A) and the development of inflammatory arthritis in ACPA-positive and ACPA-negative clinically suspect arthralgia according to tooth extraction (B). (A) The coloured circles represent the three hypotheses on the relation between PD and RA, inspired by de Pablo et al. 3 Scenario 1 in blue: PD is a risk factor for RA. Scenario 2 in orange: RA is a risk factor for PD. Scenario 3 in green: the association between PD and RA is driven by confounding factors such as smoking and SES. (B) Development of IA in ACPA-positive and ACPA-negative patients with clinically suspect arthralgia is shown according to tooth extraction, which is a late-stage of periodontal disease, showing a relation between tooth extraction and IA-development in ACPA-positive CSA-patients. ACPA, anti-citrullinated protein antibody; CSA, clinically suspect arthralgia; IA, inflammatory arthritis; PD, periodontal disease; RA, rheumatoid arthritis; SES, socioeconomic status.

Supplemental material

At baseline, 306 CSA-patients (44%) had previous tooth extraction. These patients were older than patients without tooth extraction (48.7 vs 41.4 years; online supplemental S2 ), more often had a low educational attainment (15% vs 8%), a higher BMI (27.8 vs 26.3), more often smoked (66% vs 51%) and had subclinical joint-inflammation (57% vs 47%). ACPA-positive CSA-patients with tooth extraction more often progressed to IA than ACPA-positive patients without tooth extraction (HR=1.91, 95% CI 1.10–3.32, p=0.022), while this association was not significant in ACPA-negative CSA (HR=1.41, 95% CI 0.85–2.34, p=0.19; figure 1B ). After correcting for SES, smoking, BMI and age, tooth extraction remained significantly associated with IA-development in ACPA-positive CSA-patients (HR=2.22, 95% CI 1.23–4.00, p=0.008). This association remained after additional adjustment for subclinical joint-inflammation (HR=3.10, 95% CI 1.57–6.10, p=0.001). The association between tooth extraction and RA-development was similar, as every ACPA-positive CSA-patient who developed IA also developed RA according to classification criteria. Within ACPA-positive CSA-patients (n=96), ACPA-levels, RF-positivity and number of AMPA-isotypes did not differ between individuals with and without tooth extraction ( online supplemental S3 ). Analyses stratified for autoantibody-positivity/autoantibody-negativity (negative for ACPA and RF) showed similar findings ( online supplemental S4 ).

To our best knowledge, this is the first study that longitudinally evaluates individuals with arthralgia at-risk of RA. We show that tooth extraction is a risk factor for progression to ACPA-positive RA and that this association is not confounded by environmental or SES-related factors. We acknowledge that tooth extraction has different causes among which end-stage periodontitis. This means it is a proxy, but not a perfect proxy. The finding that the risk effect is only present in developing ACPA-positive RA and not in ACPA-negative RA, suggests that tooth loss is partly related to prior PD (potentially present long before CSA-onset or recently). Future clinical and translational studies are needed to substantiate this finding. Interestingly, there were no differences in ACPA-levels and number of AMPA-isotypes as markers of autoantibody-maturation between ACPA-positive patients with and without tooth extraction. Whether antigenic triggering of autoreactive B-cells by bacteraemia plays a role in the trajectory towards ACPA-positive RA remains to be determined. 7

In conclusion, this is the first longitudinal study with data on tooth extraction as proxy for late-stage PD in both ACPA-positive and ACPA-negative at-risk patients. Tooth extraction, a late-stage of PD, associated with RA-development in ACPA-positive CSA-patients. Although our study does not show causality, it deductively supports the hypothesis that PD could confer risk for ACPA-positive RA and provides clues for future clinical and translational studies.

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Patient consent for publication.

Not applicable.

Ethics approval

• Pisetsky DS
• Brewer RC ,
• Hale CR , et al
• de Pablo P ,
• Chapple ILC ,
• Buckley CD , et al
• Do T , et al
• Mikuls TR ,
• Thiele GM ,
• Deane KD , et al
• Broers DLM ,
• de Lange J , et al
• Kristyanto H ,
• Blomberg NJ ,
• Slot LM , et al

Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1

Handling editor Josef S Smolen

Contributors SJHK and AvdH-vM designed the study. SJHK and EvM accessed and verified the data. SJHK analysed the data and acted as guarantor. All authors interpreted the data and wrote the report. AvdH-vM was the principal investigator. All authors approved the final version of the manuscript and were responsible for the decision to submit the manuscript for publication.

Funding This work was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (Starting grant, agreement No. 714312) and by the Dutch Arthritis Society.

Competing interests None declared.

Patient and public involvement Patient partners were involved in the design of the CSA-cohort, and in the design and execution of the TREAT EARLIER-trial

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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Study shows a single session of aerobic exercise improves blood pressure in rheumatoid arthritis patients

A 30-minute walk at moderate intensity temporarily reduced blood pressure in women with rheumatoid arthritis, not only at rest but also under stress. This was the conclusion drawn from a study involving physical and cognitive tests conducted at the University of São Paulo (USP) in Brazil.

Rheumatoid arthritis is an autoimmune inflammatory disease affecting synovial joints and causing pain, swelling, and progressive physical incapacity. People with rheumatoid arthritis also tend to have high blood pressure, and previous research has shown that the risk of death from cardiovascular disease is 50% higher for them than for the general population.

"A number of factors increase blood pressure in these patients, including chronic inflammation, lack of exercise, the adverse effect of the drugs used to treat the disease on the function and structure of blood vessels, and less elastic arteries that tend to narrow."

"Blood pressure can be elevated and vary more than normal during the day, even when the arthritis is controlled. For these patients, we need to think about non-pharmacological strategies that enhance blood pressure control," said Tiago Peçanha, the last author of the article.

Peçanha is a senior lecturer in cardiovascular physiology at Manchester Metropolitan University's Department of Sport and Exercise Sciences in the United Kingdom and a researcher at USP's Medical School (FM-USP) in Brazil.

Physical exercise is known to be one of the best non-pharmacological ways to control blood pressure. "However, we don't know exactly what happens in the case of rheumatoid arthritis patients with elevated blood pressure. Mental stress and pain may well raise their blood pressure over and above the elevation due to the autoimmune disease," said Tatiane Almeida de Luna, the first author of the article. The study was part of her master's research.

"The results of our study were very positive. They reinforce the importance of exercise to cardiovascular management and as a complementary form of blood pressure control for these patients."

According to Peçanha, the findings can apply to other autoimmune inflammatory diseases, such as lupus, psoriatic arthritis, inflammatory myopia, and juvenile lupus. "Rheumatoid arthritis is an inflammatory disease model that resembles these other diseases, where inflammation and its consequences, such as elevated blood pressure, occur in a similar manner," he said.

Systolic arterial blood pressure

High blood pressure, or hypertension, is a chronic disease defined by the World Health Organization (WHO) as systolic blood pressure equal to or above 140 mmHg and/or diastolic blood pressure equal to or above 90 mmHg. Rheumatoid arthritis patients tend to have elevated systolic arterial blood pressure—the higher of the two numbers in a reading, representing the pressure in the arteries when the heart beats and pumps blood.

Prior research shows that systolic blood pressure is not ideal (under 140 mmHg) in 50% of these patients, even while they are sleeping and even with treatment for hypertension.

According to the researchers, blood pressure rises in rheumatoid arthritis patients in response to mental stress, physical effort, and pain, contributing to the high risk of cardiovascular complications of the disease. A recent study by the group found blood pressure to be elevated in post-menopausal women with rheumatoid arthritis as a response to lower limb exercise, with more severe inflammation leading to more blood pressure elevation.

Temporary reduction

In the latest study, the researchers analyzed 20 women volunteers aged between 20 and 65 and diagnosed with rheumatoid arthritis and hypertension. They were undergoing treatment for rheumatoid arthritis at Hospital das Clínicas (HC), the hospital complex run by FM-USP.

Women of reproductive age took the tests during the first seven days of their menstrual cycle (follicular phase). All subjects underwent two sessions. The first involved pre-intervention measurement of blood pressure and heart rate at rest and in response to different types of stress.

In the second session, a randomly selected group walked at moderate speed on a treadmill for 30 minutes, while a control group stood on the treadmill for 30 minutes without performing any exercise. Both groups had their blood pressure measured before and after the session.

After exercise or rest, they took tests involving stress that could affect their blood pressure. One was a cognitive stress test (Stroop) in which they were shown a list of color words (e.g. "red", "blue", "green") printed in incongruent colors (e.g. "red" printed in blue) and asked to say the color of each word rather than the word itself.

Another was a pain tolerance test (Cold Pressor) in which they were asked to place a hand in cold water at 4 °C. This was designed to produce mild to moderate pain and ended with voluntary withdrawal of the hand. Again, their blood pressure and heart rate were measured after the tests.

After the post-intervention assessments, the participants were fitted with an ambulatory blood pressure monitor for 24-hour measurement in real-time. Systolic blood pressure remained stable in all 20 women before and immediately after the treadmill session but was higher in the measurements made while they were resting. "This shows that exercise prevented a rise in blood pressure," Peçanha said.

The 24-hour monitoring test showed that exercise lowered systolic pressure by 5 mmHg on average. "This is in line with the results of meta-analyses involving this type of exercise for the general population. This amount of reduction is significant, correlating with a 14% lower risk of death from stroke, a 9% lower risk of death from coronary arterial disease, and a 7% lower risk of all-cause death for people with hypertension," he explained.

"The temporary effect of just one aerobic exercise session is very important since acute reductions in blood pressure on several consecutive days are expected to accumulate and lead to a sustained reduction over time, contributing to better control of hypertension in rheumatoid arthritis."

The reduction was observed even after the stress tests. "The Stroop test is widely used in studies that analyze the cardiovascular response to mental stress, for example. In rheumatoid arthritis patients, it typically raises systolic pressure [to 16 mmHg] and diastolic pressure [to 12 mmHg] on average. In our study, however, systolic pressure fell by 6 mmHg after exercise," he said, adding that this reduction was not observed when they performed the test after a resting period (control).

In the Cold Pressor (pain tolerance) test, systolic and diastolic pressure are expected to rise to 18 mmHg and 11 mmHg respectively on average, while heart rate typically rises by 1 bpm. In the study, systolic pressure rose even more sharply (to 25 mmHg) in six patients.

On the day of the 30-minute walk, systolic pressure fell by 1 mmHg on average. On the day when they remained at rest, it rose by 4 mmHg.

"Stressful situations are known to increase the risk of cardiovascular events, such as stroke and heart attack. The study showed that the reduction in systolic blood pressure caused by physical exercise can potentially mitigate cardiovascular problems in rheumatoid arthritis patients," Peçanha said.

The research is published in the Journal of Human Hypertension .

More information: Tatiane Almeida de Luna et al, A single session of aerobic exercise reduces systolic blood pressure at rest and in response to stress in women with rheumatoid arthritis and hypertension, Journal of Human Hypertension (2023). DOI: 10.1038/s41371-023-00869-z

Provided by FAPESP

Observational study to help slow the progression of rheumatoid arthritis

Columbus-based healthcare company AndHealth launched an observational study designed to help participants slow the progression of rheumatoid arthritis (RA). Titled Project IMPACT , this initiative is dedicated to building the world's most extensive real-world evidence base, showcasing the potential to treat RA by addressing its root causes in conjunction with conventional treatments.

The study is grounded in the belief that patients can discover and understand their unique root cause symptoms, often related to lifestyle and nutrition. This whole-person specialty care approach is augmented with support from a multidisciplinary medical team.

Project IMPACT invites individuals undergoing treatment with specialty medications for RA to participate, helping countless others by contributing to this vital research.

The overarching ambition of Project IMPACT is to reshape how RA is treated within the healthcare system. "We recognize that RA is a complex condition influenced by genetics, lifestyle, nutrition and environmental factors. To provide the level of care that accounts for these factors is challenging under the current reimbursement model," states Dr. Jill Weintraub, a double board-certified rheumatologist who supervises rheumatologic care for AndHealth.

AndHealth is determined to demonstrate that comprehensive support, including root cause-targeted interventions and personalized nutrition, justifies the additional time and investment that, as of now, hinders providers from offering such services routinely.

"This level of care has historically been limited to individuals who could afford to pay out-of-pocket," notes Weintraub. "Project IMPACT, however, is intentionally structured to include patients from all socioeconomic backgrounds, with over a third of our participants currently on Medicaid."

Participants in Project IMPACT benefit from direct access to their medical team via an app on their phones, with consultations conducted online through video on Zoom—eliminating the need for in-person visits.

The study aims to eliminate financial obstacles that typically limit access to specialized, team-based care. Any treatment plan services not covered by the participant's health plan or Medicaid are included at no additional cost, such as nutritional supplements, medically tailored meal deliveries and wearable health-tech devices to monitor sleep, stress, activity and other health metrics.

"Some patients are eager to explore lifestyle changes and underlying causes of their disease, while others are more interested in simply having better access to their medical team. We welcome both approaches," Weintraub adds.

An invitation to participants

AndHealth is actively enrolling adults aged 21 and older in Ohio and Indiana who are currently being treated with a specialty medication or have been advised by their physician to start such a medication for RA.

For more information or to participate in Project IMPACT, please visit andhealth.com/impact or email [email protected] to arrange an exploratory call with a patient enrollment specialist.

About AndHealth

AndHealth was founded in 2021 in Columbus, OH, with a vision of dramatically improving access and health outcomes for patients utilizing certain types of specialty care, including rheumatology and dermatology. The opportunity to expand the depth and breadth of autoimmune care to include lifestyle, nutrition and other root cause drivers was one of the company’s first priorities. The importance of this work was quickly recognized by a number of US healthcare stakeholders, including health systems, community health centers, employers and the investment arm of the American Medical Association.