touchIMMUNOLOGY touchIMMUNOLOGY
Rheumatic Diseases
Read Time: 20 mins

Navigating Comorbidities in Chronic Inflammatory Rheumatic Diseases: Insight and Strategies

Copy Link
Published Online: Jan 22nd 2024 touchREVIEWS in RMD. 2024;3(1):Online ahead of journal publication
Authors: Ihsane Hmamouchi, Sarah Bou Jaoude, Nelly Ziade
Quick Links:
Abstract
Article
Article Information
Abstract:
Overview

Chronic inflammatory and rheumatic diseases (CIRDs) contribute significantly to the global burden of diseases, causing pain and functional impairment in patients. Associated comorbidities lead to additional healthcare costs, lower quality of life and higher mortality rates, and might limit anti-rheumatic treatment options. This narrative review article provides an overview of the prevalence of CIRDs and current recommendations for screening and managing comorbidities in patients with CIRDs, including cardiovascular disease (CVD), malignancies, infections, gastrointestinal diseases, osteoporosis and depression. In addition, it highlights the impact of these comorbidities on the selection of disease-modifying anti-rheumatic drugs. Moreover, the review emphasizes the importance of screening for CVD risk factors and implementing lifestyle changes, exercise, and smoking cessation. Specific screening approaches for malignancies for the CIRD population are discussed, as well as vaccination recommendations, osteoporosis screening and management, and the importance of depression detection. The review identifies unmet needs for updated recommendations and personalised interventions for managing comorbidities in CIRDs beyond rheumatoid arthritis and CVD, considering the diverse therapeutic options and their effects on these comorbidities. A multidisciplinary approach is necessary to effectively address and manage these comorbidities in CIRD patients and tailor therapy to each patient profile.

Keywords

Cardiovascular diseases, chronic inflammatory rheumatic diseases, comorbidities, depression, gastrointestinal diseases, infections, malignancies, osteoporosis

Article:

The global burden of disease is heavily impacted by the increased prevalence of chronic inflammatory rheumatic diseases (CIRDs [rheumatoid arthritis (RA), spondyloarthritis (SpA), connective tissue diseases (CTDs) crystal arthropathies and polyarticular osteoarthritis (OA)]), which are prevalent chronic non-communicable diseases associated with pain, functional impairment, and years lived with disability (YLDs).1–4

Comorbidities associated with CIRDs contribute significantly to the disease’s impact on patients’ lives, including long-term impairment, frequent use of healthcare, worse functional status, lower quality of life, and higher mortality.2,4 Comorbidities such as cardiovascular disease have an increased incidence in patients with CIRDs, which is often explained by the disease’s activity, its treatment, or by increased susceptibility to risk factors such as smoking, high blood pressure and hyperlipidaemia.2,5,6 Some comorbidities may also restrict therapeutic alternatives, affecting treatment plans and jeopardising optimal treatment outcomes.5–7

Additionally, screening for comorbidities in patients with CIRDs tends to be less systematic than in the general population, primarily because the emphasis is placed on managing their rheumatic disease.7 The most frequent comorbidities in general and in CIRD populations are cardiovascular diseases and cardiovascular risk factors, malignancies and depression, where screening recommendations are currently published.8–15 In addition, the European Alliance of Associations for Rheumatology (EULAR) recommends screening for osteoporosis, infections and gastrointestinal diseases in patients with CIRDs.7

In this narrative review, we summarize the current recommendations for screening and managing comorbidities in patients with CIRDs. We also highlight the impact of comorbidities on the selection of disease-modifying anti-rheumatic drugs (DMARDs).

Methods

Narrative literature review

To gather published recommendations on reporting, screening for, or prevention for each of the chosen comorbidities (cardiovascular diseases, malignancies, infectious comorbidities, gastrointestinal diseases, osteoporosis and depression), a literature review was carried out in July 2023. All information was extracted from PubMed using a research equation based on the Patient, Intervention, Comparison, Outcome (PICO) model (Supplementary Table 1).16 The literature search identified 325 articles (Supplementary Figure 1). Based on the title and the abstract, we assessed 123 full-text articles for eligibility. Moreover, we excluded 50 articles since they were written in a language other than English, had out-of-date recommendations, or did not fit the inclusion requirements for the study. Consequently, 73 articles were included in this narrative review, and 27 articles related to pulmonary comorbidities and obtained by cross-referencing were subsequently added.

Target population

The target population for this study is all patients with CIRDs comprising of RA, SpA, CTDs and crystal arthropathies, as well as patients with other musculoskeletal diseases including OA.

Choice of selected comorbidities

The choice of comorbidities for this review was based on the Comorbidity Collecting Form from the 2016 EULAR initiative.7 The criteria for these comorbidities were as follows: cardiovascular diseases (CVD) including myocardial infarction, angina, stroke, transient ischaemic attack, heart failure and lower limb peripheral arterial disease; malignancies including lymphoma, skin, lung, colon, breast, and cervical cancers; infections including serious infections, chronic viral infections, tuberculosis (TB) and non-TB opportunistic infections; gastrointestinal (GI) diseases including gastroduodenal ulcers, osteoporosis and depression.2,3,5–7 In addition, articles related to important comorbidities not included in the EULAR initiative, such as interstitial lung diseases and pulmonary arterial hypertension, were subsequently incorporated.

For each selected comorbidity, the major epidemiologic features and the current screening and management guidelines in patients with CIRDs were presented. In addition, the impact of comorbidities on the selection of DMARDs was discussed.

Results

The following data was retrieved from each selected article published between 2016 and 2022: definition of the comorbidity, how to document its presence, suggested screening method, and screening interval. For recommendations on reporting of, screening for, or prevention of each of the selected comorbidities in the general population, we referred to USPSTF’s and CDC’s databases.

Cardiovascular risk factors and diseases

Patients with CIRDs frequently underestimate the cardiovascular component of their illness, which can make managing their CVD comorbidity challenging.17 Nonetheless, due to both established and emerging risk factors including systemic inflammation and autoimmune dysregulation, patients with CIRDs have an elevated risk of CVD.18,19 Any component of the cardiovascular system can be impacted.20 CVD is the leading cause of mortality among patients with CIRDs, which can go up to 50% higher in patients with RA compared with the general population.21 Additionally, patients with RA are more likely to have silent ischaemic disease, which can result in unexpected deaths, further complicating the screening process within this population.22

Recommendations from the World Health Organization (WHO) and EULAR 2016 task force on CVD risk management in patients with CIRDs agree that rheumatologists should screen for risk factors and implement management plans with their patients.19,23 An example of this would be encouraging lifestyle changes, including adopting a healthy diet by reducing consumption of high-calorie foods and increasing fruit and vegetable intake, engaging in regular moderate-intensity exercise for at least 150 min per week with particular emphasis in patients with OA and axial spondyloarthritis (axSpA), as well as smoking cessation, as tobacco has detrimental effects on symptoms, disease activity, progression, comorbidities and response to DMARDs.19,23–26

As for screening, in addition to screening those with traditional risk factors (Table 1), patients diagnosed with CIRDs, especially RA, axSpA or psoriatic arthritis (PsA), should undergo CVD risk assessment at least once every 5 years.9,10,12–14,17,19,21,27–42 If the initial assessment indicates a low risk, routine screening after 5 years is recommended. However, rescreening may be done sooner if the risk is intermediate or disease progression is rapid. Patients with a high risk or established CVD should be treated for existing risk factors according to existing guidelines. Furthermore, it is essential to reassess CVD risk after significant changes in anti-rheumatic therapy, particularly when initiating biological DMARDs or other medications that may significantly affect lipid levels or other CVD risk factors.19

Table 1: Optimal screening and management of comorbidities and risk factors in patients with chronic inflammatory rheumatic diseases9,10,12–14,17,19,21,27–43

Comorbidity/risk factor

Eligible patients

Optimal screening

Optimal management

References

Hypertension

Patients with RMD older than 18 years

Blood pressure yearly

Refer for treatment if >140/90 mmHg

USPSTF10/EULAR19

Diabetes

Patients with RMD older than 40 years

Free blood sugar or HbA1c or oral glucose tolerance test every 3 years

Refer for treatment if HbA1c 6.5% or higher

USPSTF27/EULAR19

Hyperlipidaemia

Patients with RMD: men older than 35 years; women older than 45 years

Lipid profile every 5 years

Start statin if LDL >or = to 0.7 g/L

USPSTF28/EULAR19

Atherosclerosis

Patients with RMD

Carotid ultrasound

Start statin if presence of carotid plaque

EULAR19

CVD risk factors (all of the above + smoking)

Patients with RA, axSpA and PsA

mSCORE every 5 years

Low risk: repeat in 5 years

Intermediate risk: repeat in less than 5 years

High risk: treat

17,21,29

Breast cancer

Women between 50–74 years

Biennial mammogram

Refer to specialist

USPSTF13

Cervical cancer

All women

Cervical smear test every 3 years

Refer to specialist

USPSTF30

Lymphoma

Patients with SjS and RA

No clear recommendations, regular follow-ups with primary physician

Refer to specialist

Lung cancer

Smokers or past smokers aged 50–80

Low-dose thoracic CT scan yearly

Refer to specialist

USPSTF9,31

Colorectal cancer

All adults between 50–75 years

Colonoscopy every 5–10 years or gaiac-based faecal occult blood test every 2 years

Refer to specialist

USPSTF12

Influenza

Patients with RMD

N/A

Yearly vaccination

CDC32/EULAR33,34

Pneumococcus

Non-vaccinated pediatric patients with RMD; patients with RMD older than 65 years; patients who are prescribed biologics and/or high doses of GCs

N/A

Vaccination every 5 years

CDC35/EULAR36,37

HPV

Women between 18–26 years

Cervical smear test, every 3 years

Refer to specialist

CDC35/EULAR37

VZV

Patients starting csDMARDs, bDMARDs, tsDMARDs, immunosuppressants, and/or high dose GCs non-immune to VZV

N/A

Post-exposure prophylaxis following contact with VZV

EULAR38

HBV

Patients with RMD prior to bDMARDs, tsDMARDs, immunosuppressants, and high dose GCs

HbSAg

Refer to specialist

USPSTF39/EULAR38

HCV

Patients with elevated alanine aminotransferase levels or known risk factors, before initiating these medications

Anti-HCV antibody testing and PCR

Refer to specialist

USPSTF40/EULAR38

HIV

All patients between 15–65 years

Antigen/antibody immunoassay

Refer to specialist

CDC35/EULAR41

Tuberculosis

Adults 18 years and older at high risk

Interferon-gamma release assay preferably, or tuberculin skin test and chest X-ray

Refer to specialist

USPSTF42/EULAR41

SARS-CoV-2

Patients with RMD

PCR

Vaccination: 1–3 doses separated by at least 3–4 weeks. Vaccine booster based on physician’s judgment

CDC32

Osteoporosis

All adults 65 years and older; all patients with RMD; or presence of fragility fracture

DXA at least once

No primary prevention except in long term GCs

USPSTF31

Depression

All adults (evidence currently insufficient for adolescents aged 12-18 years)43

Clinically and based on scores

Refer to specialist

USPSTF14

axSpA = axial spondyloarthritis; bDMARDs biologic disease-modifying anti-rheumatic drugs; CDC = Centers for Disease Control and Prevention; csDMARDs = conventional synthetic disease-modifying anti-rheumatic drugs; CT = computed tomography scan; CVD = cardiovascular disease; DXA = dual-energy X-ray absorptiometry; EULAR = European Alliance of Associations for Rheumatology; GCs = glucocorticoids;HbA1c = glycated haemoglobin; HbSAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HPV = human papillomavirus; LDL = low-density lipoprotein; mSCORE = Modified Score for Cardiovascular Risk; N/A = not applicable; PCR = polymerase chain reaction; PsA = psoriatic arthritis; RA = rheumatoid arthritis; RMD = rheumatic and musculoskeletal diseases; SjS = Sjögren’s syndrome; tsDMARDs = targeted synthetic disease-modifying anti-rheumatic drugs; US = ultrasound; USPSTF = United States Preventive Services Task Force; VZV = varicella-zoster virus.

CVD risk assessment in patients with CIRDs is done by using the Systematic Coronary Risk Evaluation index (SCORE) coupled with the modified SCORE (mSCORE), as recommended by EULAR.19,21 Indeed, these risk indexes specifically tailored for patients with RA are more specific than scores used in the general population, such as the Framingham score or SCORE alone, which tend to underestimate CVD risk in patients with RA, especially older individuals, those who are rheumatoid factor (RF) positive, and those with high levels of inflammation.17,29

Screening methods used to assess cardiovascular involvement in patients with CIRDs are often the same as those used in the general population, such as echocardiography, chest X-rays, and electrocardiograms.44 Additional techniques may be utilised for further assessment – for instance, carotid ultrasound can be employed to screen asymptomatic atherosclerotic plaques in individuals with RA.45,46 Carotid magnetic resonance imaging, cardiac magnetic resonance, and serum calprotectin have also been suggested as potential screening tools for CVD risk factors, myocardial inflammation, ischaemia and fibrosis, to respectively complement carotid ultrasound, assess cardiac involvement in systemic lupus erythematosus (SLE) and RA, and serve as a biomarker for subclinical atherosclerosis in Sjögren’s syndrome.20,46,47

As for the management of CVD risk in patients with CIRDs, it closely resembles that of the general population.48 The Early Rheumatoid Arthritis COR Intervention (ERACORI) protocol proposes a unified management plan based on Danish national guidelines for CVD management, recommending prescription of angiotensin-II receptor antagonist as the preferred antihypertensive drug at the maximal dose, as well as statins, starting with an initial treatment of 40 mg simvastatin, which can be adjusted to 80 mg atorvastatin or supplemented with ezetimibe 10 mg if necessary, aiming to achieve an LDL cholesterol level below 2.5 mmol/L.49

There has been a positive correlation between the use of anti-inflammatory medications like nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids (GCs) in patients with RA and the increase in CVD risk (Figure 1).24 Indeed, GCs were associated with CVD risk factors and mortality, but they may also have a beneficial effect in reducing CVD risk through inflammation control.18,24 As for NSAIDs, they were shown to increase CVD risk in RA, even though the PRECISION (Prospective randomized evaluation of celecoxib integrated safety vs ibuprofen or naproxen; ClinicalTrials.gov identifier) trial found an acceptable CVD safety profile for some NSAIDs such as celecoxib, ibuprofen and naproxen.50 Other anti-rheumatic therapies like methotrexate (MTX) and tumour necrosis factor inhibitors (TNFi) were associated with a reduced CVD risk as they can slow down the progression of arterial thickness.18,24,51 However, concerns have been raised about the interleukin (IL)-6 blocker tocilizumab and its potential negative impact on lipid profiles, although an increase in major adverse cardiac events (MACEs) was not demonstrated.24 Moreover, studies on the safety of Janus kinase (JAK) inhibitors (JAKi), such as the ORAL Surveillance study, suggest a higher risk of venous thromboembolic events (VTEs) and MACEs when using high doses of tofacitinib compared with TNFi.40 This risk seems notable in older individuals, smokers, and those with a history of coronary artery disease.40,52,53

Figure 1: Effect of disease modifying anti-rheumatic drugs on comorbidities in patients with chronic inflammatory rheumatic diseases

DMARDs = disease-modifying anti-rheumatic drugs; IL = interleukin; JAK = Janus kinase; NSAIDs = nonsteroidal anti-inflammatory drugs; TNF = tumor necrosis factor.

In return, some comorbidities may decrease the efficacy of some anti-rheumatic drugs. For instance, smoking may reduce the effectiveness of MTX, TNFi and abatacept, while it does not affect the response to rituximab and JAKi.54–56 As for obesity, it has been shown to reduce the efficacy of conventional synthetic DMARDs (cs-DMARDs), TNFi, and JAKi, while not affecting the outcome of rituximab therapy.54,56,57

Malignancies

The risk of developing a malignancy can vary depending on the CIRD, ranging from 1.5 times higher in patients with RA to 20 times higher in patients with primary Sjögren syndrome (pSS) compared with the general population.58 58,59 Haematological cancers, particularly lymphomas, are the most common malignancies across all patients with CIRDs.58–60

According to the National Cancer Institute, the most prevalent malignancies in the general population are breast, prostate, lung, and colon cancers.61 The cancer screening recommendations are reported in Table 1. Close monitoring for lymphoma is essential, especially in patients with Sjögren’s disease and with RA who have a markedly higher risk, with mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBCL) being the most common types of lymphomas, respectively.58,59 It has been proposed that some features at Sjögren’s disease diagnosis can predict future lymphomagenesis, which may require a more intensive follow-up plan. These features include palpable purpura, salivary gland enlargement, low C4, leukopenia, cryoglobulinemia, monoclonal gammopathy, positive rheumatoid factor (RF), focus score and the total EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI).59

The incidence of lung cancer is increasing among individuals with RA, SLE, and SjS, partly attributed to smoking.60,62,63 In patients with RA, various factors could potentially contribute to the overall risk, encompassing attributes such as male gender, testing positive for RF or anti-citrullinated protein antibody, advanced age, smoking and interstitial lung disease (ILD).64,65 Potential for detection bias cannot be excluded in the CIRD population who undergoes comprehensive assessments. While targeted low-dose CT screening has been proposed, the currently available evidence does not substantiate extending this approach to encompass all patients with CIRD.65 As a preventive strategy, in conjunction with endeavors to promote smoking cessation, a recommendation is put forth for individuals aged 55–74 years with an elevated risk profile to undergo annual CT scans over 3 consecutive years.60,65 Tumour markers were deemed ineffective for lung malignancy screening; however, a positive correlation has been established between CA15-3 expression and an increased risk of developing ILD.66

Conversely, DMARDs like MTX, leflunomide, TNFi, tocilizumab, and rituximab contribute to 6–72% of drug-induced ILD, representing a minority of ILD cases.67 Interestingly, a study by Khan et al. suggested prior treatments for autoimmune disorders, like DMARDs and TNFi agents, might positively influence the patient’s response to anticancer therapies compared with individuals who haven’t received such previous treatments.68 Studies revealed no significant variance in lung cancer survival rates between individuals with CIRD and the overall population.68,69

Gynaecological malignancy screening in patients with CIRDs follows a similar approach to the general population, including biennial mammograms in women aged 50–74 years and an annual Pap smear.70,71 However, there is a need for heightened vigilance in individuals exposed to immunosuppressive drugs due to their increased risk for cervical premalignant lesions.71 For women up to 26 years old, herpes papillomavirus (HPV) vaccination is recommended and can be considered for young women with stable/inactive SLE and antiphospholipid syndrome (APS).60,70 However, caution should be exercised in those with a high-risk antiphospholipid profile.71

Screening for other malignancies should be guided by clinical suspicion and patient age, with 2–5 years of tight surveillance consisting of repeated tests if there are clinical suspicions.72 Positron emission tomography/computed tomography (PET/CT) may be considered in cases where unspecific systemic signs suggest the presence of neoplasms.72 Research conducted on serum tumour markers has failed to demonstrate their effectiveness in cancer screening.72

Earlier studies suggested that TNFi might be associated with an increased cancer risk, although more recent data from registries indicate the opposite.38,39,52,73 Also, data from the ORAL surveillance study found that the non-inferiority criterion of tofacitinib versus TNFi was not met regarding malignancies (Figure 1).40 The risk was identified only in patients above 65 years of age who were smokers. This has prompted the recent international recommendations for managing patients with RA and SpA advising assessing individual risk factors before prescribing JAKi.40

Infectious comorbidities and vaccination

Infectious diseases are a significant cause of morbidity and mortality in patients with CIRDs.37 The most prevalent infections among patients with CIRD are influenza, pneumocystis pneumonia (PCP), herpes zoster infections, and HPV.74,75 Most of these infections can be prevented through vaccination. Therefore, both pediatric and adult patients with CIRDs need to assess their vaccination status yearly and should receive routine vaccinations as per the National Immunization Program guidelines and EULAR recommendations.41,76

Screening guidelines for the general population prioritise the identification of sexually transmitted infections (STIs) and opportunistic infections, which is no different from the screening approach for individuals with CIRDs.77 Screening recommendations for higher-risk individuals include hepatitis B testing with hepatitis B surface antigen (HbsAg) tests, hepatitis C screening using anti-hepatitis C virus antibody tests for asymptomatic individuals aged 18–79 (confirmatory polymerase chain reaction testing if required), and non-treponemal and treponemal tests for syphilis screening with intervals determined by risk, while HIV testing is advised for individuals aged 15–65 with various risk factors using immunoassays and additional tests as necessary.33,34,78,79 Screening for latent tuberculosis (TB) infection is recommended for high-risk adults using Interferon-gamma release assay (IGRA) or tuberculin skin test (TST), with frequency based on risk level.42

In the CIRD population, several screening recommendations should be followed before initiating specific medications. Screening recommendations for latent TB, hepatitis B and C, HIV, and varicella-zoster virus before starting anti-rheumatic drugs are reported in Table 1.41

Prophylaxis against infections is achieved via vaccination. For the general population, vaccination calendars can be found on the CDC website according to age group.35 As for the CIRD population, non-live vaccines can be administered to both pediatric and adult patients with CIRD who are on GCs or DMARD therapy.36,37 Live-attenuated vaccines should be avoided in immunosuppressed patients, except for specific conditions like the measles, mumps and rubella (MMR) booster and varicella vaccination in pediatric patients.36 Pediatric patients with CIRD on MTX can receive MMR booster vaccinations, and varicella vaccination can be considered if they are varicella vaccination/infection-naïve and are on MTX or GCs, TNFi, anti-IL1, or anti-IL6 therapy.36 Yellow fever vaccination should be avoided in all immunosuppressed patients, regardless of age.36,37 Non-live seasonal influenza vaccination should be strongly considered for both pediatric and adult patients with CIRD treated with GCs or DMARDs.36,37 Pneumococcal vaccination with PCV10 or PCV13 is recommended for all non-vaccinated pediatric and adult patients with CIRD.75,76,80 Hepatitis A and B vaccinations should be given to at-risk patients with CIRD.37 HPV vaccination should be strongly considered in non-vaccinated pediatric patients with juvenile SLE and in other pediatric and adult patients with CIRD as per general population recommendations.37,76

The rheumatology team should assess the vaccination status and provide an individualised vaccination program to both pediatric and adult patients with CIRD.37 Vaccinations are considered safe, effective, and cost-effective in preventing certain infections in pediatric and adult patients with CIRD.76 However, vaccine efficacy may be reduced in some subgroups of patients with CIRD due to their immunosuppressed state. Therefore, vaccinations should preferably be administered during quiescent disease in both pediatric and adult patients with CIRD, if possible, 2–4 weeks before starting immunosuppression (especially B-cell depleting therapies).36,37 However, necessary treatments should never be postponed for vaccination.36

Interestingly, safety profiles of SARS-CoV-2 vaccines in patients with immune-mediated rheumatic diseases (I-RMD) were found to be reassuring and comparable to patients without I-RMD.81 Most patients tolerated the vaccines well, with only rare reports of I-RMD flare and infrequent reports of serious adverse events.81 These findings should provide reassurance, instilling confidence in the safety of SARS-CoV-2 vaccines for patients with I-RMD.81 Therefore, patients with CIRDs are strongly advised to receive any of the approved vaccines in their country.82

Additionally, it seems that patients with CIRDs do not face a higher risk of contracting SARS-CoV-2 than individuals without CIRDs, nor do they have a worse prognosis if they contract the virus.82 Nonetheless, there are concerns that individuals on certain immunosuppressive or immunomodulatory drugs may not mount an adequate protective response to COVID-19 vaccination.82 While data are not currently available to reliably identify who would benefit from a third primary dose of a SARS-CoV-2 vaccine, taking a precautionary position, some authorities recommend third primary doses in selected groups, and EULAR supports this approach.82 Additionally, concerns exist about the gradual decrease in protection vaccines provide against severe COVID-19 over time. Since insufficient time has passed to determine the expected levels of protection 4–6 months after the primary course, some authorities recommend booster doses, and EULAR supports this approach.82

As for the management of CIRD treatments during a COVID-19 infection, it is the role of rheumatologists to determine whether to maintain or discontinue immunomodulatory or immunosuppressive therapies and for those who have been vaccinated, treatment should continue unchanged. In contrast, those not vaccinated should consider the potential increased risk of severe COVID-19 when deciding on treatment.82 In patients with CIRDs who are not using immunomodulatory or immunosuppressive treatment, it is suggested that SARS-CoV-2 vaccination should precede the start of such therapy.82 For patients using rituximab or other B-cell-depleting therapies, scheduling the SARS-CoV-2 vaccination in a way that optimizes vaccine immunogenicity is recommended.82

Regarding the effect of CIRD treatments on susceptibility to infections, rituximab significantly hampers the generation of antibodies in response to vaccines, although it has minimal impact on T-cell responses.83 Similarly, medications like MTX and abatacept diminish the immune response to various vaccines and should be withheld before vaccine administration.83 TNF and JAK inhibitors generally reduce the antibodies produced after vaccination, but most patients, particularly those taking TNFi, still manage to achieve protective antibody levels.83 Conversely, therapies targeting cytokines such as IL-6, IL-12/23, and IL-17 do not appear to significantly influence the effectiveness of vaccines.83

Gastrointestinal diseases

The presence of GI complications in individuals with CIRDs is variable across different rheumatic diseases. For instance, clinically evident inflammatory bowel disease (IBD) in individuals with SpA is estimated to be around 7%.84,85 Coeliac disease (CD) affects approximately 2.9% of the overall CIRD population, particularly prevalent in patients with pSS and diffuse systemic sclerosis (SSc).86 Regarding GI motility disorders, achalasia (AC) and intestinal motility disorders (IEM) are the most frequently observed in patients with CIRDs.87

The screening process for GI comorbidities is similar in the general population and individuals with CIRDs, relying on symptom-based evaluation.7,86,88 However, certain CIRDs require a more thorough screening due to their heightened risk of specific GI issues.

In particular, an exhaustive screening for IBD is paramount in patients with SpA. This is due to the significant impact on treatment outcomes, where prompt diagnosis enhances the effectiveness of TNFi treatment and reduces the risk of disability.84 Techniques like digital chromoendoscopy and magnification colonoscopy are utilised to facilitate effective IBD screening, alongside a range of laboratory tests to assess markers like C-reactive protein, sedimentation rate, transferrin, ferritin, and vitamin B12 levels.85,88 Employing digital chromoendoscopy or magnification endoscopy aids in identifying and monitoring early lesions.89 IBD screening involves specific criteria, encompassing both major symptoms such as rectal bleeding, diarrhoea exceeding 4 weeks, and perianal disease, as well as minor indicators like prolonged abdominal pain, iron deficiency anaemia, and extra-intestinal manifestations such as aphthous stomatitis, fever, unexplained weight loss, family history of IBD, and vitamin B12 deficiency.88

A study conducted by Andréasson et al. investigated faecal calprotectin (FC) levels, commonly used in primary healthcare, to determine if patients should be referred for endoscopy in individuals with Sjögren’s syndrome.90 They found that an FC level exceeding 150 μg/g could indicate underlying GI conditions such as malignancy or IBD. This discovery suggests that FC could serve as a non-invasive biomarker for detecting GI inflammation, offering an alternative to relying solely on endoscopy for screening GI comorbidities in patients with CIRD. It is worth noting that elevated FC levels have also been observed in SSc and axSpA. However, using FC to screen for GI inflammation in patients with SpA seems to be associated with poor diagnostic properties (sensitivity 64%, specificity 73%), and FC levels are significantly affected by previous NSAID therapy.91,92

Furthermore, the screening process for CD entails evaluating IgA transglutaminase (TG) levels and conducting anti-endomysium testing for those with positive or borderline IgA TG results.86 Confirmation of CD is achieved through a duodenal biopsy.86 Notably, the early detection of CD is particularly vital in patients with pSS and diffuse SSc.86

Regarding GI motility disorders, particularly in patients with SSc, RA and SLE, oesophageal manometry is recommended to assess oesophagal function and pressure patterns.87

Gastric ulcers represent another GI comorbidity primarily linked to colonisation by Helicobacter pylori (H. pylori).93 A study by Lin et al. highlights that treating H. pylori in patients with peptic ulcer disease might elevate the chances of developing autoimmune disorders and IBD compared with untreated cases.93 Conversely, specific medications like GCs and NSAIDs exacerbate gastric harm, while proton pump inhibitors (PPIs) and COX-2-selective NSAIDs offer protection.94 Therefore, it is recommended to closely monitor patients receiving both GCs and NSAIDs, while also considering the use of PPIs and COX-2-selective NSAIDs.94

Osteoporosis

The prevalence of osteoporosis among patients with CIRD exhibits variability, yet it consistently remains elevated compared to the general population.27,28 The occurrence of osteoporosis in patients with SLE ranges from 1.4% to 68%, while instances of SSc are associated with a 23.6% prevalence of osteoporosis.27 Osteoporosis is often under-screened in high-risk populations like patients with RA and SpA due to the focus on treating the active disease and other comorbidities.28 Factors contributing to bone fragility in these diseases and requiring management include inflammation, sedentary lifestyle, menopause, corticosteroid use and intestinal inflammation.28,30

According to the US Preventive Services Task Force, screening recommendations for osteoporosis in the general population target all women aged 65 and above and postmenopausal women under 65 who are at higher risk.31 The most commonly used diagnostic test is central dual-energy X-ray absorptiometry (DXA) of the hip and lumbar spine.31

However, DXA provides quantitative assessments without considering qualitative aspects.28 CT scans may help, as they provide both morphological and density evaluation.28 Fauny et al. found that CT scans were as reliable as spine DXA for identifying patients at risk of vertebral fractures.28 The sensitivity of osteoporotic fracture risk assessment is enhanced when the Fracture Risk Assessment Tool (FRAX) and DXA scan are combined.32

In the CIRD population, the National Osteoporosis Foundation (NOF) recommends that patients with CIRD or adults taking GCs (daily dose ≥5 mg prednisone or equivalent for ≥3 months) should be screened for osteoporosis by central DXA regardless of their age. Also, using the lowest possible dose of GCs for the shortest period is recommended.30 Prophylactic vitamin D and calcium supplements are also recommended to enhance bone mass density (BMD) in GCs-induced osteoporosis.95,96 Considering the strong association between severe vitamin D deficiency and musculoskeletal disorders, it is advised to prescribe a daily dose of 1000 IU of vitamin D for individuals at a higher risk of deficiency.96 This supplementation regimen has been deemed safe and can be complemented with a loading dose or calcifediol treatment in specific patient groups to attain therapeutic levels of 25-hydroxyvitamin D.96

Supplementation alone falls short, necessitating comprehensive osteoporosis treatment: bisphosphonates (BPs) serve as the initial therapy choice, yet prolonged usage increases bone fragility and fractures.97 Hormone replacement therapies effectively reduce bone loss, but continuous use comes with substantial risks, such as cancer and thrombosis.97 Additional treatments like calcitonin relieve osteoporosis-induced bone pain, while RANKL (receptor activator of nuclear factor kappa-b ligand) inhibitors improve bone density and decrease fracture risk.97 Parathormone analogues rapidly increase bone density, necessitating co-administration with BPs, which have a slower onset. Hence. BPs are employed for maintenance, and the application of the anti-Sclerotin Antibody is restricted to specific high-risk patients.97 Recent findings indicate that concurrent use of bDMARDs and csDMARDs over a year minimizes BMD decline in the spine and hips.98 This integrated strategy not only improves joint scores and eases extra-articular symptoms, but also curtails widespread bone loss by optimizing disease activity reduction.98 Despite yielding moderate enhancements in BMD, biologic anti-rheumatic treatments have limited impact on fracture risk, underscoring their inability to replace osteoporosis-specific interventions.98

Under study are some emerging treatments encompassing stem cell therapy for the regeneration of osteoporotic bones, microRNA-based therapy for targeted interventions, and bone-specific targeting technology aiming to enhance treatment precision.97

Depression

Recent advancements in immunopsychiatry have provided a better understanding of the relationship between depression and inflammation, with elevated levels of specific inflammatory markers found in patients with depression or anxiety.99 Depression is twice as common in patients with RA compared with the general population, with approximately 17% of patients with RA experiencing major depressive disorder.99

In general, screening for depression is advised for various groups, including women during and after pregnancy, young and middle-aged adults, people of colour, those with low education levels, divorcees, unemployed individuals, those with chronic illnesses (including CIRDs), people with other mental health disorders, and those with a family history of psychiatric disorders. Several widely used depression screening tools include the Patient Health Questionnaire (PHQ) in its various forms (PHQ-2;4;8;9;15), the Hospital Anxiety and Depression Scales (for adults), the Geriatric Depression Scale (for older individuals), and the Edinburgh Postnatal Depression Scale (for pregnant and postpartum women).15,100,101

It is of the essence to diagnose depression early in patients with CIRDs to manage or refer such patients to psychiatrists. For example, the UK National Institute for Health and Care Excellence (NICE) guidelines for RA management includes psychological interventions to address fatigue, low mood, and social well-being.99 It has been proven that managing mental health and depression in chronic medical conditions improves treatment outcomes.99,102 Various tools, such as Beck Depression Inventory (BDI), Hospital Anxiety and Depression Scale (HADs), and Patient Global Assessment (PGA), are commonly used in rheumatology studies to measure mental health status and patient-reported outcomes.103–105 Additionally, non-pharmacological interventions are recommended to improve adherence, functional disability, pain, fatigue, goal setting and self-efficacy.102

Despite employing a treat-to-target strategy, many patients with CIRDs continue to face significant symptoms, particularly pain, and in cases of treatment resistance, depression can play a role.99 A study by Nagy et al. found that csDMARDs and bDMARDs were equally effective in enhancing patients’ quality of life.102 However, no significant differences were observed in their impact on anxiety and depression among patients with RA. It is important to note that failure to achieve complete disease control can result in physical limitations that exacerbate psychological and social issues.103 Therefore, the primary treatment objectives should focus on improving quality of life and reducing disability to avoid or limit depression.103

Consequently, optimizing treatment adherence is crucial and should be discussed through shared decision-making between healthcare providers and patients.102 Furthermore, it is essential to address non-inflammatory pain resulting from factors such as anxiety, depression, sleep disruptions, and psychosocial circumstances.106–108 This includes effectively managing additional sources of pain like fibromyalgia, mechanical pain, and neuropathic pain that coexist with the pain associated with CIRD.99,102

Other

Important concomitant pulmonary conditions associated with CIRDs are ILD and pulmonary hypertension (PH).109–111

ILD is the primary pulmonary concern in patients with RA, with approximately 60% of patients with RA exhibiting ILD on imaging.112,113 In contrast, the prevalence of ILD in patients with pSS varies widely, from 13% to 78%.114 Among patients with mixed connective tissue disease (MCTD), 50–80% have non-specific interstitial pneumonia (NSIP) on high-resolution computed tomography (HRCT).114 On the other hand, SLE has a lower incidence of ILD, affecting only 2–4% of patients with SLE compared with other autoimmune conditions.114 Various factors, including age, gender, disease duration, and antibodies to cyclic citrullinated peptides, contribute to the risk of developing ILD in patients with RA.112,113 Additionally, factors like smoking, unspecific interstitial pneumonia (UIP), emphysema and acute exacerbations are associated with an elevated mortality risk.112,113

PH can develop as a complication of CTDs like systemic SSc, MCTD, and SLE. Among these CTDs, SSc has the highest known prevalence of PH, affecting approximately 8–12% of patients with SSc.109

In clinical practice, the diagnosis of ILD primarily relies on HRCT findings due to practicality, given that diagnostic criteria encompass HRCT findings, lung biopsy, a combination of clinical presentation, and pulmonary function tests.110,113 To identify patients with RA who would benefit from HRCT screening, a study by Juge et al. proposed a risk score for subclinical RA-ILD incorporating four variables: sex, age at RA onset, RA disease activity assessed using DAS28-ESR, and the presence of the MUC5B rs35705950 genetic variant.115

For screening PH, a comprehensive approach is essential, involving physical examination, laboratory tests, pulmonary function tests, echocardiography and chest CT scans.109

There are conflicting findings regarding the impact of certain DMARDs like MTX, leflunomide, TNFi, rituximab, and tocilizumab on ILD progression in patients with RA.110,116 The overall evidence is inconclusive, but it suggests that some DMARDs, including MTX, leflunomide, TNFi, abatacept, and rituximab, may have potential benefits in preventing and treating patients with RA-ILD.110

The recommendations regarding the optimal screening method for each comorbidity or risk factor, the target population, the frequency of measurements and the management are summarized in Table 1. The impact of various DMARDs on the studied comorbidities is summarised in Figure 1.40,83,102,103,117–129

It is important to note that failure to achieve complete disease control can result in physical limitations, amplifying psychological distress and affecting the daily lives of patients.99,102,108 Nevertheless, this review provides a comprehensive summary of the most significant comorbidities and highlights some areas of unmet needs.

Conclusion

This narrative literature review summarizes the most recent recommendations spanning the past 6 years regarding the screening, prevention, and management of the six comorbidities documented in the core set data of the 2016 EULAR task force.7 The findings shed light on the uneven distribution of available information concerning managing comorbidities among different rheumatic diseases. Mainly, most publications seem to focus on RA and CVD, leaving a lack of clarity regarding managing other comorbidities in both RA and other CIRDs. As a result, there is an urgent need to consolidate and elucidate updated recommendations pertaining to the primary comorbidities observed in the most prevalent CIRDs. Additionally, the emergence of novel therapies introduces complexity, as each treatment uniquely influences the exacerbation or improvement of the mentioned comorbidities, prompting the application of personalized medicine.

Take-home messages

  1. Comorbidities associated with CIRDs like CVD, malignancies, infections, GI diseases, osteoporosis and depression contribute significantly to the overall burden of the disease.1–3,5,7

  2. Comorbidity screening in the general population follows established guidelines, but it is less standardized and requires more attention in the CIRD population.5,7

  3. When selecting and managing DMARDs, consideration should be given to the impact on comorbidities.117–129

  4. Individualized care and shared decision-making between healthcare providers and patients are vital for managing comorbidities in patients with CIRDs.7

  5. Regular monitoring, appropriate screening and timely interventions can help reduce the burden of comorbidities and improve overall patient outcomes.7

Article Information:
Disclosure

Ihsane Hmamouchi, Sarah Bou Jaoude and Nelly Ziade have no financial or non-financial relationships or activities to declare in relation to this article.

Compliance With Ethics

This article involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.

Review Process

Double-blind peer review

Authorship

All named authors meet the criteria of the International Committee of Medical Journal Editors for authorship for this manuscript, take responsibility for the integrity of the work as a whole and have given final approval for the version to be published.

Correspondence

Ihsane HmamouchiHealth Sciences College, International University of Rabat (UIR)Rabat, 11103, Morocco; ihsane.hmamouchi@gmail.com

Support

No funding was received for the publication of this article.

Access

This article is freely accessible at touchIMMUNOLOGY.com ©Touch Medical Media 2024.

Digital Features

This article is published with supplementary digital features. The supplementary material was peer reviewed with the manuscript. To view the material please visit here.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the writing of this article.

Received

2023-07-24

References

1. WHO Scientific Group on the Burden of Musculoskeletal Conditions at the Start of the New MillenniumThe burden of musculoskeletal conditions at the start of the new millenium. World Health Organ Tech Rep Ser. 2003;919.

2. Cook MJBellou EBowes Jet alThe prevalence of comorbidities and their impact on physical activity in people with inflammatory rheumatic diseases compared with the general population: Results from the UK Biobank. Rheumatology (Oxford). 2018;57:217282. DOI: 10.1093/rheumatology/key224.

3. Vos TFlaxman ADNaghavi Met alYears lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: A systematic analysis for the Global Burden of Disease Study 2010Lancet2012;380:216396. DOI10.1016/S0140-6736(12)61729-2.

4. Okoro CAHollis NDCyrus ACGriffin-Blake SPrevalence of disabilities and health care access by disability status and type among adults – United States, 2016. MMWR Morb Mortal Wkly Rep. 2018;67:8827. DOI: 10.15585/mmwr.mm6732a3.

5. Ziade NEl Khoury BZoghbi Met alPrevalence and pattern of comorbidities in chronic rheumatic and musculoskeletal diseases: The COMORD studySci Rep2020;10:7683DOI10.1038/s41598-020-64732-8.

6. Reyes-Rivet LBellier ABaillet Aet alAdherence to EULAR’s recommendations on comorbidity management minimises the discontinuation of bDMARDS for intolerance in patients with chronic inflammatory rheumatic diseases. Joint Bone Spine. 2021;88:105234. DOI: 10.1016/j.jbspin.2021.105234.

7. Baillet AGossec LCarmona Let alPoints to consider for reporting, screening for and preventing selected comorbidities in chronic inflammatory rheumatic diseases in daily practice: A EULAR initiative. Ann Rheum Dis. 2016;75:96573. DOI: 10.1136/annrheumdis-2016-209233.

8. Teo KKRafiq TCardiovascular risk factors and prevention: A perspective from developing countriesCan J Cardiol2021;37:73343DOI10.1016/j.cjca.2021.02.009.

9. US Preventive Services Task Force, Krist AH, Davidson KW, et al. Interventions for tobacco smoking cessation in adults, including pregnant persons: US Preventive Services Task Force recommendation statement. JAMA. 2021;325:26579. DOI: 10.1001/jama.2020.25019.

10. US Preventive Services Task Force, Krist AH, Davidson KW, et al. Screening for hypertension  adults: US Preventive Services Task Force reaffirmation recommendation statement. JAMA. 2021;325:16506. DOI: 10.1001/jama.2021.4987.

11. Hulvat MC. Cancer incidence and trends. Surg Clin North Am. 2020;100:46981. DOI: 10.1016/j.suc.2020.01.002.

12. US Preventive Services Task Force, Davidson KW, Barry MJ, et al. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement. JAMA. 2021;325:196577. DOI: 10.1001/jama.2021.6238.

13. Siu ALScreening for breast cancer: US Preventive Services Task Force recommendation statementAnn Intern Med2016;164:27996DOI10.7326/M15-2886.

14. Zis PDaskalaki ABountouni Iet alDepression and chronic pain in the elderly: Links and management challenges. Clin Interv Aging. 2017;12:70920. DOI: 10.2147/CIA.S113576.

15. Siu AL, US Preventive Services Task Force (USPSTF), Bibbins-Domingo K, et al. Screening for in adults: US Services Task Force recommendation statement. JAMA. 2016;315:3807. DOI: 10.1001/jama.2015.18392.

16. Eriksen MBFrandsen TF. The impact of patient, intervention, comparison, outcome (PICO) as a search strategy tool on literature search quality: A systematic review. J Med Libr Assoc. 2018;106:42031. DOI: 10.5195/jmla.2018.345.

17. Alonso-Molero JPrieto-Peña DMendoza Get al. Misperception of the cardiovascular risk in patients with rheumatoid arthritis. Int J Environ Res Public Health. 2020;17:5954. DOI: 10.3390/ijerph17165954.

18. DeMizio DJGeraldino-Pardilla LBAutoimmunity and inflammation link to cardiovascular disease risk in rheumatoid arthritis. Rheumatol Ther. 2020;7:1933. DOI: 10.1007/s40744-019-00189-0.

19. Agca RHeslinga SCRollefstad Set alEULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis. 2017;76:1728. DOI: 10.1136/annrheumdis-2016-209775.

20. Mavrogeni SISfikakis PPDimitroulas Tet al. Can cardiovascular magnetic resonance prompt early cardiovascular/rheumatic treatment in autoimmune rheumatic diseases? Current practice and future perspectives. Rheumatol Int. 2018;38:94958. DOI: 10.1007/s00296-018-4004-6.

21. de Campos OAMNazário NOde Magalhães Souza Fialho SCet alAssessment of cardiovascular risk in patients with rheumatoid arthritis using the SCORE risk indexRev Bras Reumatol Engl Ed2016;56:13844. DOI10.1016/j.rbre.2015.09.005.

22. Gabriel SECardiovascular morbidity and mortality in rheumatoid arthritisAm J Med2008;121(Suppl.1):S914. DOI10.1016/j.amjmed.2008.06.011.

23. Gwinnutt JMWieczorek MBalanescu Aet al2021 EULAR recommendations regarding lifestyle behaviours and work participation to prevent progression of rheumatic and musculoskeletal diseasesAnn Rheum Dis2023;82:4856. DOI10.1136/annrheumdis-2021-222020.

24. Jagpal ANavarro-Millán ICardiovascular co-morbidity in patients with rheumatoid arthritis: A narrative review of risk factors, cardiovascular risk assessment and treatmentBMC Rheumatol2018;2:10DOI10.1186/s41927-018-0014-y.

25. Wieczorek MGwinnutt JMRansay-Colle Met alSmoking, alcohol consumption and disease-specific outcomes in rheumatic and musculoskeletal diseases (RMDs): Systematic reviews informing the 2021 EULAR recommendations for lifestyle improvements in people with RMDsRMD Open2022;8:e002170DOI10.1136/rmdopen-2021-002170.

26. Roelsgaard IKThomsen TØstergaard Met alThe effect of an intensive smoking cessation intervention on disease activity in patients with rheumatoid arthritis: Study protocol for a randomised controlled trial. Trials. 2017;18:570. DOI10.1186/s13063-017-2309-5.

27. Adami GFassio ARossini Met alOsteoporosis in rheumatic diseasesInt J Mol Sci. 2019;20:5867. DOI: 10.3390/ijms20235867.

28. Fauny MAlbuisson EBauer Eet alStudy of vertebral fracture and scanographic bone attenuation coefficient in rheumatoid arthritis and ankylosing spondylitis vs. controls. Sci Rep. 2019;9:13323DOI10.1038/s41598-019-49712-x.

29. Crowson CSGabriel SESemb AGet alRheumatoid arthritis-specific cardiovascular risk scores are not superior to general risk scores: A validation analysis of patients from seven countriesRheumatology (Oxford)2017;56:110210. DOI: 10.1093/rheumatology/kex038.

30. Garelick DPinto SMFarinha Fet alFracture risk in systemic lupus erythematosus patients over 28 years. Rheumatology (Oxford). 2021;60:276572. DOI: 10.1093/rheumatology/keaa705.

31. US Preventive Services Task ForceCurry SJKrist AHet alScreening for osteoporosis to prevent fractures: US Preventive Services Task Force recommendation statement. JAMA. 2018;319:252131. DOI: 10.1001/jama.2018.7498.

32. Sharma MSingh PJoshi AAnalytical study of the risk factors affecting the fracture risk in rheumatoid arthritis patients using FRAX algorithm. J Assoc Physicians India. 2022;69:112.

33. US Preventive Services Task Force, Krist AH, Davidson KW, et al. Screening for hepatitis B virus infection in adolescents and adults: US Preventive Services Task Force recommendation statement. JAMA. 2020;324:241522. DOI: 10.1001/jama.2020.22980.

34. US Preventive Services Task Force, Owens DK, Davidson KW, et al. Screening for hepatitis C virus infection in adolescents and adults: US Preventive Services Task Force recommendation statement. JAMA. 2020;323:9705. DOI: 10.1001/jama.2020.1123.

35. Centers for Disease Control and Prevention. Immunization schedules. Available at: www.cdc.gov/vaccines/schedules/ (Date last accessed: 8 November 2023).

36. Jansen MHARondaan CLegger GEet alEULAR/PRES recommendations for vaccination of paediatric patients with autoimmune inflammatory rheumatic diseases: Update 2021. Ann Rheum Dis. 2023;82:3547. DOI: 10.1136/annrheumdis-2022-222574.

37. Furer VRondaan CHeijstek MWet al2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseasesAnn Rheum Dis2020;79:3952DOI10.1136/annrheumdis-2019-215882.

38. Raaschou PFrisell TAskling JARTIS Study GroupTNF inhibitor therapy and risk of breast cancer recurrence in patients with rheumatoid arthritis: A nationwide cohort studyAnn Rheum Dis2015;74:213743. DOI: 10.1136/annrheumdis-2014-205745.

39. Huss VBower HWadström Het alShort- and longer-term cancer risks with biologic and targeted synthetic disease-modifying anti-rheumatic drugs as used against rheumatoid arthritis in clinical practice. Rheumatology (Oxford). 2022;61:18108. DOI: 10.1093/rheumatology/keab570.

40. Winthrop KLCohen SBOral surveillance and JAK inhibitor safety: The theory of relativityNat Rev Rheumatol. 2022;18:3014DOI10.1038/s41584-022-00767-7.

41. Fragoulis GEDey MZhao Set alSystematic literature review informing the 2022 EULAR recommendations for screening and prophylaxis of chronic and opportunistic infections in adults with autoimmune inflammatory rheumatic diseases. RMD Open. 2022;8:e002726. DOI: 10.1136/rmdopen-2022-002726.

42. US Preventive Services Task Force, Mangione CM, Barry MJ, et al. Screening for latent tuberculosis infection in adults: US Preventive Services Task Force recommendation statement. JAMA. 2023;329:148794. DOI: 10.1001/jama.2023.4899.

43. US Preventive Services Task Force, Mangione CM, Barry MJ, et al. Screening for depression and suicide risk in children and adolescents: US Preventive Services Task Force recommendation statement. JAMA. 2022;328:153442. DOI: 10.1001/jama.2022.16946.

44. Vn SRathnakumar GRajkumaret alA cross sectional study on cardiovascular manifestations of systemic lupus erythematosus at tertiary care centerJ Assoc Physicians India2022;70:112.

45. Daïen CITubery Adu Cailar Get alApplication of the 2015/2016 EULAR recommendations for cardiovascular risk in daily practice: Data from an observational study. Ann Rheum Dis2018;77:6256DOI10.1136/annrheumdis-2017-211074.

46. Bissell L-AErhayiem BFent Get alCarotid artery volumetric measures associate with clinical ten-year cardiovascular (CV) risk scores and individual traditional CV risk factors in rheumatoid arthritis; a carotid-MRI feasibility studyArthritis Res Ther2018;20:266DOI10.1186/s13075-018-1761-2.

47. Balarini GMZandonade ETanure Let alSerum calprotectin is a biomarker of carotid atherosclerosis in patients with primary Sjögren’s syndromeClin Exp Rheumatol. 2016;34:100612.

48. Correction to: 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: A report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation. 2019;140:e64950. DOI: 10.1161/CIR.0000000000000725.

49. Svensson ALChristensen RPersson Fet alMultifactorial intervention to prevent cardiovascular disease in patients with early rheumatoid arthritis: Protocol for a multicentre randomised controlled trialBMJ Open. 2016;6:e009134DOI10.1136/bmjopen-2015-009134.

50. Obeid SLibby PHusni Eet alCardiorenal risk of Celecoxib compared with naproxen or ibuprofen in arthritis patients: insights from the PRECISION trialEur Heart J Cardiovasc Pharmacother2022;8:61121. DOI: 10.1093/ehjcvp/pvac015.

51. Toussirot EThe risk of cardiovascular diseases in axial spondyloarthritis. Current insightsFront Med (Lausanne). 2021;8:782150DOI10.3389/fmed.2021.782150.

52. Kragstrup TWGlintborg BSvensson ALet alWaiting for JAK inhibitor safety data. RMD Open. 2022;8:e002236. DOI: 10.1136/rmdopen-2022-002236.

53. Weitz JISzekanecz ZCharles-Schoeman C, et al. Biomarkers to predict risk of venous thromboembolism in patients with rheumatoid arthritis receiving tofacitinib or tumour necrosis factor inhibitors. RMD Open. 2022;8:e002571. DOI10.1136/rmdopen-2022-002571.

54. Saevarsdottir SWedrén SSeddighzadeh Met alPatients with early rheumatoid arthritis who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors: Observations from the Epidemiological Investigation of Rheumatoid Arthritis and the Swedish Rheumatology Register cohortsArthritis Rheum2011;63:2636DOI10.1002/art.27758.

55. Safy-Khan Mde Hair MJHWelsing PMJet alCurrent smoking negatively affects the response to methotrexate in rheumatoid arthritis in a dose-responsive way, independently of concomitant prednisone useJ Rheumatol. 2021;48:15047DOI10.3899/jrheum.200213.

56. Kiely PBusby ADNikiphorou Eet alIs incident rheumatoid arthritis interstitial lung disease associated with methotrexate treatment? Results from a multivariate analysis in the ERAS and ERAN inception cohortsBMJ Open. 2019;9:e028466. DOI10.1136/bmjopen-2018-028466.

57. Nikiphorou ENorton SCarpenter Let alSecular changes in clinical features at presentation of rheumatoid arthritis: Increase in comorbidity but improved inflammatory statesArthritis Care Res (Hoboken). 2017;69:217. DOI: 10.1002/acr.23014.

58. Kedra JSeror RDieudé Pet alLymphoma complicating rheumatoid arthritis: Results from a French case–control studyRMD Open2021;7:e001698DOI10.1136/rmdopen-2021-001698.

59. Sebastian AMadej MSebastian Met alPrevalence and clinical presentation of lymphoproliferative disorder in patients with primary Sjögren’s syndrome. Rheumatol Int. 2020;40:399404. DOI10.1007/s00296-020-04522-7.

60. Ladouceur A, Bernatsky S, Ramsey-Goldman R, Clarke AE. Managing cancer risk in patients with systemic lupus erythematous. Expert Rev Clin Immunol. 2018;14:793802. DOI: 10.1080/1744666X.2018.1519394.

61. NIH National Cancer Institute. Cancer Statistics. 2020. Available at: www.cancer.gov/about-cancer/understanding/statistics (Date last accessed: 8 January 2024).

62. Jain K, Laila D, Nandagudi A, Bharadwaj A. Long-term outcomes in rheumatoid arthritis: Review of data from the ‘Basildon Inflammatory Arthritis Cohort’. Rheumatol Adv Pract. 2022;6:rkac075. DOI: 10.1093/rap/rkac075.

63. André F, Böckle BC. Sjögren’s syndrome. J Deutsche Derma Gesell. 2022;20:9801002. DOI: 10.1111/ddg.14823.

64. Gialouri CGFragoulis GEIs there room for better screening for lung cancer in rheumatoid arthritis? RMD Open2022;8:e002774. DOI: 10.1136/rmdopen-2022-002774.

65. Fragoulis GEChatzidionysiou KLung cancer in rheumatoid arthritis. Is there a need for better risk assessment and screening Clin Rheumatol. 2020;39:95761. DOI: 10.1007/s10067-019-04882-x.

66. Lim CHTseng C-WLin C-Tet alThe clinical application of tumor markers in the screening of malignancies and interstitial lung disease of dermatomyositis/polymyositis patients: A retrospective studySAGE Open Med. 2018;6:2050312118781895. DOI10.1177/2050312118781895.

67. Skeoch SWeatherley NSwift AJet alDrug-induced interstitial lung disease: A systematic review. J Clin Med. 2018;7:356. DOI10.3390/jcm7100356.

68. Khan SAPruitt SLXuan Let alHow does autoimmune disease impact treatment and outcomes among patients with lung cancer? A National SEER-Medicare AnalysisLung Cancer. 2018;115:97102. DOI: 10.1016/j.lungcan.2017.11.024.

69. Jacob SRahbari KTegtmeyer Ket alLung cancer survival in patients with autoimmune diseaseJAMA Netw Open2020;3:e2029917DOI10.1001/jamanetworkopen.2020.29917.

70. Andreoli LBertsias GKAgmon-Levin Net alEULAR recommendations for women’s health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann Rheum Dis. 2017;76:47685. DOI: 10.1136/annrheumdis-2016-209770.

71. Vagelli RTani CMosca MPregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Practical messages from the EULAR guidelinesPol Arch Intern Med. 2017;127:11521. DOI: 10.20452/pamw.3906.

72. Lazzaroni M-GCavazzana IColombo E, et al. Malignancies in patients with anti-RNA polymerase III antibodies and systemic sclerosis: Analysis of the EULAR scleroderma trials and research cohort and possible recommendations for screening. J Rheumatol. 2017;44:63947. DOI: 10.3899/jrheum.160817.

73. Bongartz TSutton AJSweeting MJet alAnti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: Systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006;295:227585. DOI: 10.1001/jama.295.19.2275.

74. Furer VRondaan CHeijstek Met alIncidence and prevalence of vaccine preventable infections in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD): A systemic literature review informing the 2019 update of the EULAR recommendations for vaccination in adult patients with AIIRD. RMD Open. 2019;5:e001041. DOI: 10.1136/rmdopen-2019-001041.

75. Murdaca GNoberasco GOlobardi Det alSystemic sclerosis and vaccinations: A three-year register-based cohort study about vaccination rate and uptake from Liguria referral center, northwest Italy. Hum Vaccin Immunother. 2022;18:2025732. DOI: 10.1080/21645515.2022.2025732.

76. Rondaan CFurer VHeijstek MWet alEfficacy, immunogenicity and safety of vaccination in adult patients with autoimmune inflammatory rheumatic diseases: A systematic literature review for the 2019 update of EULAR recommendations. RMD Open. 2019;5:e001035. DOI: 10.1136/rmdopen-2019-001035.

77. Fragoulis GENikiphorou EDey Met al2022 EULAR recommendations for screening and prophylaxis of chronic and opportunistic infections in adults with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2023;82:74253DOI10.1136/ard-2022-223335.

78. US Preventive Services Task Force, Owens DK, Davidson KW, et al. Screening for HIV infection: US Preventive Services Task Force recommendation statement. JAMA. 2019;321:232636. DOI: 10.1001/jama.2019.6587.

79. US Preventive Services Task Force, Mangione CM, Barry MJ, et al. Screening for syphilis infection in nonpregnant adolescents and adults: US Preventive Services Task Force reaffirmation recommendation statement. JAMA. 2022;328:12439. DOI: 10.1001/jama.2022.15322.

80. Centers for Disease Control and Prevention. Immunization Schedules. 2023. Available at: www.cdc.gov/vaccines/schedules/ (Date last accessed: 28 November 2023).

80. Guerrini GFranzetti FGiacomelli Ret alItalian recommendations for influenza and pneumococcal vaccination in adult patients with autoimmune rheumatic diseasesClin Exp Rheumatol2020;38:24556. DOI10.55563/clinexprheumatol/hj69ne.

81. Machado PMLawson-Tovey SStrangfeld Aet alSafety of vaccination against SARS-Cov-2 in people with rheumatic and musculoskeletal diseases: Results from the EULAR Coronavirus Vaccine (COVAX) physician-reported registryAnn Rheum Dis. 2022;81:695709. DOI: 10.1136/annrheumdis-2021-221490.

82. Landewé RBMKroon FPBAlunno Aet alEULAR recommendations for the management and vaccination of people with rheumatic and musculoskeletal diseases in the context of SARS-Cov-2: The November 2021 updateAnn Rheum Dis2022;81:162839DOI10.1136/annrheumdis-2021-222006.

83. Friedman MACurtis JRWinthrop KLImpact of disease-modifying anti-rheumatic drugs on vaccine immunogenicity in patients with inflammatory rheumatic and musculoskeletal diseasesAnn Rheum Dis. 2021;80:125565DOI10.1136/annrheumdis-2021-221244.

84. Lorenzetti RScolieri PGuarini Aet alIntegrated gastroenterology and rheumatology ambulatory: An innovative approach for enteropathic spondyloarthritis early diagnosisAnn Ist Super Sanita2019;55:2468. DOI10.4415/ANN_19_03_08.

85. Parra Izquierdo VGutierrez JFlorez Cet alP060 screening criteria of inflammatory bowel disease: Application in Colombian patients with spondyloarthritisAm J Gastroenterol. 2021;116(Suppl. 1):S16. DOI: 10.14309/01.ajg.0000798840.73635.0f.

86. Bartoloni EBistoni OAlunno Aet alCeliac disease prevalence is increased in primary Sjögren’s syndrome and diffuse systemic sclerosis: Lessons from a large multi-center studyJ Clin Med2019;8:540DOI10.3390/jcm8040540.

87. Qureshi AJehangir AMalik ZParkman HPRheumatologic disorders in patients undergoing esophageal manometry: Prevalence, symptom characteristics, and manometric findings. Dis Esophagus. 2021;34:doaa135. DOI: 10.1093/dote/doaa135.

88. Gutiérrez-Sánchez JParra-Izquierdo VFlórez-Sarmiento Cet alImplementation of screening criteria for inflammatory bowel disease in patients with spondyloarthritis and its association with disease and endoscopic activityClin Rheumatol2023;42:41522DOI10.1007/s10067-022-06297-7.

89. Izquierdo VPFlorez CMolano WBet alP062 Chromoendoscopy with magnification colonoscopy: analysis of mucosa of colon and ileum in patients with gastrointestinal symptoms without IBDAm J Gastroenterol. 2021;116(Suppl. 1):S16. DOI10.14309/01.ajg.0000798848.57615.18.

90. Andréasson KOhlsson BMandl TElevated levels of faecal calprotectin in primary Sjögren’s syndrome is common and associated with concomitant organic gastrointestinal diseaseArthritis Res Ther2016;18:9DOI10.1186/s13075-015-0907-8.

91. Klingberg EStrid HStåhl Aet alA longitudinal study of fecal calprotectin and the development of inflammatory bowel disease in ankylosing spondylitisArthritis Res Ther. 2017;19:21. DOI10.1186/s13075-017-1223-2.

92. Cypers HVarkas GBeeckman Set alElevated calprotectin levels reveal bowel inflammation in spondyloarthritisAnn Rheum Dis2016;75:135762. DOI: 10.1136/annrheumdis-2015-208025.

93. Lin K-DChiu G-FWaljee AKet alEffects of anti–Helicobacter pylori therapy on incidence of autoimmune diseases, including inflammatory bowel diseasesClin Gastroenterol Hepatol2019;17:19919. DOI10.1016/j.cgh.2018.12.014.

94. Tsujimoto SMokuda SMatoba Ket alThe prevalence of endoscopic gastric mucosal damage in patients with rheumatoid arthritis. PLoS One. 2018;13:e0200023. DOI: 10.1371/journal.pone.0200023.

95. Charoenngam NVitamin D and rheumatic diseases: A review of clinical evidenceInt J Mol Sci. 2021;22:10659. DOI10.3390/ijms221910659.

96. Chevalley TBrandi MLCashman KDet alRole of vitamin D supplementation in the management of musculoskeletal diseases: Update from an European Society of Clinical and Economical Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working groupAging Clin Exp Res. 2022;34:260323. DOI: 10.1007/s40520-022-02279-6.

97. Liang BBurley GLin SShi YCOsteoporosis pathogenesis and treatment: Existing and emerging avenues. Cell Mol Biol Lett. 2022;27:72. DOI: 10.1186/s11658-022-00371-3.

98. Hauser BRaterman HRalston SHLems WFThe effect of anti-rheumatic drugs on the skeletonCalcif Tissue Int2022;111:44556DOI10.1007/s00223-022-01001-y.

99. Lwin MNSerhal LHolroyd CEdwards CJRheumatoid arthritis: The impact of mental health on disease: A narrative reviewRheumatol Ther. 2020;7:45771. DOI: 10.1007/s40744-020-00217-4.

100. Negeri ZFLevis BSun Yet alAccuracy of the patient health Questionnaire-9 for screening to detect major depression: updated systematic review and individual participant data meta-analysis. BMJ. 2021;375:n2183. DOI10.1136/bmj.n2183.

101. Patel JSOh YRand KLet alMeasurement Invariance of the patient health Questionnaire-9 (PHQ-9) depression Screener in U.S. adults across sex, race/Ethnicity, and education level: NHANES 2005-2016Depress Anxiety. 2019;36:81323DOI10.1002/da.22940.

102. Nagy GRoodenrijs NMTWelsing PMJet alEULAR points to consider for the management of difficult-to-treat rheumatoid arthritisAnn Rheum Dis. 2022;81:2033. DOI: 10.1136/annrheumdis-2021-220973.

103. Yayikci YIKaradag AEffects of conventional and biological drugs used for the treatment of rheumatoid arthritis on the quality of life and depressionEurasian J Med2019;51:126DOI10.5152/eurasianjmed.2018.18018.

104. Masood ASalim BNasim Aet alAre we missing the diagnosis of depression in patients with rheumatoid arthritis at a tertiary care facilityPak J Med Sci. 2017;33:3005. DOI: 10.12669/pjms.332.11856.

105. Hammam NGamal RMRashed AMet alFatigue in rheumatoid arthritis patients: Association with sleep quality, mood status, and disease activityReumatol Clín (Engl Ed)2020;16:33944DOI10.1016/j.reuma.2018.07.010.

106. Karageorgas TIoakeimidis DMavragani CPPsychological comorbidities associated with subclinical atherosclerosis in Greek patients with primary Sjögren’s syndrome: A potential contribution of sleep impairmentClin Exp Rheumatol2018;36(Suppl.112):6872.

107. Gavilán-Carrera BGeenen RHughes Cet alNET-RMDs study: Networks of fatigue and pain in rheumatic and musculoskeletal diseases – protocol for an international cross-sectional studyBMJ Open. 2022;12:e061099. DOI10.1136/bmjopen-2022-061099.

108. Genty MCombe BKostine Met alImprovement of fatigue in patients with rheumatoid arthritis treated with biologics: Relationship with sleep disorders, depression and clinical efficacy. A prospective, multicentre studyClin Exp Rheumatol2017;35:8592.

109. Vonk MCVandecasteele Evan Dijk APPulmonary hypertension in connective tissue diseases, new evidence and challenges. Eur J Clin Invest. 2021;51:e13453. DOI: 10.1111/eci.13453.

110. Dai YWang WYu YHu SRheumatoid arthritis–associated interstitial lung disease: An overview of epidemiology, pathogenesis and managementClin Rheumatol2021;40:121120DOI10.1007/s10067-020-05320-z.

111. Luppi FSebastiani MSilva Met alInterstitial lung disease in Sjögren’s syndrome: a clinical reviewClin Exp Rheumatol2020;38 Suppl 126:291300.

112. Kadura SRaghu GRheumatoid arthritis-interstitial lung disease: Manifestations and current concepts in pathogenesis and management. Eur Respir Rev. 2021;30:210011. DOI: 10.1183/16000617.0011-2021.

113. Qiu MJiang JNian Xet alFactors associated with mortality in rheumatoid arthritis-associated interstitial lung disease: A systematic review and meta-analysisRespir Res2021;22:264DOI10.1186/s12931-021-01856-z.

114. Lee CTStrek METhe other connective tissue disease-associated interstitial lung diseases: Sjogren’s syndrome, mixed connective tissue disease, and systemic lupus erythematosusCurr Opin Pulm Med2021;27:38895. DOI10.1097/MCP.0000000000000791.

115. Juge P-AGranger BDebray M-Pet alA risk score to detect subclinical rheumatoid arthritis–associated interstitial lung diseaseArthritis Rheumatol. 2022;74:175565. DOI: 10.1002/art.42162.

116. Fazeli MSKhaychuk VWittstock Ket alRheumatoid arthritis-associated interstitial lung disease: Epidemiology, risk/prognostic factors, and treatment landscape. Clin Exp Rheumatol. 2021;39:110818. DOI: 10.55563/clinexprheumatol/h9tc57.

117. Saxena PSharma PKPurohit PA journey of celecoxib from pain to cancer. Prostaglandins Other Lipid Mediat. 2020;147:106379. DOI: 10.1016/j.prostaglandins.2019.106379.

118. George MDBaker JFWinthrop Ket alRisk for serious infection with low-dose glucocorticoids in patients with rheumatoid arthritis: A cohort studyAnn Intern Med2020;173:8708DOI10.7326/M20-1594.

119. Farrell CO’Keane VEpigenetics and the glucocorticoid receptor: A review of the implications in depression. Psychiatry Res. 2016;242:34956. DOI: 10.1016/j.psychres.2016.06.022.

120. Chandler LCYusuf IHMcClements MEet alImmunomodulatory effects of hydroxychloroquine and chloroquine in viral infections and their potential application in retinal gene therapyInt J Mol Sci. 2020;21:4972. DOI10.3390/ijms21144972.

121. Salles GBarrett MFoà Ret alRituximab in B-cell hematologic malignancies: A review of 20 years of clinical experience. Adv Ther. 2017;34:223273. DOI: 10.1007/s12325-017-0612-x.

122. Simon TABoers MHochberg Met alComparative risk of malignancies and infections in patients with rheumatoid arthritis initiating abatacept versus other biologics: A multi-database real-world study. Arthritis Res Ther. 2019;21:228. DOI: 10.1186/s13075-019-1992-x.

123. Wang WZhou HLiu LSide effects of methotrexate therapy for rheumatoid arthritis: A systematic review. Eur J Med Chem. 2018;158:50216. DOI: 10.1016/j.ejmech.2018.09.027.

124. Briot KRoux C[Corticosteroid-induced osteoporosis] [Article in French]. Rev Med Interne. 2013;34:31523. DOI: 10.1016/j.revmed.2012.11.005.

125. Both TZillikens MCSchreuders-Koedam Met alHydroxychloroquine affects bone resorption both in vitro and in vivo. J Cell Physiol. 2018;233:142433. DOI: 10.1002/jcp.26028.

126. Clarke BYates MAdas Met alThe safety of JAK-1 inhibitors. Rheumatology (Oxford). 2021;60(Suppl.2):ii2430. DOI: 10.1093/rheumatology/keaa895.

127. Atzeni FNucera VGalloway Jet alCardiovascular risk in ankylosing spondylitis and the effect of anti-TNF drugs: A narrative review. Expert Opin Biol Ther. 2020;20:51724. DOI: 10.1080/14712598.2020.1704727.

128. Smolen JSLandewé RBMBergstra SAet alEULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying anti-rheumatic drugs: 2022 update. Ann Rheum Dis. 2023;82:318. DOI: 10.1136/ard-2022-223356.

129. Park JKLee YJKang EHet alEffect of the methotrexate discontinuation for 1 versus 2 weeks on vaccine response to seasonal influenza vaccine in rheumatoid arthritis: A noninferiority randomised controlled trialArthritis Rheumatol2023DOI10.1002/art.42644.

Further Resources

Share this Article
Related Content In Rheumatic Diseases
  • Copied to clipboard!
    accredited arrow-down-editablearrow-downarrow_leftarrow-right-bluearrow-right-dark-bluearrow-right-greenarrow-right-greyarrow-right-orangearrow-right-whitearrow-right-bluearrow-up-orangeavatarcalendarchevron-down consultant-pathologist-nurseconsultant-pathologistcrosscrossdownloademailexclaimationfeedbackfiltergraph-arrowinterviewslinkmdt_iconmenumore_dots nurse-consultantpadlock patient-advocate-pathologistpatient-consultantpatientperson pharmacist-nurseplay_buttonplay-colour-tmcplay-colourAsset 1podcastprinter scenerysearch share single-doctor social_facebooksocial_googleplussocial_instagramsocial_linkedin_altsocial_linkedin_altsocial_pinterestlogo-twitter-glyph-32social_youtubeshape-star (1)tick-bluetick-orangetick-red tick-whiteticktimetranscriptup-arrowwebinar Sponsored Department Location NEW TMM Corporate Services Icons-07NEW TMM Corporate Services Icons-08NEW TMM Corporate Services Icons-09NEW TMM Corporate Services Icons-10NEW TMM Corporate Services Icons-11NEW TMM Corporate Services Icons-12Salary £ TMM-Corp-Site-Icons-01TMM-Corp-Site-Icons-02TMM-Corp-Site-Icons-03TMM-Corp-Site-Icons-04TMM-Corp-Site-Icons-05TMM-Corp-Site-Icons-06TMM-Corp-Site-Icons-07TMM-Corp-Site-Icons-08TMM-Corp-Site-Icons-09TMM-Corp-Site-Icons-10TMM-Corp-Site-Icons-11TMM-Corp-Site-Icons-12TMM-Corp-Site-Icons-13TMM-Corp-Site-Icons-14TMM-Corp-Site-Icons-15TMM-Corp-Site-Icons-16TMM-Corp-Site-Icons-17TMM-Corp-Site-Icons-18TMM-Corp-Site-Icons-19TMM-Corp-Site-Icons-20TMM-Corp-Site-Icons-21TMM-Corp-Site-Icons-22TMM-Corp-Site-Icons-23TMM-Corp-Site-Icons-24TMM-Corp-Site-Icons-25TMM-Corp-Site-Icons-26TMM-Corp-Site-Icons-27TMM-Corp-Site-Icons-28TMM-Corp-Site-Icons-29TMM-Corp-Site-Icons-30TMM-Corp-Site-Icons-31TMM-Corp-Site-Icons-32TMM-Corp-Site-Icons-33TMM-Corp-Site-Icons-34TMM-Corp-Site-Icons-35TMM-Corp-Site-Icons-36TMM-Corp-Site-Icons-37TMM-Corp-Site-Icons-38TMM-Corp-Site-Icons-39TMM-Corp-Site-Icons-40TMM-Corp-Site-Icons-41TMM-Corp-Site-Icons-42TMM-Corp-Site-Icons-43TMM-Corp-Site-Icons-44TMM-Corp-Site-Icons-45TMM-Corp-Site-Icons-46TMM-Corp-Site-Icons-47TMM-Corp-Site-Icons-48TMM-Corp-Site-Icons-49TMM-Corp-Site-Icons-50TMM-Corp-Site-Icons-51TMM-Corp-Site-Icons-52TMM-Corp-Site-Icons-53TMM-Corp-Site-Icons-54TMM-Corp-Site-Icons-55TMM-Corp-Site-Icons-56TMM-Corp-Site-Icons-57TMM-Corp-Site-Icons-58TMM-Corp-Site-Icons-59TMM-Corp-Site-Icons-60TMM-Corp-Site-Icons-61TMM-Corp-Site-Icons-62TMM-Corp-Site-Icons-63TMM-Corp-Site-Icons-64TMM-Corp-Site-Icons-65TMM-Corp-Site-Icons-66TMM-Corp-Site-Icons-67TMM-Corp-Site-Icons-68TMM-Corp-Site-Icons-69TMM-Corp-Site-Icons-70TMM-Corp-Site-Icons-71TMM-Corp-Site-Icons-72