Introduction

Comorbidities are additional disease states or organ involvement that exist parallel to an index disease, and can delay diagnosis, confound the assessment of disease status, jeopardise treat-to-target strategies and reduce the quality of life or increase mortality [1]. Rheumatic and musculoskeletal diseases (RMDs) are chronic conditions that accrue damage as well as comorbidities over the years. An initiative from the European League Against Rheumatism (EULAR) stresses six significant comorbidities that need to be addressed in RMDs: ischaemic cardiovascular diseases, depression, infections, gastrointestinal diseases, osteoporosis and malignancies [2].

The most common comorbidity is likely cardiovascular. The risk of a myocardial event is at least 50% higher in patients with rheumatoid arthritis, gout and psoriatic arthritis than for the general population [3]. The risk is also higher for patients with osteoarthritis, and possibly for those with ankylosing spondylitis [3]. In chronic painful conditions like arthritis, there is catastrophising and thus, concomitant depression arising out of such inadept defence mechanisms [4]. Also, the chronic inflammation predisposes to neuroendocrine suppression, fatigue, sarcopenia, osteopenia and possibly a lean variant of the metabolic syndrome (“cachectic obesity”) [5]. A meta-analysis has shown that patients with rheumatoid arthritis (RA) are at higher risk for lymphoma and lung malignancies [6]. All these comorbidities including cardiovascular disease, diabetes, osteoporosis, neoplasms, depression, and infections are often sub-optimally diagnosed and managed [2].

Comorbidities in RMDs have gained an extreme significance as they may be associated with increased risks of hospitalisation and death in the wake of the coronavirus-19 (COVID-19) pandemic. Preliminary data from patients with RMDs in Spain have shown that the presence of comorbidities as well as disease activity were associated with severe COVID-19 and death [7]. The initial cohort of patients with RMDs who had developed COVID-19 in Wuhan, China, included 17 patients, of which at least nine had comorbidities and one of these patients expired. Follow-up interviews of the 16 discharged patients revealed that 10 of them had discontinued or changed their rheumatology drugs [8]. Similarly, the report of the first 600 patients in the COVID-19 Global Rheumatology Alliance (C19-GRA) physician-reported registry also reiterated that age above 65 years and presence of comorbidities were more likely to be hospitalised [9].

Therefore, it is important to appraise the various comorbidities in RMD in the context of risk for COVID-19, and also, to anticipate how the pandemic influences the management and the prevention of comorbidities in RMDs. Closely entwined is the question of whether exposure to the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) in patients with RMDs would increase the risk of future comorbidities (Fig. 1).

Fig. 1
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Comorbidities and COVID-19

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Search strategies

Searches were carried out on MEDLINE/PubMed and Scopus in the first week of Oct 2020 for the literature on COVID-19 in RMD patients as per standard recommendations [10]. The common keywords used for the first search were “rheumatic disease”, “inflammatory arthritis”, “rheumatic and musculoskeletal diseases” in various combinations with “COVID-19” or “SARS-CoV-2”. The second search included “COVID-19”or “SARS-CoV-2” with different combinations with “comorbidities”, “metabolic syndrome”, “diabetes”, “hypertension”, “lung disease”, “cardiovascular disease”, “stroke” and “myocardial infarction”. The third search used “rheumatic disease”, “inflammatory arthritis”, or “rheumatic and musculoskeletal diseases” with the different comorbidities keywords included in the second search. The searches were updated in the third week of November to include any articles published since the initial searches.

COVID-19 in RMD patients

In the initial data from China, there were 21 patients with RMDs and length of hospital stay was similar to those without RMDs [11]. A retrospective study from Spain has shown a higher prevalence of hospital diagnosed COVID-19 was more in patients on biologicals but in those on conventional DMARDs [12]. The results are summarised in Table 1. Telephonic or internet-based surveys estimating the incidence of infection without mentioning comorbidities have not been included in this table. Studies having higher co-morbidities seem to have more severe cases, often attributing it to the presence of RMDs. However, in studies with lower co-morbidities, there appears to be no difference of COVID-19 severity in RMDs and general populations. For patients with RMDs, prior knowledge about avoiding infections may play a role in reducing SARS-CoV-2 infection [13].

Table 1 Summary of the available literature on COVID-19 in RMDs
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Comorbidities and death in COVID-19

In one of the first retrospective cohorts published from Wuhan, China, almost 50% of patients hospitalised with COVID-19 had comorbidities [36]. In the first 200 patients admitted in New York, the three most common comorbidities were hypertension (76%), hyperlipidemia (46.2%), and diabetes (39.5%) [37]. In an analysis of 3626 patients regarding the effects of race on COVID-19 outcomes, a higher score on the Charlson Comorbidity Index was associated with increased rates of hospitalisation [38]. Thus, comorbidities are common in patients with COVID-19. Table 2 summarises various meta-analyses looking at the associations of multiple comorbidities with mortality or severe disease in COVID-19.

Table 2 Meta-analyses on effects of comorbidities on COVID-19
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One meta-analysis looking at patients with autoimmune diseases developing COVID-19 found no association with severe disease (3 studies, 1276 patients, OR = 1.21, 95% CI: 0.58–2.50, p = 0.79) or with mortality (3 studies, 835 patients, OR = 1.31, 95% CI: 0.33–5.20, p = 0.95) [56]. However, it should be kept in mind that the RMDs may be only a part of all autoimmune diseases, and the numbers are too small to analysis those with comorbidities.

Comorbidities in RMD that may predispose to severe COVID-19 and death

The different co-morbidities in various RMDs have different prevalence. Patients with difficult to control diseases often have higher comorbidities [57]. The most common comorbidities in each are enumerated in Table 3. Paediatrics patients often have limited comorbidities, and a systematic review has identified only one single child with RMD who had acquired COVID-19 [58].

Table 3 Prevalence of various comorbidities in RMDs
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Metabolic syndrome

Rheumatoid arthritis is associated with most facets of the metabolic syndrome. A meta-analysis has shown that the presence of RA is a risk factor for developing diabetes [97]. The system inflammation in RA, along with the use of glucocorticoids, has been implicated in the development of insulin resistance in RA [98]. This can be closely associated with obesity. At least a quarter of RA patients are overweight (BMI > 25) [62]. Besides being a direct risk factor, it also contributes indirectly by increasing disease activity and making remission more difficult to achieve [99]. Hypertension can be seen in around 50% of RA and is possibly more in patients with resistant disease [57]. Also, underdiagnosis and undertreatment of hypertension and dyslipidaemia in RA are reported [63]. The relationship of psoriatic arthritis with metabolic syndrome is stronger with common mechanistic pathways leading to both [100]. The cardiovascular risks of various rheumatic diseases have been explored in depth in various reviews [101, 102].

Accelerated atherothrombosis at premature age

The metabolic syndrome, as well as the pro-inflammatory state, leads to accelerated thrombosis. COVID-19 is intrinsically a pro-thrombotic state [103]. Thus, the risk of thrombosis may be multiplied in the setting of COVID-19.

Interstitial lung diseases

Amongst lung diseases, interstitial diseases (ILD) have the highest association with rheumatic disease. In RA, it is reported to have a prevalence from 1–60% depending on the methodology used [67]. Many of these patients may not be symptomatic, and only a proportion will have progressive lung disease. However, it is not known whether this will predispose to severe lung COVID-19. ILD are often a major concern in patients with systemic sclerosis (SSc) and with idiopathic inflammatory myopathies (IIM). ILD is the most frequent cause of death in SSc [104]. Registry data show around 40–50% of SSc patients are documented to have ILD [105]. A similar proportion of patients with mixed connective tissue disorder have ILD that is slowly progressive and increases the mortality rate [106]. Also, in the spectrum of IIM, the presence of ILD has been associated with 50% excess mortality [107]. ILD in Sjogren is reported from 8–35% with a 5-year survival of 84% [93, 108, 109].

Chronic kidney disease

Patients with lupus nephritis may develop chronic kidney damage including interstitial fibrosis and glomerulosclerosis. Similarly, patients with Sjogren and long-standing RA may also develop features of chronic kidney disease (CKD). A meta-analysis of cohort studies has shown that patients with RA have a higher incidence of developing CKD [110]. Though previously, it was attributable to the high use of non-steroidal anti-inflammatory drugs, and uncontrolled inflammation (leading to amyloidosis), currently, it is more likely to be associated with accelerated atherosclerosis [111]. Though the mortality in lupus has come down drastically in the last 2 to 3 decades, renal impairment is still seen in up to 40% of patients [85]. Scleroderma renal crisis, though uncommon, is the leading cause of renal transplantation in SSc patients, and 5 years mortality after transplant is 82.5% [112]. It is well known that COVID-19 can directly precipitate acute kidney injury (AKI) and presence of CKD is a poor prognostic marker.

Effects of depression

The association between inflammatory rheumatic diseases and depression is well established. A meta-analysis has shown that depression is prevalent in at least one-third of patients with RA [113].

Immunomodulatory therapy seems to improve mental parameters independent of improvement in physical disease activity [114]. Conversely, it is expected that depression would also alter immune parameters in an individual. It can alter the hypothalamic–pituitary–adrenal axis and sympathetic outflow [4]. Depression is associated with immune dysregulation, independent of RMDs [115]. This may predispose to infections and possibly even severe COVID-19. In mice models, it has been shown that repeated social defeat leads to immune suppression [116]. Though there may be a risk of confounding by indication, a cohort of 59,301 people followed up for 14.8 years has shown that those with depression have a higher incidence of blood-stream infections [117].

Risk of infections

RMDs are independently associated with the risk of infections [118]. The various disease-modifying anti-rheumatoid drugs (DMARDs) are immunomodulatory agents. Especially the use of targeted synthetic and biological DMARDs possibly predispose to a higher rate of infections including opportunistic infections [119]. Though rituximab has been implicated to have a higher risk of infections as compared to other biologicals, a meta-analysis has shown no difference [120].

People with RMDs usually have poorer compliance with vaccination [121] though they are often at increased risks for various infections including pneumococcal, meningococcal, herpetic and other vaccine-preventable infections [122].

Risk stratification for severe COVID-19 and death in RMDs

Quantifying the risks for severe COVID-19 and mortality is required. A risk score to predict this will need to include the number of comorbidities providing a weightage score based on the severity and duration of each. The previous history of infections, hypogammaglobulinemia, hospitalisations should also be included in the score. Current immunosuppressive drugs including cumulative exposure to steroids may also be important predictors for severe COVID-19 in the presence of comorbidities [9].

Management of comorbidities to reduce risk of severe COVID-19 and death

Management of hypertension, diabetes and coronary artery disease can help in reducing mortality in COVID-19. Currently, there is ample evidence that the use of angiotensin-converting enzyme (ACE) inhibitors and ACE-receptor blockers in patients with hypertension help in reducing both COVID-19 severity and mortality [123]. A good number of meta-analyses have been carried out looking at the effects of renin–angiotensin inhibitors in COVID-19, and now there is sufficient proof that the use of ACE-inhibitors for any indication reduces mortality in COVID-19 [124].

Statins have been shown to be able to reduce cardiovascular mortality in RA [125]. There is a biological basis for statins in reducing atherosclerotic disease in other RMDs like lupus as well [126]. Statins have also been proposed for COVID-19 [127], and there is emerging evidence that statins can reduce mortality in COVID-19. Analysis of hospital data from China has shown that statin treatment was associated with lower mortality (adjusted hazard ratio of 0.63, 95% CI 0.48–0.84, p = 0.001) compared to non-statin users [128].

Hydroxychloroquine (HCQS) is a cornerstone drug for lupus and has potential role against atherothrombosis via downregulation of Toll-like receptor signalling, cytokine production, T cell and monocyte activation [129]. Rodent models have demonstrated beneficial effects on endothelial dysfunction [130]. Though not established as a standard of care in vasculitis yet, it has been shown to be helpful in anti-neutrophilic neutrophilic cytoplasmic antibody (ANCA) associated vasculitis, IgA vasculitis, Takayasu's arteritis and polyarteritis nodosa [131]. A significant part of this action may be due to its potential anti-endothelial dysfunction and anti-thrombotic mechanisms in vasculitis. Endothelial dysfunction with ‘endotheliitis’ plays a significant part in COVID-19 pathogenesis [132]. It has been shown that hydroxychloroquine does not protect from COVID-19 in rheumatology patients [133]. However, higher disease activity in RMDs is independently associated with higher mortality in COVID-19. HCQS should not be stopped in patients already taking them. There is speculation with the demonstration of anti-phospholipid antibodies in COVID-19 patients [134] that these antibodies may have a pathological role. If so, there can be a strong case for HCQS in preventing thrombosis in COVID-19.

Lower vitamin D levels have been associated with more severe COVID-19 [135]. Serum levels of vitamin D have been suggested as a biomarker for outcomes in COVID-19 [136]. The association of mortality with obesity may have low vitamin D as a confounding factor [137]. Many RMDs have low serum vitamin D levels [138]. There is some preliminary evidence of the benefit of vitamin D in RMDs [139]. It needs to be seen whether vitamin D will also help in RMD patients with COVID-19.

Many patients with RMDs receive vitamin D supplementation for osteopenia or osteoporosis. It remains to be seen if this influences the outcomes of COVID-19. One study has shown that people receiving denosumab, zoledronate and duloxetine had a negative association with COVID-19 incidence [140]. This was not true for vitamin D supplementation. It is difficult to interpret the study now and more evidence including the validations of these findings is required.

Maintaining physical health through activity is an essential part of the battle against the pandemic. It is important not to marginalise the benefits of physical activity [137]. Social distancing should not mean any patient has to be isolated at home without any activity like walking. Even staying at home, there is scope for introducing interventions like resistance training, respiratory muscle training (including deep breathing exercises) with aerobics wherever feasible [141]. The breathing exercises described as a part of Yoga may help both respiratory muscles as well have short-term favourable outcomes on depression [142].

Effect of COVID-19 on comorbidities in RMDs

There are case reports of several new rheumatic diseases being diagnosed after SARS-CoV-2 infection. Some may be atypical features of COVID-19 itself while others might be simmering RMDs unmasked during the inflammation of COVID-19. However, COVID-19 may itself also initiate autoimmune diseases including RMDs [143]. One immune-mediated syndrome is Multisystem inflammatory syndrome in children (MIS-C) [144]. The inflammatory pathways involved in COVID-19 have remarkable overlap with those of rheumatoid arthritis [145]. However, COVID-19 has not been shown to precipitate arthritis except case reports [146, 147] that are possibly the exceptions that prove the rule. Similarly, there is little evidence to suggest that COVID-19 can worsen pre-existing arthritis [148].

COVID-19 has been shown to precipitate cardiomyopathy, and lung fibrosis had may have more tremendous implications for patients pre-existing RMDs. Magnetic resonance imaging of patients recovered from COVID-19 has shown active cardiac involvement in 60%, independent of pre-existing conditions and severity of COVID-19 [149]. A similar study had also been reported from China [150]. Post-COVID-19 pulmonary fibrosis is likely to be associated with older age, the severity of pneumonia, and background lung disease [151]. Patients with RMDs predisposing to lung pathology may have higher risks of post-COVID-19 fibrosis.

In data from Switzerland, there was no increase in disease activity of RMDs in the short term since the onset of the pandemic. However, drug non-compliance has increased [152]. This might lead to increased flares in the near future. This can also increase the inflammatory burden and add to cardiovascular risks. Thus, patients with RMDs may have an increased risk of developing comorbidities after exposure to SARS-CoV-2.

Implications for the rheumatologist

The pandemic has forced an unprecedented shift to online platforms and virtual consultations. Now patient-reported outcomes have taken antecedence over physician assessments [153]. However, these will focus more on the primary manifestations of diseases and are likely to relegate comorbidities to the background. Comorbidities, already being sub-optimally managed [2], maybe neglected further. Newer comorbidities may be missed on teleconsultations.

Many drugs used in rheumatology have been proposed for COVID-19 [154]. However, these have not shown any evidence of benefit to date [155]. The small benefit of these drugs may be offset by the presence of the various comorbidities in RMDs. Thus, unless comorbidities are addressed, we may be missing out on much relevant information.

Again, the pandemic may influence drug compliance due to unavailability of drugs, missing appointments with rheumatologists, or even just a fear of using ‘immunosuppressant’ drugs. This itself might lead to flares and increased comorbidities that might be attributed as a direct pathobiological effect of COVID-19 [156].

Conclusion

Thus, there is a need to stratify RMDs as per the presence and number of comorbidities. This will help physicians predict risk for severe COVID-19 as well as future overall outcomes. It may also have implications on prioritising candidates for future COVID-19 vaccines.

The knowledge about various comorbidities and how to tackle these has expanded in the last couple of decades, but the current pandemic threatens to take the focus away. It is crucial to incorporate protocols to address them during consultations, particularly teleconsultations. Holistic management will only be possible when we focus on the patients as a whole, and not just what is mandated by the primary disease targets.