Influence of the COVID-19 Pandemic on Medical Management and on Healthcare Delivery of Immune-Mediated Rheumatic and Musculoskeletal Diseases during the First Pandemic Period February to July 2020: A Systematic Review

(1) Background and Objectives: The COVID-19 pandemic influenced the management of patients with immune-mediated rheumatic and musculoskeletal diseases (imRMDs) in various ways. The goal of our systematic review was to determine the influence of the first period of the COVID-19 pandemic (February 2020 to July 2020) on the management of imRMDs regarding the availability of drugs, adherence to therapy and therapy changes and on healthcare delivery. (2) Materials and Methods: We conducted a systematic literature search of PubMed, Cochrane and Embase databases (carried out 20–26 October 2021), including studies with adult patients, on the influence of the COVID-19 pandemic on the management of imRMDs. There were no restrictions regarding to study design except for systematic reviews and case reports that were excluded as well as articles on the disease outcomes in case of SARS-CoV-2 infection. Two reviewers screened the studies for inclusion, and in case of disagreement, a consensus was reached after discussion. (3) Results: A total of 5969 potentially relevant studies were found, and after title, abstract and full-text screening, 34 studies were included with data from 182,746 patients and 2018 rheumatologists. The non-availability of drugs (the impossibility or increased difficulty to obtain a drug), e.g., hydroxychloroquine and tocilizumab, was frequent (in 16–69% of patients). Further, medication non-adherence was reported among patients with different imRMDs and between different drugs in 4–46% of patients. Changes to preexisting medication were reported in up to 33% of patients (e.g., reducing the dose of steroids or the cessation of biological disease-modifying anti-rheumatic drugs). Physical in-office consultations and laboratory testing decreased, and therefore, newly implemented remote consultations (particularly telemedicine) increased greatly, with an increase of up to 80%. (4) Conclusions: The COVID-19 pandemic influenced the management of imRMDs, especially at the beginning. The influences were wide-ranging, affecting the availability of pharmacies, adherence to medication or medication changes, avoidance of doctor visits and laboratory testing. Remote and telehealth consultations were newly implemented. These new forms of healthcare delivery should be spread and implemented worldwide to routine clinical practice to be ready for future pandemics. Every healthcare service provider treating patients with imRMDs should check with his IT provider how these new forms of visits can be used and how they are offered in daily clinical practice. Therefore, this is not only a digitalization topic but also an organization theme for hospitals or outpatient clinics.


Introduction
In 2019, the novel coronavirus "Severe Acute Respiratory Syndrome-Corona Virus 2 (SARS-CoV-2)" was identified in China [1].Coronaviruses have led to several critical disease outbreaks in the past.Important to mention are the outbreak of severe acute respiratory syndrome (SARS) in China in 2002 and of middle east respiratory syndrome (MERS) on the Arabian Peninsula in 2012 and in Korea in 2015.While these former disease outbreaks were geographically localized, SARS-CoV-2 spread rapidly over countries, causing a worldwide pandemic [2].The disease caused by SARS-CoV-2 was subsequently named coronavirus disease   [3,4].At the beginning of the pandemic, the focus was primarily on an infection of the lungs with pneumonia and pneumonitis occurring, as well as the associated problems in severe cases such as acute respiratory distress syndrome (ARDS).By now, COVID-19 is known to be a multisystem infectious disease that affects different organ systems [5].The course of COVID-19 ranges from mild to severe and critical cases (depending on risk factors) often requiring intensive care.Risk factors for a severe disease course are cardiovascular risk factors, chronic lung diseases, male sex, age over 65 years, obesity, high-dose corticosteroid use, and immunodeficiency or immunosuppressive medication [6].Patients with immune-mediated rheumatic and musculoskeletal diseases (imRMDs) including inflammatory arthropathies (rheumatoid arthritis, spondyloarthropathies), connective tissue diseases or vasculitis are at a higher risk of infections especially due to the use of immunosuppressive medication [7].
COVID-19 and the following pandemic have therefore raised concerns amongst rheumatologists, especially regarding immunocompromised patients.Data from 2021 show that the risk for infection with SARS-CoV-2 is not increased [7] or only slightly [8] elevated in patients with imRMDs compared to the general population, but, if infected, the risks for hospitalization or for a severe disease course and death are increased by a factor of 1.58 to 2.92 [9].Regarding medication, most conventional synthetic (csDMARD), biological (bDMARD) and targeted synthetic disease-modifying anti-rheumatic drugs (tsDMARDs) do not seem to increase the risk of infection with SARS-CoV-2 or the risk of poor outcomes of COVID-19, the exceptions being glucocorticoids > 10 mg/day, rituximab, mycophenolate mofetil (MMF) and potentially Janus kinase inhibitors (JAKis) [9].
The disease course of patients with imRMDs and SARS-CoV-2 infection has been studied widely, but systematic reviews describing the influence of the pandemic on the treatment of imRMDs are lacking.
The aim of this systematic review is to describe the influence of the COVID-19 pandemic on the management of imRMDs during the first wave from February 2020 to July 2020 regarding availability of drugs, adherence and changes in medications, on the access to rheumatological care and medications and on the use of other healthcare delivery forms.

Materials and Methods
This review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [10].A comprehensive search was carried out in PubMed, Cochrane and Embase databases regarding publications from 1 December 2019 to 31 October 2021.We used specific MeSH headings and additional keywords to identify studies (see search strategy in Supplementary File S1).
We selected articles in English or German including adult patients with imRMDs that evaluated the influence of the COVID-19 pandemic on the general management of imRMDs (influence on adherence or changes in medications), on the access to rheumatologically care and medications, and on the use of other healthcare delivery forms.There were no restrictions regarding study design except for systematic reviews and case reports that were excluded as well as articles on the disease outcomes in case of SARS-CoV-2 infection.
Studies found were screened independently by two reviewers (MS, SBa) for inclusion.In the first phase, the studies were screened for title and abstract, followed by full-text screening and data extraction.In case of disagreements, a consensus was reached after discussion between the two raters.Quality rating was performed according to the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence [11].Covidence systematic review software (version of 2021, Veritas Health Innovation, Melbourne, Australia) [12] was used as the literature management program and Zotero (version 6, Corporation for Digital Scholarship, Fairfax, VA, USA) as reference management software [13].
Because no randomized controlled trials were published and data were very heterogeneous, no meta-analysis was performed.Out of the included studies, two clusters of "influences of COVID-19 pandemic" were formed and analyzed further regarding: (i) the influence on the medical management of imRMDs; (ii) influences on healthcare delivery regarding imRMDs.

Study Selection
The search strategy identified 5969 potentially relevant studies.Based on title and abstract and after removal of duplicates, 155 studies were assessed in full-text screening.A final total of 34 studies with data from 182,746 patients and from 2018 rheumatologists were included in the systematic review.Figure 1 shows the study flow according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [10].

Study Characteristics and Levels of Evidence
The majority of included studies were surveys or questionnaires , which are evidence grade IV according to the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence [11].One was a cohort study, graded level III [48].

Study Characteristics and Levels of Evidence
The majority of included studies were surveys or questionnaires , which are evidence grade IV according to the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence [11].One was a cohort study, graded level III [48].
77% of the patients, who were communicating with their physician, were recommended to continue bDMARD therapy.Overall, 22% of the patients discontinued their medications.In patients with SpA, 54% discontinued their medication.bDMARDs were the most frequent drugs to be stopped: anti-IL-1 agents in 40%, anti-TNF agents in 35%, interferon in 33%, tocilizumab in 29%, rituximab in 7% of the patients.Prednisolone (low dose), azathioprine, methotrexate, leflunomide, colchicine and sulfasalazine were least likely to be stopped (≤10% for each drug).11% of the patients on hydroxychloroquine had to skip or stop the drug due to shortage or failure of prescription renewal.86% of patients with rheumatic diseases were unwilling to go to the hospital.Only 14% of patients visited the outpatient clinic "as it was before", 43% "did not want to come" and 28% "were advised to postpone their visits".

Sloan et al. 2021, UK [31] Survey IV
To assess the influence of the COVID-19 pandemic on medical care and healthcare behavior of patients with SLE and other autoimmune rheumatic diseases 111 patients with autoimmune rheumatic diseases 10% of patients reduced or stopped their medication, and 10% increased the dose of their medication without advice of their doctor.70% reported a canceling of their appointments, tests and treatments more or much more frequently since the pandemic.Between 35% and 45% felt that care from GPs, rheumatologists and other specialists had been worse/much worse during the pandemic.Of these, 40% of patients needed to change their medication due to non-availability.1% of patients had missed their scheduled cyclophosphamide dose due to non-availability of drug or problems to attend outpatient clinics for intravenous infusion.22% of patients faced difficulty in the availability of hydroxychloroquine.54% of patients missed their scheduled follow-up visits.37% of patients were unable to obtain their diagnostics carried out due to closure of laboratories and hospitals.

Gupta et al. 2021, England [41] Survey IV
To determine the influence of the COVID-19 pandemic on the healthcare of systemic scleroderma patients 291 patients with scleroderma from all over the world 15.1% of the patients on steroids required an increase in dose in the current situation.38.1% of respondents faced hurdles in procuring medicines.Of the 14.4% that were on infusions.
45% had to delay it.Physiotherapy sessions were disrupted in 25%.7% could not contact their specialist.Another 24% experienced difficulty contacting their specialist.Overall follow-up visit volume decreased by 25% in the COVID-19 period but rebounded within a few months to pre-COVID-19 levels.Telehealth visits pre-COVID-19 were nearly non-existent and increased to 41% and 28% of all follow-up clinician visits in the COVID-19 period and after the first wave of the pandemic.90% of telehealth visits were video-based, 7% via phone and 2% digital.Up to maximum of 60% of visits were cancelled during the COVID-19 transition period.In the COVID-19 period in 2020, the odds of starting a new biologic or JAKi therapy for an RA patient was substantially lower (adjusted odds ratio = 0.55) compared to the corresponding 6-week period in 2019.ARD = autoimmune rheumatic disease; AxSpA = axial spondyloarthritis; bDMARDs = biological diseasemodifying anti-rheumatic drugs; CQ = chloroquine; csDMARDs = conventional synthetic disease-modifying anti-rheumatic drugs; GPs = general practitioners; HCQ = hydroxychloroquine; NSAID = non-steroidal antiinflammatory drug; OR = odds ratio; PsoA = psoriasis arthritis; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; SpA = spondyloarthritis; tsDMARDs = targeted synthetic disease-modifying antirheumatic drugs.

Influence on the Medical Management of imRMDs (a) Non-availability of drugs
The non-availability of rheumatic medication was a prevalent issue, important examples being hydroxychloroquine (HCQ) and tocilizumab.Shortages or difficulties in the availability of HCQ was an issue in 16-69% of patients [14,15,17,20,23,30,47], with the highest level reported from India [20].Shortages of tocilizumab was reported in 14% of patients [45,47].

(b) Non-adherence to medication
Non-adherence to prescribed drugs was another issue.Non-adherence was very heterogeneously defined in the different studies as changing medication, the adaptation of dose or intervals without professional health advice or stopping medication or the irregular intake of medication without professional health advice.The overall non-adherence rate among all included studies was 4-46% of patients [16,26,[29][30][31][32]43].High rates of nonadherence were reported by four studies [20,21,24,33], with the highest level (46% of patients) reported from India [20].
A Swiss study [16] comparing the medication adherence of patients with different imRMDs before and during the pandemic found only slight adherence reductions.A significant increase in non-adherence was only seen in patients with axial spondyloarthritis (axSpA) (13% medication non-adherence in pre-COVID-19 period versus 20% during the first wave).The lowest level of medication non-adherence was reported from Denmark [21].In this study, compliance with medication was compared between the start of the first lockdown to three months later, when society was gradually reopened.Low levels of non-adherence were reported (4-6% at the start of the lockdown versus 2-4% three months later).Further, there was a direct correlation of the incidence of SARS-CoV-2 infections in the general population and medication non-adherence: the higher the incidence of COVID-19, the lower the medication adherence [24].

(c) Drugs changed or stopped
The drugs mostly changed or stopped were bDMARDs and JAKi [28,32].Low-dose prednisolone and csDMARDs were the least likely medications to be stopped.Longer disease durations of the underlying rheumatic disease and higher disease activity were significantly associated with medication discontinuation [19].Disease flares were described in high proportions of the patients (63-74%) who had stopped their DMARDs [15,18].
(d) Influence on the treating rheumatologist Lastly, there was also an influence of the pandemic on the treating physician regarding medication.Rheumatologists reduced the dose of steroids in 23-36% of patients [14,47], and in 17% of patients, steroids were stopped completely [14].In contrast, csDMARDs were stopped only rarely (in 2% of patients) [14], whereas bDMARDs were stopped more frequently (in 33% of patients) [15].In a few cases, drug application intervals of bDMARDs were extended [28].Moreover rheumatologists were hesitant to start a bDMARD in 75% [47] or a tsDMARD in 14% [14] of cases.

Influences on Healthcare Delivery
(a) Avoidance of in-person visits George et al. [27] and Banerjee et al. [36] reported the avoidance of laboratory testing in 42% and 47% of patients, respectively.Patients with imRMDs were significantly less likely to avoid in-person visits (OR 0.79 (95% CI 0.70-0.89))or laboratory tests compared to patients with non-autoimmune RMDs (35% versus 39%, OR 0.84 (95% CI 0.73-0.96))[26,48].Other factors associated with the avoidance of in-person visits and laboratory testing were older age, low socioeconomic status, living in urban areas or in countries with higher COVID-19 activity and regarding medication receiving a bDMARD or JAKi [48].
(b) Alternative types of visits Singh et al. [45] reported an increase in alternative types of visits to the rheumatologist related to COVID-19 compared to the pre-COVID-19 era, such as telephone visits (plus 53%), video-based Veterans Affairs Video Connect (VVC) visits (plus 44%) and clinical video tele-health (CVT) visits with a facilitator (plus 29%).Bos et al. [46] reported telephone visits to be the most commonly used form of remote consultation, with 80% of rheumatologists using exclusively telephone consultations.In-person visits were conducted only in special circumstances, such as for joint aspiration [46].

Discussion
This systematic review showed that COVID-19 influenced healthcare behavior in patients with imRMDs, as well as in rheumatologists and other doctors during the first pandemic wave from February to July 2020.In many cases, patients or doctors discontinued established medication.Further, the pandemic resulted in a collapse of supply chains, causing the non-availability of medication, especially in the case of HCQ and tocilizumab.Healthcare appointments took place less frequently than usual, and telehealth emerged as a solution, with remote consultations with physicians or with newly established telerehabilitation services.
Medication non-adherence was a common problem among patients.A possible explanation could be the low availability of remote consultations at the beginning of the pandemic, resulting in feelings of insecurity with patients stopping their medication as a self-management strategy.The classes of medication that were discontinued most frequently were bDMARDs and JAKi [26,30], possibly because these immunosuppressive medications are considered the most dangerous regarding infections.
Between different imRMDs, relevant differences in non-adherence to medication have been reported.Low numbers of non-adherence were reported in patients with vasculitis [37,38].Patients with vasculitis are usually aware of the disease course with serious relapses in the absence of maintenance therapy, which results in an adherence to treatment [38].Another factor increasing medical compliance is that parenteral treatments are often only possible in the hospital setting and are therefore not postponed by patients.
The sudden discontinuation of anti-rheumatic therapy is a relevant issue because it can lead to disease flares.A large proportion of patients with different imRMDs reported a flare after modifying their treatment [15,18].This supports the recommendation of not stopping treatment during the pandemic in situations other than suspected or confirmed SARS-CoV-2 infection because resulting disease flares and higher requirements for glucocorticoids could increase the risk of SARS-CoV-2 infection [36].
The pandemic, and mostly the fear of infection with SARS-CoV-2, had a severe influence on the medication behavior of rheumatologists.A large proportion of rheumatologists reduced the dose or frequency of steroids [14,47,49], many changed DMARDs [14,22] or stopped them [14,15] and there was hesitancy to start new DMARDs [47,49].
N. Rebić et al. conducted a systematic review about the adherence to medication in patients with imRMDs [49].They described non-adherence rates of 6.5-34.2%and discontinuation rates of 2-31.4% which are similar rates compared to the overall nonadherence rate of 4-46% in our systematic review.They found slightly higher numbers of physicians who reduced the dose of steroids (23-56% vs. 23-36% in our review), and they also reported of a reluctance to start bDMARDs or tsDMARDs.
Different non-compliance rates to medical visits were reported between the different studies [22,30].Patients with autoimmune RMDs were significantly less likely to avoid in-person visits and laboratory tests compared to patients with non-autoimmune rheumatic diseases [26,48].These results may be explained with the fact that patients with imRMDs needed close monitoring because of their disease as well as their immunosuppressive treatment and the fear of an infection with SARS-CoV-2 was a more dominant factor determining behavior.Interestingly, a study from North America [48] reported a normalization of the rates of follow-up visits a few months after the start of the pandemic, suggesting a rapid adaptation of patients and doctors to the pandemic circumstances.
The COVID-19 pandemic posed many challenges, but it also opened new opportunities for the development of healthcare systems.Because of the environmental risk factors for acquiring a SARS-CoV-2-infection before vaccines existed, practical steps to reduce the infection risk were introduced, including social distancing, hand hygiene and use of face masks [9].As a consequence of social distancing, patient consultations were performed remotely whenever possible, leading to an increase in telehealth care.Prior to 2019, telehealth care was very rare or non-existent, but its use grew rapidly during the COVID-19 pandemic.Nevertheless, there were huge differences between different countries in the implementation of telehealth.Data from the USA and Australia showed an increase in telehealth, whereas data from India reported that only a small proportion of patients were aware that telehealth existed, and even fewer used it.It is likely that many patients with imRMDs, especially those from non-urban parts of emerging countries, had no access to telehealth care during the COVID-19 pandemic.A major goal of telehealth was to try to avoid dis-ruption of healthcare and to prevent patients from stopping their medication.In addition, telephone and video-based consultations were preferred in "stable patients" with known disease courses and without the need for changing immunosuppressive medication [45].
Based on our personal experience, we believe that telehealth was a valuable tool to avoid disruption in healthcare and to prevent medication non-adherence in these special circumstances.However, since the pandemic period is over, the rate of telehealth consultations went back, and the advantages of telehealth and remote consultations are only seen in patients who have mobility difficulties to reach the treating physician's office.In these situations, telehealth and remote consultations are still a valuable instrument to increase or hold adherence to medications.

Strengths and Limitations
This study has several strengths.Although most studies were of low evidence grade (III or IV), data from 182,746 patients and 2018 interviewed rheumatologists were included.Together with the fact that studies from four different continents and different countries were included, these large numbers paint a global picture of the influence of the pandemic on imRMDs.The influence covers a broad spectrum of issues occurring during the COVID-19 pandemic, including compliance with medication, the shortage of certain medications and problems with the delivery of healthcare.In addition, new aspects are described, such as telemedicine and telerehabilitation services, which were set up as substitutes for former in-person routine care.The study also has limitations.First, regarding the heterogeneity of the reported outcomes and the study designs, it was not possible to carry out a metaanalysis and to evaluate the results statistically using odds ratios.Inhomogeneous reporting and differences in research methodology between the studies made comparisons difficult, and a generalization of the results may not be suitable.Furthermore, definitions of nonadherence with medication varied between studies.Therefore, it was demanding to extract and compare the different results rationally.Most of the included studies were surveys, which leads to some typical limitations regarding the study design.Surveys may lead to inclusion biases, as patients who are more interested or worried about COVID-19 are generally more willing to participate.The responses are self-reported and cannot be verified.Survivorship bias is also probable as very sick or deceased patients cannot participate.Further, patients with a relatively higher socioeconomic status have a greater online presence and affinity to online surveys and are therefore probably overrepresented.As many of the results were published only as case reports and congress abstracts, those results were not included in the present study.Important information may therefore have been missed.Finally, this review shows only results regarding the influence on the treatment of imRMDs of the first wave of the COVID-19 pandemic lasting February 2020 to July 2020.

Conclusions
The COVID-19 pandemic influenced the management of patients with imRMDs, especially during the first wave from February 2020 to July 2020.The influence of the pandemic was diverse regarding adherence to medication, shortage of some medications, adherence to doctor visits or laboratory testing and governmental interventions.To preserve adherence to healthcare, the COVID-19 pandemic was a starting point for new healthcare systems.Remote and telehealth consultations were implemented.These new forms of healthcare delivery should be spread and implemented worldwide to routine clinical practice to be ready for future pandemics.Every healthcare service provider treating patients with imRMDs should check with his IT provider how these new forms of visits can be used and how they are offered in daily clinical practice.Therefore, this is not only a digitalization topic but also an organization theme for hospitals or outpatient clinics.

Table 1 .
Characteristics of included studies.

Table 2 .
Rates of non-adherence and of difficulties obtaining medication regarding different immunemediated RMDs.