Self-Reported Symptoms in a Cohort of Rheumatoid Arthritis and Systemic Lupus Erythematosus during the COVID-19 Quarantine Period

1. INTRODUCTION

The 2019 coronavirus disease (COVID-19) pandemic has significantly affected the world for nine months and will continue to do so until an effective treatment or a vaccine is discovered. As of December 13, 2020, the infection has affected more than 70 million people and caused the death of almost 1.6 million individuals globally [1]. Containment measures that have been in place since the middle of March 2020, including community quarantine and physical distancing, have slowed down the spread of the infection. However, this has significantly limited the access of patients with chronic diseases to medical care. Among these chronic diseases are Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) which have estimated prevalence of 0.6% and 0.03-0.05%, respectively, among Filipinos [2, 3].

During the first few months of the pandemic, several drugs, including hydroxychloroquine were evaluated in randomized clinical trials to determine their efficacy and safety in the treatment or post-exposure prophylaxis for COVID-19 [4-9]. This, and the prevailing limited mobility from 16 March to 31 May 2020, when the enhanced community quarantine was in a place affected the supply of medicines. Many patients in the Philippines with SLE and RA, among other rheumatology patients, had difficulty maintaining their supply of medications like hydroxychloroquine and methotrexate [10].

The focus on hydroxychloroquine as a possible treatment option for COVID-19 especially affected patients with SLE and RA. As an anchor drug, it is recommended for all patients with SLE at a dose not exceeding 5 mg/kg real body weight. It is effective in controlling lupus rash and arthritis and preventing SLE disease flares [11]. The 1995 HERA study showed its significant benefit on synovitis, pain, and physical disability of recent-onset rheumatoid arthritis [12]. Despite its relatively delayed onset of action, its benefits in reducing cardiovascular morbidity in patients with RA have been recognized, making it a good second-line Disease-Modifying Anti-Rheumatic Drug (DMARD) therapy for patients with inadequate response to methotrexate [13]. The surge in demand for hydroxychloroquine as a COVID treatment has severely affected access to this drug, putting additional burden on our patients with SLE and RA [14]. For Filipinos with SLE who already had increased baseline (pre-pandemic) depression and anxiety scores [15] and certain vulnerabilities, such as coping, self-esteem, and social support [16], the life changes resulting from the pandemic and quarantine, anxiety over their vulnerability to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and lack of supply of hydroxychloroquine and/or methotrexate may predispose these patients to disease flare.

By June 2020, however, the National Institutes of Health and the World Health Organization advised against the use of anti-malarial drug based on results from randomized clinical trial in hospitalized patients that showed it has no benefit for decreasing the likelihood of death or speeding recovery among hospitalized patients with COVID-19 and in preventing the development of symptoms among exposed individuals [17, 18].

This study aimed to investigate self-reported symptoms of disease flares among patients with SLE and RA during the COVID-19 pandemic. Documentation of the health status of our patients during this health crisis will assist the government and the health sector in facilitating care for non-COVID patients whose treatment support may have been inadvertently marginalized at this time when the supplies of hydroxychloroquine and other common medications for these patients were inaccessible.

2. METHODS

3. RESULTS

3.2. Self-Reported Symptoms

The majority of respondents (345/521, 66.2%) rated their current health status as good. Twenty-four percent (25.9% of SLE and 18.7% of RA) had no symptoms. Among those symptomatic, 25% had one symptom, 19% had two symptoms, and 12% had three. Most of these symptoms were nonspecific, but some may be related to lupus or RA disease flare (joint pains, muscle pains, edema, foamy urine, rash, oral ulcer, pallor, or bleeding). Four patients tested for COVID-19 (3 SLE, 1 RA) and three (all SLE) were quarantined. However, there was no information as to when they had the tests in relation to the survey and what their symptoms were during quarantine.

The most common symptoms during the two-week period prior to the survey were joint pain, muscle pain, headache, and skin rash, with respective percentages of 51%, 35%, 26.8%, and 19.1%, respectively (Table 2). There were combined symptoms of joint pain, headache, muscle pain, and rashes in 4.6% (Fig. 1).

Fewer than 10% of respondents had fever, chills, colds, cough, sore throat, difficulty breathing, diarrhea, bubbly or foamy urine, facial or leg edema, pallor, or bleeding.

Irregular supply of hydroxychloroquine among patients with SLE (n=323) was associated with a higher occurrence of muscle pain (40.6% vs 27.9%, p=0.03) or rash (27.4% vs 11.7%, p<0.001, (Table 3). Irregular supply of methotrexate among RA patients prescribed hydroxychloroquine and methotrexate (n=36) was associated with a higher occurrence of joint pains with or without swelling (73.9% vs 38.5%, p=0.04). Irregular supply of hydroxychloroquine was associated with a lower occurrence of dizziness (0 vs 66.7%, p<0.001) among RA patients (n=18).

Table 2.

Symptoms	Diagnosed Illness		Total (N=512)
	Systemic Lupus erythematosus (N=405)	Rheumatoid arthritis (N=107)
Joint pain with or without swelling	192 (47.4)	69 (64.5)	261 (51.0)
Muscle pain	141 (34.8)	38 (35.5)	179 (35.0)
Headaches	119 (29.4)	18 (16.8)	137 (26.8)
Rash	86 (21.2)	12 (11.2)	98 (19.1)
Dizziness	49 (12.1)	10 (9.3)	59 (11.5)
Cough	33 (8.1)	2 (1.9)	35 (6.8)
Chest pain	31 (7.7)	6 (5.6)	37 (7.2)
Bubbly or foamy urine	27 (6.7)	11 (10.3)	38 (7.4)
Sore throat	27 (6.7)	2 (1.9)	29 (5.7)
Oral ulcer	24 (5.9)	4 (3.7)	28 (5.5)
Difficulty breathing	24 (5.9)	9 (8.4)	33 (6.4)
Leg edema	23 (5.7)	4 (3.7)	27 (5.3)
Nausea, vomiting, diarrhoea	17 (4.2)	3 (2.8)	20 (3.9)
Facial edema	15 (3.7)	1 (0.9)	16 (3.1)
Runny nose	10 (2.5)	5 (4.7)	15 (2.9)
Persistent fever (>38°C for at least 1 day)	9 (2.2)	1 (0.9)	10 (2.0)
Chills	8 (2.0)	3 (2.8)	11 (2.1)
Bleeding	3 (0.7)	1 (0.9)	4 (0.8)
Persistent fever and cough or difficulty breathing	2 (0.5)	0 (0.0)	2 (0.4)
Pallor	2 (0.5)	0 (0.0)	2 (0.4)

Table 3.

Diagnosis	Disease-modifying drug(s) prescribed	No. of Patients	Supply of Drug Analyzed	Symptoms	Drug Supply
					Regular	Irregular	p-value
Systemic Lupus Erythematosus	Hydroxychloroquine	323	Hydroxychloroquine	Muscle pain	31 (27.9)	86 (40.6)	0.03
Systemic Lupus Erythematosus	Hydroxychloroquine	323	Hydroxychloroquine	Rash	13 (11.7)	58 (27.4)	<0.001
Rheumatoid Arthritis	Hydroxychloroquine	18	Hydroxychloroquine	Dizziness	2 (66.7)	0 (0.0)	<0.001
Rheumatoid Arthritis	Hydroxychloroquine and methotrexate	36	Methotrexate	Joint pain with or without swelling	5 (38.5)	17 (73.9)	0.04

4. DISCUSSION

The benefits of hydroxychloroquine for lupus have been previously demonstrated [20-23]. Its use is recommended for all patients with SLE unless contraindicated [11]. In the survey, 90% of patients with SLE were on hydroxychloroquine. In RA, hydroxychloroquine is usually added to the treatment regimen when there is an inadequate response to methotrexate monotherapy. It is notable that 50% of our RA respondents are on hydroxychloroquine. Both hydroxychloroquine and methotrexate are slow-acting drugs with prolonged clinical effects. Hydroxychloroquine has long plasma terminal elimination half-life (approximately 40-60 days), which reflects a high volume of distribution [21]. For methotrexate, the half-life is less than 10 hours, but its active polyglutamated form may remain in tissues for extended periods and explain the prolonged effects [24].

Patients with chronic autoimmune rheumatic diseases such as SLE and RA require long-term use of combination treatments for disease control. Regular monitoring for adverse effects of drugs and episodes of disease flares are needed for careful calibration of their medications. In most instances, premature discontinuation of disease-modifying drugs leads to a flare or aggravation of disease activity [25-27]. When adequate disease control is achieved, a few studies have shown that withdrawal of these disease-modifying drugs is possible without rebound disease flare [28-30]. There are, however, limited data on the effects and safety of unplanned discontinuation of these drugs on disease activity.

Our Filipino SLE and RA cohort shared the same drug supply concern of patients in the United States, Europe and Canada [31]. In a questionnaire developed by EULAR and distributed to rheumatologists, it was concluded that there was a shortage of hydroxychloroquine, according to 49% of the respondents [32]. This is most likely attributable to the off-label use of hydroxychloroquine for treatment and prophylaxis for COVID-19, as well as the limited importation of medicines from India that adversely affected the availability of these drugs [33, 34]. Approximately, 55% of our cohort of lupus and RA resulted in abrupt, unplanned discontinuation of disease-modifying drugs. More respondents with SLE and irregular supply of hydroxychloroquine experienced muscle pain or rashes. Likewise, more RA patients receiving the combination of hydroxychloroquine and methotrexate had flares of joint pains when methotrexate supply became irregular. To begin with, these patients were likely those whose disease activity was more difficult to control.

While almost 75% reported one or more symptoms, only 37% were able to consult their attending physicians. Drug unavailability and inability to reach out to their doctors were additional challenges that they had to deal with during the quarantine period. Changes in school and job workload, financial difficulty, changing patterns of family dynamics and other human interactions were significant life events which they had to cope with as well. The feeling of helplessness may fully mediate anxiety, depression, and perceived stress among patients with SLE [35]. Daily stress and stressful life events such as these have been associated with flares of SLE [36].

In response to the situation, several medical organizations, including the Philippine Rheumatology Association, issued statements against the irrational use of hydroxychloroquine [37]. The need for rapid establishment of communication links between patients and health providers became one of the priorities of the community and the government. Our institution resorted to virtual consultation as we enhanced our telemedicine system. The Department of Health issued guidelines to enable the use of e-prescriptions sent via various tele-platforms [38]. It also set up telemedicine platforms through which people could avail of free consultations. Through these strategies, alternative therapies and other appropriate actions were advised. Counseling for apparent mental health concerns was also prioritized.

That some patients do not have the basic know-how and technical requirements for teleconsultation such as smartphones, computers, or internet limited the adoption of these innovative platforms. On-going efforts from both government and private sectors to assist these communities are expected to enhance health care delivery.

The study has several limitations. The use of an online survey has limited the subjects to those with access to the internet. There were only a few respondents from the Visayas and Mindanao where there were more reports of constraints in the supply of the medicines of concern. We do not have data on disease activity prior to the pandemic. Due to the study design, the self-reported symptoms cannot be definitely attributed to rheumatic disease flare. We did not look at factors other than supplies of hydroxychloroquine and methotrexate that may affect the occurrence of symptoms. There is no documentation of the length of time when hydroxychloroquine and/or methotrexate were unavailable. Standardized patient reported outcome measures, such as the Medical Outcomes Study Short Form-36 and Lupus Quality of Life, were not used in this study, as it was deemed difficult to deploy these measures through a survey disseminated through social media.

CONCLUSION

In our cohort of 512 patients with lupus erythematosus or rheumatoid arthritis, 75% had at least one symptom, the most common being joint pain, muscle pain, headache, and rash. Only 37% were able to access their physicians. Among those prescribed the drug, 68% and 65% had irregular supplies of hydroxychloroquine and methotrexate, respectively, during the two-month period of enhanced community quarantine in the Philippines. Irregular supply of these drugs was associated with increased occurrence of muscle pains or rash among SLE hydroxychloroquine-users and joint pains among RA patients who were taking the hydroxychloroquine-methotrexate combination. These symptoms likely indicate the occurrence of disease flares among these patients.

REFERENCES