Impact of COVID-19 and vaccination campaign on 1,755 systemic sclerosis patients during first three years of pandemic. Possible risks for individuals with impaired immunoreactivity to vaccine, ongoing immunomodulating treatments, and disease-related lung involvement during the next pandemic phase

Abstract

Introduction: The impact of COVID-19 pandemic represents a serious challenge for 'frail' patients' populations with inflammatory autoimmune systemic diseases such as systemic sclerosis (SSc). We investigated the prevalence and severity of COVID-19, as well the effects of COVID-19 vaccination campaign in a large series of SSc patients followed for the entire period (first 38 months) of pandemic.

Patients and method: This prospective survey study included 1755 unselected SSc patients (186 M, 1,569F; mean age 58.7 ± 13.4SD years, mean disease duration 8.8 ± 7.3SD years) recruited in part by telephone survey at 37 referral centers from February 2020 to April 2023. The following parameters were carefully evaluated: i. demographic, clinical, serological, and therapeutical features; ii. prevalence and severity of COVID-19; and iii. safety, immunogenicity, and efficacy of COVID-19 vaccines.

Results: The prevalence of COVID-19 recorded during the whole pandemic was significantly higher compared to Italian general population (47.3 % vs 43.3 %, p < 0.000), as well the COVID-19-related mortality (1.91 % vs 0.72 %, p < 0.001). As regards the putative prognostic factors of worse outcome, COVID-19 positive patients with SSc-related interstitial lung involvement showed significantly higher percentage of COVID-19-related hospitalization compared to those without (5.85 % vs 1.73 %; p < 0.0001), as well as of mortality rate (2.01 % vs 0.4 %; p = 0.002). Over half of patients (56.3 %) received the first two plus one booster dose of vaccine; while a fourth dose was administered to 35.6 %, and only few of them (1.99 %) had five or more doses of vaccine. Of note, an impaired seroconversion was recorded in 25.6 % of individuals after the first 2 doses of vaccine, and in 8.4 % of patients also after the booster dose. Furthermore, the absence of T-cell immunoreactivity was observed in 3/7 patients tested by QuantiFERON® SARSCoV-2 Starter Set (Qiagen). The efficacy of vaccines, evaluated by comparing the COVID-19-related death rate recorded during pre- and post-vaccination pandemic periods, revealed a quite stable outcome in SSc patients (death rate from 2.54 % to 1.76 %; p = ns), despite the significant drop of mortality observed in the Italian general population (from 2.95 % to 0.29 %; p < 0.0001).

Conclusions: An increased COVID-19 prevalence and mortality rate was recorded in SSc patients; moreover, the efficacy of vaccines in term of improved outcomes was less evident in SSc compared to Italian general population. This discrepancy might be explained by concomitant adverse prognostic factors: increased rate of non-responders to vaccine in SSc series, low percentage of individuals with four or more doses of vaccine, ongoing immunomodulating treatments, disease-related interstitial lung disease, and/or reduced preventive measures in the second half of pandemic. A careful monitoring of response to COVID-19 vaccines together with adequate preventive/therapeutical strategies are highly recommendable in the near course of pandemic in this frail patients' population.

Keywords: COVID-19; COVID-19 vaccine; Interstitial lung disease; SARS-CoV-2; Scleroderma; Systemic sclerosis.

Fig. 1

The figure describes the main findings of the impact of COVID-19 in systemic sclerosis (SSc) patients; namely, prevalence and death rate recorded during the whole pandemic period and before/after the vaccination campaign. Upper panel: the prevalence of COVID-19 was significantly higher in SSc compared to Italian general population; it significantly increased in both patients and controls during the second phase of pandemic. In contrast, the death rate remained quite stable in SSc patients comparing the pre-/post vaccination campaign, while markedly decreased in Italian general population (panel below).

Fig. 2

The figure describes two SSc patients with impaired immunoreactivity to COVID-19 vaccines, both undergoing immunomodulating treatments with mycophenolate mofetil (2 g/day). A 42-year-old woman (panel A) showed the absence of seroconversion after the first two doses of COVID-19 vaccine, possibly due to a late effect of rituximab administered 8 months before the first dose of COVID-19 vaccine. In this patient, the booster dose of vaccine was followed by a valuable humoral response. In the second case, a 66-year-old woman (panel B), the administration of the first two doses plus a booster dose of vaccine was unable to stimulate neither humoral nor cellular response. Based on this recent finding, the patient was advised to follow the necessary precautions in her daily life and to attempt a fourth dose of vaccine after adequate period of discontinuation of mycophenolate mofetil treatment.

Fig. 3

The upper panel summarizes the impact of COVID-19 pandemic on our series of 1755 Italian SSc patients observed during the entire pandemic period, from February 2020 to April 2023. Both prevalence and severity (hospitalization and mortality rates) are significantly higher in SSc patients than Italian general population. Possible adverse prognostic factors were the pre-existing interstitial lung disease (ILD) and long-term steroid treatment. In contrast, ongoing treatments with both conventional synthetic disease-modifying antirheumatic drugs (csDMARDs; see reference n.16) and/or low dose aspirin appeared to be able to prevent the worst COVID-19 outcomes. The panel below summarizes the findings regarding the COVID-19 vaccination; namely, the humoral and cellular response evaluated after the first two and the booster doses of vaccine in SSc patients consecutively investigated, as well as the efficacy of vaccines evaluated by death rate variation before/after the introduction of vaccination.

Fig. 4

The experience of the first three years of the pandemic suggests that in the new pandemic phase we still have to manage a number of ‘frail’ scleroderma patients needing immunomodulating treatments and who at the same time have an impaired protection against SARS-CoV-2 infection possibly due to the negative effects of immunomodulating drugs themselves on vaccine immunoreactivity and/or an insufficient number of vaccine booster doses. Therefore, a periodic check of patients' immune status is recommended in order to avoid a dangerous appearance of COVID-19 manifestations in a frequently frail patient because of multi-organ scleroderma involvement, possible comorbidities, and often undergoing immunomodulatory drugs. The upper panel represents a SSc patient with absent/low disease activity and impaired immune response to COVID-19 vaccine; in this case it is possible to discontinue the ongoing therapy and proceed with vaccination or booster dose administration. The panel below concerns a patient with active-progressive disease, eg interstitial lung disease, requiring immunomodulating therapies but without immune protection against SARS-CoV-2 infection; in this case, it is possible to start/continue the immunomodulating therapy and postpone vaccination or booster vaccine doses. In addition, tight clinical control and anti-SARS-CoV-2 infection protection measures are highly advisable, as well the timely administration of specific antiviral drugs in the event of COVID-19 manifestations.