As the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread rapidly, there are still many unresolved questions of how this virus would impact on autoimmune inflammatory joint diseases and autoinflammatory disorders. The main aim of this paper is to describe the main studies focusing their attention on COVID-19 incidence and outcomes of rheumatoid arthritis (RA), spondylarthritis (SpA), and autoinflammatory disease cohorts. We also revised possible pathogenic mechanisms associated with. Available data suggest that, in patients with RA and SpA, the immunosuppressive therapy, older age, male sex, and the presence of comorbidities (hypertension, lung disease, diabetes, CVD, and chronic renal insufficiency/end-stage renal disease) could be associated with an increased risk of infections and high rate of hospitalization. Other studies have shown that lower odds of hospitalization were associated with bDMARD or tsDMARDs monotherapy, driven largely by anti-TNF therapies. For autoinflammatory diseases, considering the possibility that COVID-19 could be associated with a cytokine storm syndrome, the question of the susceptibility and severity of SARS-CoV-2 infection in patients displaying innate immunity disorders has been raised. In this context, data are very scarce and studies available did not clarify if having an autoinflammatory disorder could be or not a risk factor to develop a more severe COVID-19. Taking together these observations, further studies are likely to be needed to fully characterize these specific patient groups and associated SARS-CoV-2 infection. Keywords: Rheumatoid arthritis, Spondiloarthritis, Psoriatic arthritis, COVID-19, SARS-COV-2 Introduction underlining autoimmune and autoinflammatory condi- As the coronavirus disease 2019 (COVID-19) pandemic tions are critically involved in the host defense and re- caused by severe acute respiratory syndrome coronavirus sponse versus SARS-COV-2, and in more severe cases, 2 (SARS-CoV-2) continues to spread rapidly, there are leading to a cytokine storm syndrome (CSS), with an still many unresolved questions of how this virus would acute respiratory distress syndrome (ARDS), multiorgan impact on rheumatic musculoskeletal diseases (RMDs) failure and death [4–6]. Not at last, several studies have [1–3]. Evidence have highlighted that mechanisms been conducted and are ongoing to evaluate the efficacy of biologic disease modifying antirheumatic drugs * Correspondence: firstname.lastname@example.org (bDMARDs) and targeted synthetic DMARDs Piero Ruscitti, Alessandro Conforti, Marco Tasso, Luisa Costa and Francesco (tsDMARDs) to treat COVID-19 CSS [7, 8]. Of note, Caso have contributed equally to this work among those, there are agents targeting interleukin-6 Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy (IL-6) and IL-1, and Janus Kinase Inhibitors (JAKis), Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Ruscitti et al. Advances in Rheumatology (2021) 61:45 Page 2 of 11 currently used for the treatment of inflammatory ar- reference lists of the relevant articles to find possible thropathies and autoinflammatory disorders. However, additional studies. Out of retrieved 417 articles, both ob- due to the heterogeneity of randomized controlled trials servational studies and case series were assessed if (RCTs) design and cohorts, and the presence of limita- reporting data about COVID-19 incidence and outcomes tions, as for example concomitant steroidal treatment, in patients with RA, SpA, or autoinflammatory diseases. studies have showed mixed results on the impact of these therapies on COVID-19 outcomes [7, 8]. Many SARS-CoV-2 infection and immune response questions remain still open and one of the most import- The host immune response has a crucial role for the ant is whether patients with autoimmune arthropathies resolution of COVID-19, but, at the same time, it is im- and autoinflammatory disorders may have different re- plicated in the occurrence of major clinical manifesta- sponses to the SARS-CoV-2 infection, because of im- tions of the disease, mostly in more severe patients, as paired immunological and genetic background and/or shown in Fig. 1 . Thus, SARS-CoV-2 infection is an concomitant antirheumatic treatment [9–11]. example of environmental factor which could trigger an Until today, scientific literature has described high in- aberrant inflammatory reaction . As for previous evi- cidence and severe outcomes of COVID-19 in middle- dence, it is well known that an infective trigger may ex- aged and elderly subjects and/or patients with underlin- acerbate an inflammatory disease . In fact, a ing diseases, such as diabetes, cardiovascular disease, persistent infection may result in the uptake of microbial chronic obstructive pulmonary disease (COPD) [12, 13]. antigens by antigen presenting cells (APCs) and presen- Whether patients with RMDs, especially those receiving tation of these antigens to microbe-specific T cells . Disease Modifying Antirheumatic drugs (DMARDs), are The consequent activation of the pro-inflammatory cas- at an increased risk of SARS- CoV-2 infection or severe cade in a persistently infected site may lead to a tissue COVID-19 disease remains to be clarified. On the other damage and uptake of self-antigens by APCs . The hand, it is well known that viral infection susceptibility presentation of these self-antigens to self-reactive T cells and clinical aspects may be influenced both by inflam- may induce an immune reaction against self-tissues, matory diseases, as well as immunomodulant and im- spreading from a one against microbial antigen epitopes munosuppressive therapies [14–16]. For this last point, to some non-cross-reactive self-epitopes . This several studies highlighted that patients with immunoin- mechanism leading to a reaction against self-antigens is flammatory diseases on biologic (bDMARDs) may be at recognized as epitope spreading. Simultaneously, a mo- higher risk to test positive for COVID-19 and hospital- lecular mimicry may occur. This is a step related to a ized, but with a not increased risk of Intensive Care sufficient similarity between the amino acid sequences of Units (ICU) admission or death in comparison with gen- the pathogen and some of the host antigens producing a eral population. Hence, the COVID-19 pandemic has reaction directed against the host . Furthermore, the represented a hard challenge for Rheumatologists [17, pro-inflammatory process during an infection may en- 18]. hance the production of proteases and the processing of Today, most studies on incidence and clinical out- self-antigens by APCs. Additionally, subdominant cryptic comes are available. Thus, the aims of this paper are to antigens, which are unnoticed by the immune system describe the main studies focusing their attention on under normal conditions, may be implicated in this COVID-19 incidence and outcomes of rheumatoid arth- process. Infections may also result in the development of ritis (RA), spondylarthritis (SpA), and autoinflammatory pro-inflammatory disorders by driving the APCs to disease cohorts. We also revised possible pathogenic process and display such cryptic antigens . mechanisms associated with. SARS-CoV-2 infection may cause a significant reduc- tion in circulating T cell subsets . The specific deple- Methods tion of CD4+T cells may lead to an enhanced immune- We designed a comprehensive research of literature on mediated interstitial pneumonitis and delayed clearance incidence and outcomes of COVID-19 during RMDs of SARS-CoV in the lungs . In fact, in the pulmonary and autoinflammatory disorders by a review of reports interstitium of SARS-CoV-infected patients, CD8+T published in international journals. We searched rele- cells are the most common infiltrative inflammatory vant English-language articles in MEDLINE (via cells, playing an important role in virus clearance as well Pubmed) until up February 2021, with the research as in immune-mediated injury . In addition, SARS- terms: (“SARSCoV2” OR “COVID-19”)AND (“RMDs” CoV2 infection may activate lymphocytes and macro- OR “autoinflammatory disorders”). We also revised pos- phage by the binding with angiotensin-converting en- sible pathogenic mechanisms involved with. In preparing zyme 2 (ACE-2) receptor . During COVID-19, it has this work, we followed the proposed guidelines for nar- been shown that ACE2-expressing macrophages con- rative review . Furthermore, we hand-searched tained SARS-CoV-2 nucleoprotein antigen. These cells Ruscitti et al. Advances in Rheumatology (2021) 61:45 Page 3 of 11 Fig. 1 The figure describes the structure of SARS-CoV2 and the possible infection associated mechanism of autoimmunity. SarsCov2 infects epitelial cells by receptors angiotensin converting enzyme 2 (ACE2) resulting in replication and release of the virus with consequent pyroptosis and the release of damage associated molecular patterns. This process leads to local inflammation and secretion by alveolar macrophages of pro- inflammatory cytokines such as IL-6, IL-10, macrophages inflammatory protein 1 alfa (MIPa), and TNF. Furthermore, this figure describes epitope spreading where persistent infection leads to the uptake of microbial antigens by antigen presenting cells (APCs) and antigen presentation of T- cells. This mechanism carries an inflammatory cascade resulting in a tissue damage, a possible uptake of self-antigens by APC and subsequent presentation of these self-antigens to Tc ells causing an anti-self-reaction. After microbial infection self-antigens could be recognised and processed by APC; subsequently cryptic epitopes could be exposed and presented to self-reactive T-cells leading to an autoimmune response. This figure also describes the mechanism of molecular mimicry where microbial antigens could share antigenic similarly with self-antigens. The presentation of these self-antigen mimics by APC to cross reactive cells leads to an inflammatory response because T cells recognize both the microbial mimic and its respective self-antigens. Finally, viral particles and proinflammatory cytokines induce the activation of blood monocytes which respond by inducing tissue factor membrane expression contributing to a pro-thrombotic state also showed an upregulation of IL-6, which may contrib- with tissue repair and fibrosis, possibly leading to the fi- ute to the excessive inflammatory burden and correlate brotic complications in these patients under mechanical with the disease severity . Moreover, other pro- ventilation . In addition, a massive expansion of inflammatory chemokines and pro-inflammatory cyto- CD8+T cells with a tissue-resident memory T cell gene kines may be secreted by SARS-CoV-2-infected alveolar signature has been observed in bronchoalveolar fluid pa- macrophages, which may further enhance the inflamma- tients with mild COVID-19, associated with a minimal tion . Interestingly, during COVD-19, two chemo- infiltration of pro-inflammatory monocytes . This kines (CCL2 and CCL7) resulted to be increased in the finding suggested that some pre-existing populations of bronchoalveolar fluid . Thus, the recruitment of CC- tissue-resident memory T cells, with a possible cross- chemokine receptor 2-positive (CCR2+) pro- reactivity against SARS-CoV-2, may limit the activation inflammatory monocytes is favored in COVID-19 with of pathological macrophages, thus resulting in a protec- an associated depletion of tissue-resident alveolar mac- tion against a more severe pro-inflammatory process. rophages . These pro-inflammatory macrophages These observations paralleled with infections due to have been described to be enriched in genes associated other highly pathogenic coronaviruses, such as SARS- Ruscitti et al. Advances in Rheumatology (2021) 61:45 Page 4 of 11 CoV and MERS-CoV [24, 25]. In fact, an extensive cellu- a combination of underlying disease characteristics and lar infiltration dominated by macrophages was found in treatment-related factors. In fact, it must be pointed out post-mortem lungs from these patients [24, 25]. Simi- that inflammatory diseases may also be associated with larly, high levels of interferon-γ (IFN-γ), IL-6, IL-12, some immunological dysfunctions increasing the risk of transforming growth factor-β (TGF-β), CCL2, CXCL10, infections . In addition, both csDMARDs and CXCL9, and IL-8 were reported in patients with SARS- bDMARDs are associated with a higher risk for serious CoV [25, 26]. Probably, during these disease, high rates infections . These drugs, targeting key molecules in- of viral replication may lead to host cell cytolysis and the volved in the immune response against infectious anti- production of pro-inflammatory cytokines and chemo- gens, may consequently increase the susceptibility to kines by infected epithelial cells . In addition, a de- viruses and bacteria. At the same time, these therapies layed induction of antiviral interferon responses, owing could provide substantial benefit for controlling RMDs to specific virus escape mechanisms, could promote the and limiting long-term disability and improving the accumulation of pro-inflammatory cells in the lungs. quality of life . This finding could be probably related to viral structural In this context, it is well-known that glucocorticoids and non-structural proteins antagonizing IFN responses (GCs) usage is associated with an enhanced risk of infec- . The antagonism could occur at various stages of tions, which is correlated with dosages and time of treat- the IFN signaling pathway: (1) preventing the pattern- ment. In fact, a prolonged therapy, even if at low recognition receptors (PRRs) recognition of viral; (2) dosages, may enhance the risk of serious infections, impairing the PRR signaling through TBK1/inhibitor of which is further increased by the concomitant adminis- nuclear factor-κB kinase subunit-ε (IKKε), TRAF3 and tration of csDMARDs [31, 32]. Among these drugs, IRF3; (3) inhibiting the downstream of IFN signaling methotrexate (MTX) is the most common administered through STAT1; (4) promoting the host mRNA degrad- in RMDs and it is also associated with an increased risk ation and inhibiting host protein translation . Fur- of infection [33, 34]. In fact, recently a meta-analysis thermore, SARS-COV 2 replication in airway epithelial showed that MTX is associated with a higher risk of all cells could cause high levels of virus-linked pyroptosis infections, mainly in RA . with associated vascular leakage . This could also be In addition, TNFis are associated with an increased a trigger for the subsequent pro-inflammatory response risk of serious infections, since the inhibition of this . By PRRs, alveolar epithelial cells and alveolar mac- molecule may impair its regulation of immune cell pro- rophages may detect the released pathogen-associated liferation, differentiation, and survival . In fact, it has molecular patterns (PAMPs), such as viral RNAs, and been shown that TNF knockout mice rapidly succumb damage-associated molecular patterns (DAMPs) . to tuberculosis infection . National registries, open- This may lead to a local inflammation resulting in an in- label extension studies, and retrospective cohorts creased secretion of the pro-inflammatory cytokines and showed that TNF inhibition may enhance the risk of tu- chemokines IL-6, IFN-γ, MCP1, and IP-10 into the berculosis in patients with RMD [36–39] TNFi could blood of COVID-19 patients . In addition, the pul- also influence the odds of clearance or reactivation of monary recruitment of immune cells from the blood and chronic hepatitis B virus infection . Furthermore, the infiltration of lymphocytes into the airways may ex- TNFi may increase the risk of fungal infections, such as plain the lymphopenia and an increased neutrophil– cryptococcosis, aspergillosis, and pneumocystis jirovecii lymphocyte ratio observed in patients with SARS-CoV-2 pneumonia [36, 38]. infection . Finally, some studies reported the devel- IL-6-targeted agents are largely used in the treatment opment of autoantibodies in patients with COVID-19, of patients with RMDs and autoinflammatory disorders particularly anti-cardiolipin, anti-β2-glycoprotein, and [40–43]. The inhibition of this cytokine, whose signaling antinuclear antibodies [27, 28]. An increase of ACPA pathway uses the protein gp130 as a common signal was reported after SARS-CoV2 infection suggesting an transducer, could impair the host capacity for generating epitope spreading before the clinical onset of arthritis acute phase responses, including Th17 differentiation [27, 28]. Additional studies reported that the onset of and long-lived plasma cell generation [36, 42, 43]. In anti-cardiolipin, anti-β2-glycoprotein, and lupus anti- fact, some clinical data derived from RCTs supports the coagulant could be associated with the thromboembolic notion that IL-6-targeting agents increase the risk of in- complications occurring in COVID-19 . fection to a degree similar to TNFis [36, 40, 52, 53]. On the other hand, neutropenia induced by IL-6 inhibition Risk of infections in RMDs and autoinflammatory disorders would frequently occur, due to a margination of neutro- Patients with RMDs are recognized to have an increased phils rather than peripheral sequestration. This finding risk of infections related to disease activity, comorbidi- could increase the risk of infection following this thera- ties, and immunomodulatory therapy . This is due to peutic strategy [40, 41]. Ruscitti et al. Advances in Rheumatology (2021) 61:45 Page 5 of 11 Different IL-17-targeted agents have been recently ap- arthritis (ReA), enteropathic, and undifferentiated spon- proved for patients with PsA and SpA. IL-17 stimulates dylarthritis (uSpA) [52, 53]. In patients with RA and neutrophil granulopoiesis and chemotaxis, expression of SpA, it is recognized that the immunosuppressive ther- antimicrobial peptides (β-defensin-2) [41–44]. Thus, pa- apy and the presence of comorbidities are associated tients with RMDs treated with IL-17-targeted agents with an increased risk of infections [54–57]. On these may be exposed to an increased risk of mucocutaneous bases, a growing body of evidence described the charac- candidiasis [42–44]. No cases of active tuberculosis have teristics of COVID-19 patients affected by RA [54–57]. been reported in a review of clinical trial data [37, 42, In this context, it is unclear whether these patients may 43, 45]. have an increased risk of infection or a higher risk of a Abatacept is a fusion protein designed to interfere with severe course for COVID-19 [55–57]. On one hand, the the binding of CD80/86 molecules on antigen presenting host immunity could provide a strong immunological re- cells/dendritic cells with their CD28 receptors on the sponse adequate for virus clearance, whereas, on the surface of CD4 T cells, used in the treatment of RA. Al- other hand, an aberrant production of pro-inflammatory though lower than TNFis, the risk of infection-related cytokines induced by the uncontrolled immune response hospitalizations is further recognized in patients treated may contribute to a development of cytokine storm syn- with abatacept [36, 43, 46]. drome worsening the prognosis of COVID-19 . Furthermore, rituximab (RTX), a chimeric monoclonal A recent nationwide Swedish study by Bower et al., antibody against the B-cell specific CD20-antigen, is comparing March-September 2020 inflammatory joint commonly administered in RMDs. Considering that diseases cohort and 2015–2019 population referent, has RTX is related to the development of hypogammaglobu- evidenced that the risks of hospitalisation (0.5% vs 0.3% linemia, it could increase the risk of infections . In in their population referents), admission to intensive this context, it has been suggested that patients with low care (0.04% vs 0.03%) and death (0.10% vs 0.07%) due to levels of IgG post-RTX may be at increased risk of ser- COVID-19 were low in patients with RMDs and similar ious infections since IgG levels are relevant for protect- to general population . This study has reported that ive immunity. Infections seem to be more frequent overall absolute and excess risks for patients with in- during the first 3 months post-treatment, but they may flammatory joint diseases are low and the level of risk occur anytime . In addition to the immunosuppres- increases are largely proportionate to those in the gen- sion caused by the hypogammaglobulinemia and the col- eral population and explained by comorbidities . lapse of B and T cell immunity, RTX may also induce Thus, this study showed a similar risk of severe COVID- neutropenia, which may furtherly contribute to the risk 19 in either RMDs or general population and suggested of infections in these patients . Finally, JAKis are ap- the negative prognostic impact of comorbidities in this proved for the treatment of RA, and they may enhance context. the risk of pneumonia and skin and soft tissues infec- In a German registry, 468 patients with RMDs and a tions . JAK are transmembrane proteins that mediate PCR-confirmed SARS-CoV-2 infection were studied and amplify extracellular signals from growth factors . Patients were stratified into three groups by using and cytokines [43, 48, 49]. In accordance, JAKis exert a the hospitalization as indicator for a more severe course: deleterious impact on adaptive immunity by decreasing (1) non-hospitalised patients, (2) hospitalised patients CD4+T-cell expansion and Th1 and Th17 differenti- without the need for invasive ventilation, (3) hospitalised ation, among other effects [48–51]. Particularly, it was patients with the need for invasive ventilation. In this co- reported than the incidence rate for Herpes Zooster was hort, the most common disease was RA, affecting 225 higher than those estimated for other infectious events patients (48%) and it was associated with a high rate of [49–51]. hospitalization. Out of those, 62 were hospitalised and 17 needed an invasive ventilation . Out of 140 SpA Incidence and outcomes of COVID-19 in arthritis patients patients with a PCR-confirmed SARS-CoV-2 infection RA and SpA are chronic inflammatory diseases, mainly showed that 20 were hospitalized and 5 needed an inva- affecting the joint, mediated by autoimmune and inflam- sive ventilation . In this cohort, when compared with matory process [52, 53]. RA, patients with SpA showed a lower risk of More specifically, whereas RA is characterized by pre- hospitalization (OR 0.46; 95% CI 0.23–0.91) . In this dominant peripheral synovial inflammation sustained by cohort, only 38% did not have any other chronic condi- autoantibodies and B- and T-lymphocytes mechanisms, tion, frequently concomitant comorbidities were regis- SpAs provide a main innate-immunity mediated patho- tered in these patients. The most frequent one was high genesis leading to inflammation of synovial-entheseal blood pressure, followed by obesity, cardiovascular dis- structures and axial skeleton. SpA group includes anky- ease (CVD), and diabetes. Regarding the administered losing spondylitis (AS), psoriatic arthritis (PsA), reactive therapy for the RMD, 193 patients were treated with Ruscitti et al. Advances in Rheumatology (2021) 61:45 Page 6 of 11 csDMARD monotherapy, 167 patients with bDMARDs, RMDs attending their rheumatology department and and 145 patients with GCs, mostly low dose GCs of ≤ who were infected by SARS-CoV2 . They described 5 mg/day. Older age, associated comorbidities, GCs at 62 patients with COVID-19, 42 were hospitalized and 20 doses of > 5 mg/day, and moderate to high RMD disease were followed-up at home . The most common activity were related to the rate of hospitalization . RMD was RA in 20 affected patients (32%), of whom 3 In the COVID-19 Global Rheumatology Alliance patients died. Male gender, preexisting lung disease and physician-reported registry, a large collection of data treatment with GCs (≥ 5 mg per day) were associated about COVID-19 infection in RMD was reported, evalu- with a more severe infection requiring hospitalization ating 600 patients from 40 countries, of whom 277 were . The Authors also described 16 patients with SpA/ hospitalized and 55 were deceased . COVID-19 were PsA, representing the 26% of the entire enrolled cohort predominately diagnosed through PCR testing. In this with RMD and COVID-19 . Eleven of those were cohort, 230 patients were affected by RA which was the hospitalized and 5 were followed-up at home. One of most represented RMD. A high percentage of these pa- those died . tients with RA (104 out of 230) were hospitalized. Re- When compared with non-rheumatic hospitalized pa- sults showed that 48 and 74 SpA and PsA patients, tients with SARS-COV2 infections, greater odds of respectively, were diagnosed with COVID-19 predomin- hospitalization for patients with inflammatory arthropa- ately diagnosed through PCR testing . A lower pro- thies and connective tissue diseases were described by a portion of patients who were hospitalized had PsA and Spanish group . In a retrospective observational other SpA (8% and 6%, respectively) compared with matched cohort study , 456 RMDs and non- those who were not (16% and 10%, respectively) . rheumatic hospitalized patients with SARS-COV2 infec- Furthermore, a higher prevalence of comorbidities was tion were described. Amongst them, 65 patients were af- also registered (hypertension 199 patients, lung disease fected by RA and 35 patients were affected by SpA . 127 patients, diabetes 69 patients, CVD 63 patients and This study also showed that comorbidities are associated chronic renal insufficiency/end-stage renal disease 40 with severe COVID-19 . In this cohort, independent patients) . The authors showed that older age and factors associated with severe COVID-19 were increased comorbidities were associated with the rate of age, male sex, and having a connective tissue disease, hospitalization. On the contrary, the therapy with b/ but nor inflammatory arthritis nor previous immunosup- tsDMARD monotherapy, just before COVID-19 diagno- pressive therapies were associated with severe COVID- sis, was significantly associated with a lower rate of ad- 19 . mission to the hospital when compared with no DMAR In addition, an observational multicenter study (Reu- D therapy . maCoV Brasil register) assessed adult RMD patients with In addition, an observational French cohort described COVID-19 . In this study, 334 patients with SARS- the characteristics of 694 patients with RMDs affected COV2 infection were included; the most common RMD by COVID-19 . The severity of COVID-19 was was RA (28.4%). Hydroxychloroquine (34.9%), GCs stratified as follows: (1) mild/ambulatory, (2) moderate/ (34.2%), MTX (20.1%), and TNFi (75/338; 22.2%) were hospitalized out of intensive care unit, (3) severe/inten- the most common therapies . This study showed sive care unit or deceased. SARS-CoV2 infection was that older age, use of GCs and cyclophosphamide were mostly confirmed by PCR and/or specific antibodies. A associated with unfavorable outcomes of SARS-CoV-2 large percentage of patients (492 out of 694) had at least infection. Conversely, TNFi appeared to have a protect- one comorbidity (182 hypertension, 146 obesity, 99 re- ive role being associated with a reduction of the develop- spiratory disease, 85 CVD). Fifty-eight patients in this ment of a more severe COVID-19 . Finally, other cohort died, resulting in an overall death rate of 8.3%, small case series were available furtherly confirming and of 22.6% in the hospitalized subgroup. In this study, these findings, as described in Table 1 [65, 66]. 213 patients were affected by RA . In this study the Authors described the characteristics of 165 patients Arthritis and potential risk factors for severe COVID-19 with SpA and 70 patients with PsA . Of those, great In describing the characteristics of RA and SpA with part of SpA patients showed mild infection [n. SpA pa- COVID-19, many potential risk factors for a more severe tients: 135 (30.8%); n. PsA patients: 52 (11.9%)] and disease have been suggested [59–63]. Similarly, to gen- moderate infection (n. SpA patients: 25 (14.8%); n. PsA eral population, age is considered a poor prognostic fac- patients: 12 (7.1%)). SpA and PsA patients showing se- tor of COVID-19 for RA patients . The possible age- vere infection were 5 (5.8%) and 6 (6.9%), respectively. associated shift in both innate and adaptive immune sys- One patient with SpA and three patients with PsA died tems could reduce the capacity to deal infections and during the follow-up . In a Spanish retrospective ob- could contribute to the development of a chronic in- servational study, the Authors assessed patients with flammatory state . Moreover, a chronic low-grade Ruscitti et al. Advances in Rheumatology (2021) 61:45 Page 7 of 11 Table 1 Main studies focusing on Incidence, outcomes, and prognostic factors of COVID-19 in rheumatoid arthritis and spondiloarthritis patients First author Study design Sample RA SpA PsA Outcome of COVID-19 pa- Prognostic factors size patients patients patients tients with inflammatory arthropathies FAI2R /SFR/SNFMI/SOFREMIP/CRI/ Observational 694 213 165 70 Severe COVID-19/hospitalization Older age IMIDIATE consortium and study in RA: 29; SpA: 5; PsA: 6 Comorbidities contributors Death in RA: 20; SpA: 1; PsA: 3 Longer term of GCs Gianfrancesco et al. Observational 600 225 48 74 Severe COVID-19/hospitalization Older age study in RA: 104; SpA: 16; PsA: 22 Comorbidities Death in the overall cohort Higher doses of GCs including also CTD: 55 Hasseli et al. Retrospective 468 146 125 * Severe COVID-19/hospitalization Older age observational in RA: 79; SpA: 20 severe COVID- Comorbidities study 19 Treatment with GCs Death in the overall cohort at doses > 5 mg/day including also CTD: 19 Moderate to high RMD disease activity Montero et al. Retrospective 62 20 16 * Severe COVID-19/hospitalization Male Gender observational in RA: 15; SpA: 11 Preexisting lung study Death in the overall cohort disease including also CTD: 10 Treatment with GC at dose > 5 mg/day Pang et al. Observational 21 15 –– Severe COVID-19/hospitalization Comorbidities study in RA: 15 0 death Cheng et al. Observational 54 –– 5 hospitalised Not reported study 0 death Marques et al. Observational 334 95 45 23 110 hospitalised Age > 50 years study 28 death Treatment with GCs and cyclophosphamide GCs: Glucocorticoids; PsA: Psoriatic arthritis; RA: Rheumatoid arthritis; RMD: Rheumatic Diseases; SpA: Spondiloarthritis *In these studies, PsA patients are included in the SpA group inflammation called inflammaging is associated with treatment of RA reported that the use of GCs was asso- immunosenescence, driven by a reduced ability to en- ciated with a poorer outcome which may parallel with dure inflammatory triggers as well as an increased pro- previous studies showing an increased risk of infection duction of pro-inflammatory cytokines, acute phase with higher doses of these drugs . On the contrary, it proteins, and oxidative stressors, may lead to higher has been suggested that no substantial risk was detected rates of infection and disease . neither csDMARDS nor ts/bDMARD. mostly TNFis. In addition, comorbidities, including chronic respiratory Interestingly, the use of ts/bDMARD was also associated disease, CVD, diabetes, hypertension, obesity, and renal fail- with a lower rate of complications during COVID-19 . ureincreased theriskfor severe COVID-19,asreportedin These findings are consistent with previous studies that general population [55–62]. In fact, these comorbidities found lower odds of hospitalization with ts/bDMARD could modulate host‐viral or host‐immune system interac- monotherapy [60–63]. It could be possible that tions favoring a more aggressive course of the disease . bDMARDs could reduce the high levels of cytokines, in- Furthermore, the metabolic alterations produced by cluding IL-6 and TNF, associated with a more severe COVID-19 could decrease cardiorespiratory reserves fol- COVID-19, thus reducing the possibility to develop a CCS lowing a possible stressor agent, enhancing the dysregula- [61–63]. Of note, similar observations, about a beneficial tion of the immune system, and favoring a pro-thrombotic effect of bDMARDs, were suggested on the risk of sepsis and pro-inflammatory state. The presence of diabetes after serious infection or a fatal outcome . would be considered one of the major risk factors for in‐ Taking together these observations, to fully manage hospital mortality increasing the risk of thromboembolism patients with RMDs and SARS-CoV-2 infection, it would in COVID‐19 patients, disease severity, and mortality . be of crucial importance to understand how the charac- Antirheumatic drugs have been reported as not asso- teristics of the underlying disease, associated comorbidi- ciated with increased risk of serious COVID-19 out- ties, and the use of immunotherapies could be comes, although data accuracy was partial for certain associated with a more severe COVID-19 and a poorer drugs . Moreover, some studies concerning the outcome of affected patients [57, 60–63, 71] Ruscitti et al. Advances in Rheumatology (2021) 61:45 Page 8 of 11 Incidence and outcomes of COVID-19 in patients affected disorders needs to be fully clarified [1–3]. Whether pa- by autoinflammatory disorders tients with RMDs could be at an increased risk of SARS- Autoinflammatory diseases are caused by self-directed CoV-2 infection or severe COVID-19 disease remains to inflammation due to an alteration of innate immunity be entirely evaluated [14–16]. Incidence and outcomes leading to episodic systemic inflammation attacks [72, of COVID-19 among RMDs and autoinflammatory dis- 73]. Familial Mediterranean Fever (FMF) is the most orders patients would appear to be consistent with gen- common monogenic autoinflammatory diseases. It is an eral population affected by SARS-CoV-2 infection. In autosomal recessive disease characterized by recurrent fact, patients with such diseases who are older and/or systemic inflammatory attacks with fever and serositis have comorbidities may have a higher odd of a more se- . Considering the possibility that COVID-19 could vere COVID-19 [55–57, 60, 63]. For the autoinflamma- be associated with a CCS , the question of the sus- tory disorders, the question is about a possible increased ceptibility and severity of SARS-CoV-2 infection in pa- susceptibility to develop CCS in the context of COVID- tients displaying innate immunity disorders, such as 19 since the prominent pathogenic involvement of the FMF, has been raised. In this context, a survey on SARS- innate immune system in these diseases. However, the CoV-2 infection in patients with FMF followed in Paris available data did not fully clarify this issue due to the area was conducted, including patients fulfilling the low prevalence of these patients suggesting the need of international FMF criteria and a genetic confirmed FMF further studies on this topic. diagnosis . The authors collected the data of 342 pa- In addition, some data suggested that the real risk of tients, of whom 27 FMF patients (7.8%) were infected by developing severe forms of COVID-19 in patients with SARS-CoV-2. Specifically, 7 patients were hospitalized, 6 RMDs treated with csDMARD or bDMARDs might not required oxygen therapy, 3 developed acute respiratory increase [60–63]. It could be possible that these medica- distress syndrome and required admission to the inten- tions could reduce the high levels of proinflammatory sive care unit, and 2 patients died. Severe SARS-CoV-2 cytokines thus possibly reducing the risk of a more se- infection occurred in patients with risk factors including vere disease during COVID-19 [60–63]. However, the advanced age, chronic kidney disease, hypertension, vas- risk of infections is reported to be consistent with such cular disease, obesity, and lung dysfunction . Based drugs [36–43] and further studies with a longer follow- on these results, a dysfunction of the innate immune up are needed to fully understand the real risk of these system of FMF could not appear to be a risk factor to patients to develop a more severe SARS- CoV-2 infec- develop a more severe COVID-19 . In addition, a tion. In this context, a possible theory could be that pa- French national cohort study described 27 patients out tients with RMDs could avoid risky behavior for of 694 with autoinflammatory disease affected by SARS- infections being more aware for the possible risks associ- Cov2 infections . Fifteen patients were affected by ated with their immunosuppressive therapies. Further- periodic fever syndromes, 7 patients by other autoin- more, patients with RMDs may be associated with an flammatory diseases, and 5 patients were diagnosed with increase frailty, which is defined as a syndrome charac- adult onset Still’s disease (AOSD) . Five patients ex- terized by a decrease of strength, endurance, reduced perienced a severe COVID-19 and 4 died. Although of physiological function, and increased the individual’s interest, these results should be cautiously interpreted vulnerability . The chronic RMD inflammation may due to the very low number of patients assessed by the possibly contribute to the development of frailty associ- authors . Finally, a growing body of evidence points ated with a characteristic pro-inflammatory T- out that severe COVID-19 is characterized by an over- lymphocyte phenotype as well as with an elevated con- lapping clinical picture with AOSD and macrophage ac- centration of IL-6 . tivation syndrome (MAS), since these are characterized In addition, coagulation abnormalities are increasingly by fever, hyperferritinemia, and a hyper-inflammatory associated with a poor prognosis in COVID- . process with a massive release of pro-inflammatory cyto- Microthrombi of the lungs have been described in these kines [74, 75]. These findings would suggest that a patients [1, 24]. In fact, the activation of intravascular hyperinflammatory lung injury, either in severe COVID- coagulation is a hallmark of organ injury in SARS-CoV- 19 or MAS, would amplify the immune response leading 2 infection, which is mediated by pro-inflammatory cyto- to an overwhelming release of inflammatory mediators kines [24, 73]. Furthermore, IL-1, IL-6, and TNF produc- and the occurrence of a CCS . tion and the endothelial cell dysfunction, associated with COVID-19, may play an important role in the thrombo- Appraisal of literature inflammatory processes ultimately impairing normal vas- As catastrophic COVID-19 pandemic continues to cular haemostasis, fibrinolysis, and vessel wall permeabil- spread rapidly, many unresolved questions of how this ity . Thus, a high thrombotic risk of COVID-19 is virus would impact on RMDs and autoinflammatory clearly recognized which could be further increased by Ruscitti et al. Advances in Rheumatology (2021) 61:45 Page 9 of 11 the concomitant RMDs [70, 79]. In fact, during these associated with risk factors similar to the general popu- diseases, the pro-inflammatory milieu may induce a lation. In this context, it must be pointed out that fur- hyper-coagulation by an upregulation of procoagulant ther studies are likely to be needed to fully characterize factors and a simultaneous downregulation of anticoagu- these specific patient groups and associated SARS-CoV- lant and fibrinolytic systems, thus leading to this clinical 2 infection. phenotype . This risk is also associated with trad- Acknowledgements itional CVD risk factors, such as an older age and dia- We thank Mrs. Federica Sensini for her technical assistance. betes, but also with the burden of the pro-inflammatory Authors' contributions process over time and specific disease features [80, 81]. All authors made substantial contributions to the conception or design of Taking together these observations, an accurate evalu- the work, the acquisition and interpretation of data. All authors contributed ation of the hyper-coagulation burden in the patients to the critical review and revision of the manuscript and approved the final version. All the authors agreed to be accountable for all aspects of the work. with RMDs affected by SARS-CoV2 infection is needed, PR, AC, MT, LC, and FC contributed the conception and design of the review. since possibly associated with a worse prognosis. PC and RG provided substantial supervision and interpretation of the review. Vaccination against SARS-CoV-2 is now available All authors drafted and revised the manuscript. All authors read and approved the final manuscript. leading to a significant improvement in the management of COVID-19 [82, 83]. However, it could be matter of Funding debate if the development of protective immunity could None. occur in patients with RMDs due to a possible impair- Availability of data and materials ment of the immune system by underlying inflammatory The reviewed data are included in the body of the article. disease or therapies [82, 83]. Conflicting results are avail- Declarations able in literature about this point [82, 83]. In a mono- centric study enrolling 26 patients with immune- Ethics approval and consent to participate mediated inflammatory diseases (IMIDs), mainly RMDs, Not applicable. SARS-CoV-2 mRNA vaccines led to development of Consent for publication antibodies in immunosuppressed patients without con- Not applicable. siderable side effects . Differently, another study on 84 patients with IMIDs, mostly RMDs, showed that im- Competing interest The authors declare that they have no conflicts of interest for this work. mune responses against the SARS-CoV-2 were delayed and reduced . In fact, the concomitant use of MTX Author details appeared to adversely affect both humoral and cellular Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy. Rheumatology and immune response to COVID-19 vaccines as shown in a Immunology Unit, Department of Medicine, University of Rome ‘Campus more recent cohort study . Taking together these Biomedico’, Rome, Italy. Rheumatology Unit, Department of Clinical observations, further studies are needed to entirely clar- Medicine and Surgery, School of Medicine, University of Naples Federico II, Naples, Italy. ify this topic. 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Advances in Rheumatology – Springer Journals
Published: Jul 8, 2021
Keywords: Rheumatoid arthritis; Spondiloarthritis; Psoriatic arthritis; COVID-19; SARS-COV-2