ERN ReCONNET documents

ERN ReCONNET documents

New rapidly evolving challenges on the management and vaccination of rare and complex connective tissue and musculoskeletal diseases patients in the COVID-19 era: points of view of the ERN ReCONNET

R. Talarico*, C. Tani*, C. Cardelli, F. Di Cianni, J.C. Abril, S. Aguilera, T. Alexander, Z. Amoura, J. Andersen, L. Arnaud, T. Avcin, S.M. Barril, L. Beretta, S. Bombardieri, I. Bulina, G. Burmester, S. Callens, S. Cannizzo, L. Cavagna, I. Cavazzana, B. Chaigne, A. Cornet, N. Costedoat-Chalumeau, A. Doria, A. Ferraris, R. Fischer-Betz, J. E. Fonseca, C. Frank, A. Gaglioti, I. Galetti, V. Guimarães, E. Hachulla, E.M. Hauge, F. Houssiau, L. Iaccarino, S. Jacobsen, M. Limper, F. Malfait, X. Mariette, D. Marinello, T. Martin, L. Matthews, M. Matucci-Cerinic, A. Meyer, A.J. Milas, P. Moizandeh, M.J. Molnar, C. Montecucco, L. Mouthon, U. Mueller-Ladner, E. Patarata, M. Pileckyte, C. Pruunsild, S. Rednic, V.C. Romão, M. Schneider, V. Smith, A. Sulli, F. Tamirou, A. V. Taulaigo, S. Ticciati, A.M. Troldborg, J. M. van Laar, A. Vieira, J. de Vries-Bouwstra, M. Cutolo, M. Mosca.
*: equally contributed


The COVID-19 pandemic has led to increasing challenges for both patients and health care professionals managing patients affected by rare and complex Connective Tissue Diseases (rCTDs). They include limited access of patients to specialized health care with difficulties in early diagnosis and or routine follow-up, the risk of contracting severe SARS-CoV2-infections in this population, and the need for balancing the infectious risk under immunosuppressive treatment against the risk of uncontrolled disease activity (1-2). Since the first wave of the COVID-19 pandemic in Spring 2020, rCTDs patients were faced with multiple unforeseen issues related to COVID-19, particularly vulnerability to severe SARS-CoV2 infections under continued DMARD therapies, uncertainty about special hygiene measures and reliability of test results, and difficulties to contact their treating physicians, often resulting in frustration due to lack of information or even anxiety or depression. In addition, clinicians had to face the complexity of treating rCTDs patients with active disease who required rapid therapeutic decisions despite the risk of being immunocompromised in the middle of a pandemic (3-6). Moreover, after the COVID-19 vaccination campaign started in Europe, other burning questions for rCTDs patients concerning the effectiveness of COVID-19 vaccination have raised.

In this framework, the European Reference Network on rare and complex connective tissue and musculoskeletal diseases (ERN ReCONNET) (7) organized two online workshops gathering patients’ and clinicians’ opinions to discuss the most critical challenges and to try to define a common approach related to the management of rCTDs during the COVID-19 pandemic.

The first workshop was held in March 2021 and aimed at discussing treatment strategies for patients with rCTDs. However, the major points of the first workshop needed to be constantly updated given the new evidence and new challenges rapidly emerging in the ensuing months  More recently, patients representatives from Lupus Europe, an umbrella organization bringing together national lupus patient organisations across Europe, have expressed the need to provide a common and shared expert opinion on vaccination strategies against COVID-19 in systemic lupus erythematosus (SLE) patients and for this reason, a second workshop was held in June 2021, with the perspective that many principles related to SLE can also be applied to other rCTDs.

The first workshop was aimed to address some clinical challenges related to the clinical management of rCTDs patients in the context of COVID-19 with special focus on three main aspects:

  1. the management of therapies for rCTDs during the pandemic;
  2. the need to test rCTD patient for SARS-CoV-2 before the beginning of a new immunosuppressive therapy;
  3. the management of immunosuppressive therapies before and after vaccination against SARS-CoV-2.

The discussion of the workshop was supported by an expert in infectious disease. For each of the discussed main points, the knowledge base at the time of the workshop and tentative conclusions are summarised in the following paragraphs.

What we knew

Among risk factors for severe cases of SARS-CoV2 infection, the use of glucocorticoids (GCs) (at a daily dosage >10 mg prednisone equivalent) emerged as important risk factor for severe COVID-19 disease, while there is still controversial data on conventional and biological disease modifying antirheumatic drugs (cDMARDs and bDMARDs). On the other hand, the activity of the underlying rheumatological disease is associated with a poor outcome and this is particularly true for rCTDs patients compared to patients with primary inflammatory arthritis (8-11). From these premises, the discussion among the experts resulted in a general agreement on the following conclusions:

  • A careful balance between the need to treat rheumatological conditions and the need to minimize the infectious risk is essential.
  • GCs should be kept at the lowest possible dose allowed by the disease activity.
  • Any immunosuppressive treatment should be continued unless the patient has a certain or strongly suspected diagnosis of COVID-19. In the latter case, the patient should discontinue cDMARDs and bDMARDs until the infection is resolved, but the CTD activity should be continuously monitored and treated on a case-by-case strategy
  • The workshop participants noted uncertainty concerning rituximab in this situation. However, in all cases, close control of CTD activity is required on an individual basis; moreover, also taking into consideration the current epidemiological situation, both a delay of RTX re-treatment in stable patients and a postponement of its initiation in other patients should be considered if other treatment options are available.

At the time of the workshop, the discussion was in line with the recommendations published by the leading scientific societies related to rheumatic diseases (12).

What we knew

Since immunosuppressive agents modulate several aspects of the host immune response, the severity of COVID-19 could potentially be affected by the type, combinations, and intensity of immunosuppression. For example, certain immunosuppressive medications can either directly (e.g. lymphocyte-depleting antibodies) or indirectly (e.g. antimetabolites) cause lymphopenia, which is a reported risk factor for severe COVID-19 illness (13).

A careful check for active infection is recommended before starting any immunosuppressive therapy. Therefore, all symptomatic patients with suspected COVID-19 infection should undergo testing; nucleic acid amplification testing (NAAT), most commonly with a reverse-transcription polymerase chain reaction (RT-PCR) assay, to detect SARS-CoV-2 RNA from the upper respiratory tract is the preferred initial diagnostic test for COVID-19 (14).

Because symptoms-based screening may be unreliable in selected populations, testing asymptomatic individuals may be necessary for public health or infection control purposes. The discussion was based on available knowledge, in the general population and different disease areas (15-17). Specifically, indications for testing asymptomatic individuals included:

  1. Following close contact with an individual with COVID-19
  2. Early identification of infection in congregate living facilities that house individuals at risk for severe disease
  3. Screening hospitalized patients at locations where prevalence is high (e.g. ≥10 percent PCR positivity in the community)
  4. Before to surgical procedures or aerosol-generating procedures.
  5. Prior to receiving immunosuppressive therapy (including before transplantation) because there is concern that the intense immunosuppression given at the time of transplantation could result in rapidly progressive and potentially fatal COVID-19.

Based on these premises, the panel agreed on the following conclusions:

  • All patients should be carefully investigated for signs or symptoms of COVID-19 before and during immunosuppressive treatment.
  • It is not strictly necessary to test for SARS-CoV2 before starting a treatment with traditional DMARDs. However, as a general principle, clinicians should decide whether to test rCTD patients according to the pandemic situation and current viral circulation rate.
  • Performing a swab before introducing therapy with rituximab, high dose GCs or cyclophosphamide could be considered. However, in case of a positive swab in a patient with high disease activity, the opportunity to postpone treatment should be carefully balanced against the underlying disease-related risk.
  • As a prevention measure for the community, a regular test for SARS-CoV2 should be considered in patients who often come to the clinic to undergo intravenous treatment/get hospitalized, as they get in contact with other fragile patients.

What we knew

The American College of Rheumatology (ACR) COVID-19 Vaccine Guidance Task Force issued a guidance on how to manage immunosuppressive therapy during the COVID-19 vaccination period; of note, the consensus among the experts was moderate for many aspects and data on use and timing of immunomodulatory medications was mainly based on extrapolation of the available evidence from other vaccines (18).

As far as for the efficacy of COVID-19 vaccination in patients with rCTDs, based on previous studies on pneumococcal and influenza vaccination, there was general agreement on the marked reduction of the humoral response under treatment with glucocorticoids (>10 mg/day prednisolone or equivalent) and anti-CD20 (19-20).

A recent study showed that SARS-CoV-2 vaccines are immunogenic in rheumatic patients receiving immunosuppression, when assessed by a combination of serology and cell-based assays. However, the response is impaired compared with healthy individuals. Indeed, only 8.7% of infection-naïve patients had neither antibody nor T-cell responses detected following the second-dose vaccine. Moreover, the study also showed that B-cell depletion following rituximab impairs serological responses, but T-cell responses are preserved (21).

Starting from these considerations, the participants of the workshop agreed on the following statements:

  • Regarding the preferred type of vaccine in patients with rCTDs, no data are currently available from comparisons studies in terms of effectiveness in this population. Therefore, national/local guidelines for the general population should be considered.


  • Patients should not modify their undergoing treatment. Possible exceptions might be:

– patients on rituximab: to be vaccinated 3 to 4 months after the previous infusion and at least 6 weeks before the next one;

– patients on methotrexate: consider pausing 1 week after each vaccination dose, as long as the disease is in remission. This point did not reach a full agreement among the experts included in the discussion, due to the low evidence available when the workshop took place and national/local guidelines should be considered.

  • Test response to vaccination. Although we still do not know to which extent a high serum anti-COVID19 titre is associated with protection against the infection, it remains the only current available tool to provide an overall evaluation of immune response to vaccination. New data on the interpretation of the antibody tests from observational studies are awaited.

The second, recently held workshop was aimed to address issues and needs raised by the SLE community. Although the discussion was focused on vaccination against COVID-19 in SLE patients, therefore including several disease-specific aspects, some principles related to the impact of therapy seemed relevant also for patients with other CTDs. The discussion among the different stakeholders was structured around four central questions, reported as follows.

1. As a Lupus patient, should I be vaccinated against SARS-CoV-2? Is the vaccine safe?

What we knew

Vaccination against SARS-CoV-2 is recommended in all SLE patients. Indeed, after several months of vaccination campaigns, data accumulating from the scientific literature show that the benefits of vaccination outweigh the possible risks in terms of side effects and disease flares (22-24). However, little evidence is available to date around the safety and efficacy of vaccination specifically in SLE patients. An increasing number of studies are ongoing to better understand the impact of vaccination in this category of subjects. Among these, the French VACOLUP reported data coming directly from a patients’ survey (25). As of May 4th 2021, about 50% of a sample of almost 600 SLE patients experienced side effects, generally mild or moderate, after the first or the second dose. In this cohort of patients, only 3.5% reported of disease flares.

Preliminary experience from the Lupus Clinic of Padua (Italy) shows a low prevalence of adverse events (AEs) following the vaccination: during an initial follow-up period of 1-3 months, a limited number of patients reported some AEs, none of which could be classified as severe (SAEs). Most of these patients were vaccinated with mRNA vaccine and nobody experienced disease relapse. A different experience comes from another Italian cohort, the Lupus Clinic of Pisa. Around a half of SLE patients who are already vaccinated, most of them receiving mRNA vaccine, experienced short-term AEs, in all cases mild, and a minimal number of patients had a disease flare. Moreover, in a Danish cohort of approximately 150 SLE patients that had received an mRNA vaccine, no disease flares were reported. AEs were generally mild and similar to these observed in the general population, but more frequently reported (26). Last, the EULAR-COVAX registry has included more than 5,000 patients with RMDs vaccinated, including 367 patients with SLE, 223 with pSS and 162 with scleroderma, and found a rate of severe flare of 0.6% and of severe AE of 0.4%, identical as in non-inflammatory RMDs and identical to the rate of SAE with placebo in the general population (Machado et al submitted).

Therefore, the participants of the workshop agreed on the following statements:

  • Although the potential risks of COVID-19 vaccination remain unknown for patients with SLE, the risks of not receiving the vaccine are far more significant at present.
  • Whether an SLE patient with active disease should be vaccinated is a difficult question. The situation should be considered case by case, taking into account various aspects (i.e. the current risk of SARS-CoV-2 infection based on the epidemiological data, the risk of a more serious clinical course of the infection in case of active underlying disease with major organ involvement, etc.).
  • Although we do not yet have consistent evidence-based data, we can reasonably suggest vaccinating SLE patients preferentially in an inactive or at least low disease activity stage.
  • The vaccination should not be delayed if the pandemic situation requires it, even in active patients.

2. Which is the best vaccine for me? Is there a vaccine I should avoid? 

What we knew

All vaccines against COVID-19 currently approved for use in Europe have been used to vaccinate patients with SLE; however, the vast majority of data came from studies on mRNA vaccines. To date, no clinical trials have directly compared the vaccines. Therefore, there is currently insufficient evidence to recommend a specific vaccine for people with SLE (27) and there are no official contraindications for any of the available vaccines.

However, recent concerns have been raised regarding rare clotting events with the AstraZeneca/Oxford and Janssen vaccines; these vaccines have been associated with rare blood clots with low blood platelets, estimated to occur in 1 in 100.000 vaccinated people (28), especially women under 55 years of age. The empowering effect exerted by oestrogens on immune responses and pro- tection against infections, can explain the reduced morbidity and mortality in premenopausal female patients after COVID-19 infection, but also adverse events to vaccination (29).

As a precaution, in some countries people under 55 years of age are offered an alternative vaccine.

More evidence to obtain unambiguous recommendations is needed as we yet do not know whether a history of blood clots per se increases the risk of this extremely rare occurrence.

Based on these premises, the participants agreed on the following statements:

  • The administration of viral vector vaccines in people of any age showing a higher disease-correlated risk of blood clots (for instance patients with SLE and/or APS [antiphospholipid syndrome]) should be considered in the presence of a favourable risk/benefit ratio.
  • In these cases, patients should be recommended to find an agreement with their treating physician to define the best option evaluating risks and benefits.
  • To date, although there is no proof that viral vector vaccines can increase the thrombotic risk in patients with SLE or APS, the consensus is to choose first mRNA vaccines, when possible.

3. Which is the best timing for vaccination? Should I discontinue my therapies for SLE during the vaccination period?

What we knew

To date, there are no specific data on SLE patients on the optimal timing for COVID-19 vaccination and we can refer to the recommendations issued for patients with systemic autoimmune diseases in general (see first section).

With a specific reference to SLE patients, the panel agreed on the following statements:

  • It is recommended not to discontinue SLE therapy, to avoid the risk of a disease flare. Under any circumstances, treatment should be delayed if it is needed to control disease activity.
  • Disease remission maintenance has priority over treatment discontinuation; thus, the final suggestion is to consider treatment discontinuation only in case of stable clinical remission and low risk of disease flare.

4. Should I monitor the vaccine response by measuring the antibodies titre? If I’m not responding, is it recommended to do a third dose of the vaccine? 

What we knew

COVID-19 vaccination aims to induce the production of antibodies against the spike surface protein of SARS-CoV-2. However, whether a higher antibody titre corresponds to a better immune response is still to be determined (30). Indeed, a more reliable evaluation of the efficacy of anti-SARS-CoV-2 vaccination might be the measurement of the development of memory T-cells response, which is not directly correlated to the antibodies’ titre level. Unfortunately, it is not routine practice to test the ability of memory T-cells to react to COVID-19 new infections.

Recently, Center for Disease Control (CDC) recommended that individuals with certain immunocompromising conditions who received a two-dose mRNA vaccine series receive a third dose of the same vaccine and the Emergency use authorization for the mRNA vaccines was updated to include a third dose, to be given at least 28 days after the second dose, for such individuals. Immunocompromising conditions that would warrant a third dose include active use of chemotherapy for cancer, hematologic malignancies, hematopoietic stem cell or solid organ transplant, advanced or untreated HIV infection with CD4 cell count <200 cells/microL, moderate or severe primary immunodeficiency disorder, and use of immunosuppressive medications (i.e. Rituximab, MMF, prednisone >20 mg/day). Several countries, including Denmark, France, Germany, and Israel, have made similar recommendations (30-37). Recently, some countries, such as Portugal, recommend administering a third dose of vaccine for those treated with more than 10 mgr per day of prednisone or with rituximab, cyclophosphamide, mycophenolate, azathioprine, methotrexate or leflunomide.

Regarding SLE patients, there is little evidence of their ability to build up a serum titre of anti-SARS-CoV-2 antibodies similar to the general population.

Personal experiences from the participants reported the impression that rituximab can significantly impact serological response in a time-dependent manner; moreover, even if further studies are needed to clarify the specific impact of rituximab on serological response, data from Denmark suggests that the serological response to the vaccine is significantly affected, when patients have received rituximab less than 12 months before their COVID-19 vaccine (26).

Regarding the most appropriate timing for performing vaccination, French recommendations for patients under immunosuppressive therapy suggest testing patients’ serological responses 4 weeks after the second dose in order to have a general overview of the immune response. A third dose of vaccine in any patients receiving rituximab, cyclophosphamide, mycophenolate and azathioprine, regardless of their anti-SARS-CoV serum titre is also recommended by the same scientific society (38).

Lastly, numbers of studies have shown a decline of the level of anti-spike Ab 6 months after the second vaccine injection in aged people and immunosuppressed patients and have recommended a third dose in the general population over 60 and now 30 (Israel) or 65 (France).

This aspect raised considerable debates among the experts who agreed on the following statements:

  • At the time of the discussion, it was not possible to either recommend or not recommend the administration of a third dose of any vaccine, since no safety data are currently available in this regard. Patients under some immunosuppressive treatments (RTX, MMF, AZA, CCP, PDN > 10 mg/day) are at risk of sever COVID and likely to be unable to build an efficient immune response to the vaccine. Hence, it is highly probable that they will benefit from additional doses of vaccine, especially if they did not reach a significant level of anti-Spike Ab after 2 injections.
  • As it is now proposed in some countries to the general population over a certain age, a systematic 3rd vaccine dose 6 months after the second one in all patients with CTD and on immunosuppressors whatever they are, has to be discussed.

Therefore, based on the participants’ clinical experience two options can be considered by local authorities to solve this issue:

  1. If a patient’s serological response is absent or very low, the administration of additional vaccines (booster doses) should be considered.
  2. Patients under immunosuppressive treatments are likely to be unable to build an efficient immune response to the vaccine even if their antibodies titre is positive. Hence, they might be candidates for additional doses of vaccine irrespective of their serological titre.

Challenges in the management and vaccination in rCTDs are various and ever-changing. While in the early phases of the pandemic several actions were planned to ensure continuity of care for rCTDs patients, at this crucial stage is fundamental to ensure both a homogeneous approach to therapy management and vaccination in a definite cohabitation with the coronavirus by now.

As rCTDs community, it is crucial to translate each challenge in lessons and promote good practice to be shared, even if not all the answers are available. This is in fact a commitment of the ERN ReCONNET, that can indeed contribute to develop specific strategies supporting the vulnerability of rCTDs patients.

With the aim to collect the appropriate evidence on the effectiveness of vaccination against SARS-CoV-2 in rCTDs, the European-wide observational study VACCINATE was launched and it is currently ongoing across the centres of the ReCONNET Network (39).

The example provided by the ERN ReCONNET shows that thanks to the involvement of the leading experts on rCTDs and the main stakeholders, crucial issues raised during the pandemic can be addressed and a common approach to the management of rCTDs can be defined while providing the community of rCTDs patients with the much-needed information derived from the evidence and the sharing of the clinical and patient experiences of the Network.

Disclosures: All the authors declare no conflict of interest for this work.

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