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Primary Sjögren syndrome (pSS) is a prototypical autoimmune disease. The involvement of B cells in the pathogenesis of pSS has long been suspected on the basis of clinical observations that include the presence of serum autoantibodies, hypergammaglobulinaemia, increased levels of free light chains and increased risk of B cell lymphoma. Moreover, the composition of the B cell subset is altered in pSS. In this Review, we discuss the mechanisms that support the increased activation of B cells in pSS, including genetic and epigenetic factors and environmental triggers that promote B cell activation via the innate immune system. B cell activating factor (BAFF, also known as TNF ligand superfamily member 13B) is at the crossroads of this process. An important role also exists for the target tissue (exocrine glands, namely the salivary and lachrymal glands), which promotes local B cell activation. This continuous stimulation of B cells is the main driver of lymphomatous escape. Identification of the multiple steps that support B cell activation has led to the development of promising targeted therapies that will hopefully lead to the development of an efficient therapeutic strategy for pSS.

Immune-related manifestations are increasingly recognized conditions in patients with COVID-19, with around 3,000 cases reported worldwide comprising more than 70 different systemic and organ-specific disorders. Although the inflammation caused by SARS-CoV-2 infection is predominantly centred on the respiratory system, some patients can develop an abnormal inflammatory reaction involving extrapulmonary tissues. The signs and symptoms associated with this excessive immune response are very diverse and can resemble some autoimmune or inflammatory diseases, with the clinical phenotype that is seemingly influenced by epidemiological factors such as age, sex or ethnicity. The severity of the manifestations is also very varied, ranging from benign and self-limiting features to life-threatening systemic syndromes. Little is known about the pathogenesis of these manifestations, and some tend to emerge within the first 2 weeks of SARS-CoV-2 infection, whereas others tend to appear in a late post-infectious stage or even in asymptomatic patients. As the body of evidence comprises predominantly case series and uncontrolled studies, diagnostic and therapeutic decision-making is unsurprisingly often based on the scarcely reported experience and expert opinion. Additional studies are required to learn about the mechanisms involved in the development of these manifestations and apply that knowledge to achieve early diagnosis and the most suitable therapy.Immune-related disorders in patients with COVID-19 are increasingly being reported worldwide, with thousands of cases recorded of manifestations that can mimic a broad range of systemic and organ-specific inflammatory and autoimmune diseases.

Primary Sjögren syndrome (pSS) is a systemic autoimmune disease that is characterized by a triad of symptoms that affect all patients (dryness, pain and fatigue). In addition, systemic involvement can affect between one-third and one-half of patients. The management of patients with pSS has been negatively affected by a lack of effective treatments; however, knowledge of the epidemiology of pSS has increased, and advances in developing classification criteria, systemic disease activity scoring and patient-reported outcomes have been made during the past decade. Progress has also been made in understanding the mechanisms that underlie the pathogenesis of pSS, which has enabled a more targeted therapeutic approach to be taken. At present, therapeutic decisions rely on the evaluation of symptoms and systemic manifestations and are mostly formed on the basis of experience rather than evidence, and on similarities with other autoimmune diseases, although the 2019 management recommendations from EULAR are now being used to inform clinical management of pSS. This Review summarizes the available evidence for systemic treatments for pSS and includes discussions of advances in outcome assessment, the current evidence for DMARD use and an overview of promising future therapeutics.Advances in understanding the pathogenic mechanisms of primary Sjögren syndrome (pSS) and the development of new outcome measures are aiding drug development for this disease. This Review describes current treatments and highlights promising candidates for future therapies for pSS.

Cancer immunotherapies have changed the landscape of cancer treatment during the past few decades. Among them, immune checkpoint inhibitors, which target PD-1, PD-L1 and CTLA-4, are increasingly used for certain cancers; however, this increased use has resulted in increased reports of immune-related adverse events (irAEs). These irAEs are unique and are different to those of traditional cancer therapies, and typically have a delayed onset and prolonged duration. IrAEs can involve any organ or system. These effects are frequently low grade and are treatable and reversible; however, some adverse effects can be severe and lead to permanent disorders. Management is primarily based on corticosteroids and other immunomodulatory agents, which should be prescribed carefully to reduce the potential of short-term and long-term complications. Thoughtful management of irAEs is important in optimizing quality of life and long-term outcomes. Checkpoint inhibitors are increasingly being used in clinical practice; however, these therapies can be associated with adverse events that can affect almost any organ system. This Primer by Ramos-Casals and colleagues summarizes the epidemiology, mechanisms, diagnosis and treatment of these adverse events.

Post-transcriptional regulation is a fundamental process in gene expression that has a role in diverse cellular processes, including immune responses. A core concept underlying post-transcriptional regulation is that protein abundance is not solely determined by transcript abundance. Indeed, transcription and translation are not directly coupled, and intervening steps occur between these processes, including the regulation of mRNA stability, localization and alternative splicing, which can impact protein abundance. These steps are controlled by various post-transcription factors such as RNA-binding proteins and non-coding RNAs, including microRNAs, and aberrant post-transcriptional regulation has been implicated in various pathological conditions. Indeed, studies on the pathogenesis of autoimmune and inflammatory diseases have identified various post-transcription factors as important regulators of immune cell-mediated and target effector cell-mediated pathological conditions. This Review summarizes current knowledge regarding the roles of post-transcriptional checkpoints in autoimmunity, as evidenced by studies in both haematopoietic and non-haematopoietic cells, and discusses the relevance of these findings for developing new anti-inflammatory therapies.Post-transcriptional regulation of gene expression is important in various cellular processes, and disruption of this process can lead to aberrant immune responses, including autoimmune processes. This Review discusses the role of post-transcriptional checkpoints in autoimmunity and potential therapeutic implications.

ObjectivesThere is a need for effective and safe treatment during pregnancy in women with chronic inflammatory diseases. This study evaluated placental transfer of certolizumab pegol (CZP), an Fc-free anti-tumour necrosis factor drug, from CZP-treated pregnant women to their infants.MethodsCRIB was a pharmacokinetic (PK) study of women ≥30 weeks pregnant receiving commercial CZP for a locally approved indication (last dose ≤35 days prior to delivery). Blood samples were collected from mothers, umbilical cords and infants at delivery, and infants again at weeks 4 and 8 post-delivery. CZP plasma concentrations were measured with a highly sensitive and CZP-specific electrochemiluminescence immunoassay (lower limit of quantification 0.032 μg/mL).ResultsSixteen women entered and completed the study. Maternal CZP plasma levels at delivery were within the expected therapeutic range (median [range] 24.4 [5.0–49.4] μg/mL). Of the 16 infants, 2 were excluded from the per-protocol set: 1 due to missing data at birth and 1 due to implausible PK data. Of the remaining 14 infants, 13 had no quantifiable CZP levels at birth (<0.032 μg/mL), and 1 had a minimal CZP level of 0.042 μg/mL (infant/mother plasma ratio 0.0009); no infants had quantifiable CZP levels at weeks 4 and 8. Of 16 umbilical cord samples, 1 was excluded due to missing data; 3/15 had quantifiable CZP levels (maximum 0.048 μg/mL).ConclusionsThere was no to minimal placental transfer of CZP from mothers to infants, suggesting lack of in utero foetal exposure during the third trimester. These results support continuation of CZP treatment during pregnancy, when considered necessary.Trial registration number NCT02019602; Results.

ObjectivesTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We report an integrated safety summary of tofacitinib from two phase I, nine phase II, six phase III and two long-term extension studies in adult patients with active RA.MethodsData were pooled for all tofacitinib-treated patients (data cut-off: 31 March 2015). Incidence rates (IRs; patients with event/100 patient-years) and 95% CIs are reported for adverse events (AEs) of interest.Results6194 patients received tofacitinib for a total 19 406 patient-years' exposure; median exposure was 3.4 patient-years. IR (95% CI) for serious AEs was 9.4 (9.0 to 9.9); IR for serious infections was 2.7 (2.5 to 3.0). IR for (all) herpes zoster was 3.9 (3.6 to 4.2); IR for disseminated or multidermatomal herpes zoster was 0.3 (0.2 to 0.4). IR for opportunistic infections (excluding tuberculosis) was 0.3 (0.2 to 0.4) and was 0.2 (0.1 to 0.3) for tuberculosis. IR for malignancies (excluding non-melanoma skin cancer (NMSC)) was 0.9 (0.8 to 1.0); NMSC IR was 0.6 (0.5 to 0.7). IR for gastrointestinal perforations was 0.1 (0.1 to 0.2). Analysis of IR for serious infections, herpes zoster and malignancies by 6-month intervals did not reveal any notable increase in IR with longer-duration tofacitinib exposure.ConclusionThis analysis of tofacitinib exposure up to 8.5 years allowed estimation of safety events with improved precision versus previous tofacitinib reports. AEs were generally stable over time; no new safety signals were observed compared with previous tofacitinib reports.Trial registration numbers NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT00413699, NCT00661661; Results.

Long COVID is the name given to a syndrome comprising a wide variety of symptoms persisting more than 3 months after acute benign COVID-19, with a prevalence ranging from 10 to 80%. Symptoms are very close to fibromyalgia. Several studies showed that long COVID prevalence was much higher after the first wave of the pandemics and was associated to the fact of thinking having had COVID rather than having had really COVID. Thus, it was the stress of the first wave with the lockdown and not the consequences of the infection that probably induced this high frequency of long COVID. Numbers of studies tried to find objective biological abnormalities for explaining long COVID but none of them could be replicated and convincing. The concept of long COVID seems to be a repetition of history of medicine, in which the doctors and the society gave different names to fibromyalgia with the objective of trying to highlight the fact that fibromyalgia could be a somatic disease with a well understood pathophysiology and to avoid to focus on the psychosomatic aspects of the disease. In conclusion, “to name is to soothe” as said by Roland Barthes. However, “Naming things wrongly adds to the world's unhappiness” was saying Albert Camus. Thus, the term of long COVID, which suggests viral persistence of impaired immune response to the virus, is unappropriated and should be replaced by fibromyalgia-like post-COVID syndrome. Research on the psychosomatic and somatic mechanisms involved in these fibromyalgia-like post-viral syndromes must be encouraged.

ObjectivesImmune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated protein 4 and programmed cell death protein 1 (PD-1) have demonstrated improved survival for multiple cancers. However, these new drug classes have led to increased immune-related adverse events (IrAE). Rheumatic IrAEs have not been well described in clinical trials. We report here cases of rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR) occurring after ICI treatment.MethodsThis was a retrospective study of patients receiving an ICI in whom symptoms of arthritis or arthralgia developed and revealed a diagnosis of RA or PMR.ResultsIn 10 patients who received ICI therapy (all anti-PD-1 or anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after exposure. No patient had pre-existing rheumatic or autoimmune disease. RA developed in six patients; all six were positive for anti-cyclic citrullinated peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies were detected in two out of three patients tested before immunotherapy. Disease-modifying antirheumatic drugs were needed for three patients; the three others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was diagnosed in four patients, all responded to corticosteroids. Despite these IrAEs, immunotherapy was pursued for all but one patient until cancer progression.ConclusionsThis is the first description of RA occurring after ICI therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1 therapy. All cases responded to corticosteroids or with immunosuppressive therapy. Collaboration between rheumatologists and oncologists is crucial and could lead to better recognition and care of these patients.