The INSPIRE (Investigating Neuropsychiatric Symptom Prevalence and Impact in Rheumatology Patient Experience) study provides an opportunity to explore through a mixed methodology the possible identification of prodromes (symptom-related manifestations that occur prior to the appearance of clinical findings typically related to the onset or complication of a disease). In the case of autoimmune diseases, this is desirable, due to the difficulty and time patients have to wait before receiving a diagnosis. This is the case for systemic lupus erythematosus (SLE), but especially for the neuropsychiatric involvement of SLE. 

Some suggestive prodromes of SLE and other autoimmune diseases include: joint pain, headache, fatigue, and anxiety. However, these are nonspecific and may be present in a large number of patients, making them difficult to involve in establishing a diagnosis. 

In the case of SLE with nervous system involvement (so-called neuropsychiatric SLE), the identification of prodromes is even more difficult, as the diagnosis presents difficulties related to the lack of specific biomarkers and the reliance on a cognitive process of the patient to interpret the physician's questions and try to establish the presence of signs and symptoms related to the disease. It is in this sense that the authors of the mixed-method study aim to contribute to the identification of prodromes for the future development of manifestations related to neuropsychiatric SLE. 

The study design has several biases, such as selection bias (patients were self-selected to answer online surveys), collection bias (patients were asked to recall the presence of symptoms many years before the diagnosis of their disease) and anchoring bias (related to their experience at the time of disease diagnosis). Another limitation is the lack of measurement of confounding variables related to time of disease evolution, disease activity at the time of the survey, disease severity, treatments, etc. The quantitative analysis of the study is limited to a descriptive one where only the frequencies and percentages of possible prodromes at different times related to the diagnosis of the autoimmune disease are reported: before diagnosis, in the year of diagnosis of the disease and after diagnosis of the disease.  

This analysis highlights the presence of some symptoms one year before the onset of their disease including severe headache (41%), low mood (34%), sleep disruptions or nightmares (32%), anxiety (39%), seizures (36%) and obsessive thoughts or compulsive behaviours (36%), which, according to the authors, suggests that these prodromes could be early manifestations of neuropsychiatric involvement in SLE and other autoimmune diseases with systemic involvement. However, in order to clarify the predictive role that these manifestations may have in the onset of the disease or a reactivation episode, it is necessary to perform studies with quantitative methodology where these frequencies can be extrapolated to an inferential analysis and where there is less bias. 

Qualitative studies, in general, are valuable because they are great generators of hypotheses, which can then be tested in studies with better controlled designs or with greater rigour, and from them we can obtain results with high scientific value. The difficulty in developing these studies with prospective designs will be in linking patients' symptoms (dependent on a cognitive process inherent to the individual) with the presence of biomarkers, so that they can be extrapolated to a heterogeneous population. 

As an important message of this publication, I would like to reflect on the difficulties faced by patients with autoimmune diseases and neuropsychiatric involvement. The main one is related to their diagnosis, as it is common for them to be seen by four to six doctors with different areas of specialisation until they reach the rheumatologist, who finally establishes their diagnosis. The reason why many of these prodromal symptoms have not been clarified may stem precisely from the previous wandering of patients with doctors from other specialties, which inclines me to think that these prospective studies should be performed not in rheumatology clinics, but in other types of services such as psychiatry or neurology, where patients with early manifestations present when the diagnosis of an autoimmune disease is not yet clear. 

Ideally, these studies should be accompanied by the identification of biomarkers related to the development of autoimmunity.  

The idea of these prodromes in the development of autoimmunity does not seem far-fetched to me, given that there is evidence of autoantibody development (anti-CCP) up to 10 years before disease onset in rheumatoid arthritis. These changes in the immune system may be giving rise to prodromal manifestations that have yet to be elucidated and could certainly be useful in the early management of the disease. In the case of autoimmunity this is desirable, as early treatment has been shown to significantly decrease the occurrence of complications and improve the quality of life of patients. 

Finally, it is important to reflect on the need to improve the doctor-patient relationship at all levels of care. We must be vigilant and a little more permissive in terms of patient involvement in their own disease. It is desirable that the patient develops an awareness of illness and a self-awareness of what their experiences mean in terms of improvement or worsening of their illness.