Psoriatic Arthritis Recurrence After Discontinuing DMARDs
Psoriatic Arthritis Recurrence After Discontinuing DMARDs
Due to earlier diagnosis, tighter management and the broader armamentarium of DMARDs, an increasing number of patients with inflammatory arthritis experience sustained clinical remission. This situation attributes to both RA and PsA patients and represents a future challenge for rheumatologists since patients question the need for ongoing drug therapy despite the absence of musculoskeletal symptoms . High costs of biological DMARD therapy as well as the controversial data on efficacy of MTX in patients of PsA further raise the importance of this question. As a matter of fact, two different concepts can be envisioned: (i) long-term successful management of inflammatory disease could lead to a reset of the entire underlying process of immune activation, which allows for cure of disease and successful cessation of treatment. In opposition to this view, (ii) current antirheumatic therapy, despite successfully suppressing the inflammatory response, may not cure the underlying cause of disease. This scenario would imply that once treatment has been stopped, disease and, in consequence, also clinical symptoms return.
We were surprised by the extraordinary high rate of recurrence of disease in patients with PSA in continuous remission after stopping treatment. More than two-thirds of the patients had to restart their original medication within the first 6 months of cessation of treatment. One additional patient developed disease activity only 30 days after the 6-month follow-up visit, suggesting that recurrence of PsA can occur even after a 6 months of symptom-free interval. This observation clearly favours the latter of the aforementioned scenarios, suggesting that neither MTX treatment nor TNFi fundamentally change the susceptibility of the patients to develop PsA. The reasons for this situation are unclear, but several explanations may be envisioned: first, genetic susceptibility to develop disturbed barrier function and/or altered immune response with activation of the IL-23/IL-17 axis in the skin may persist lifelong in patients with PsA and cannot be corrected by current antirheumatic interventions. Second, the joints of patients with PsA may be altered and become primed by the inflammatory tissue, possible due to damage of the entheseal organ, the bone and the cartilage. Affected joints may repeatedly and effectively home inflammatory tissue. This memory function of the tissue is supported by the observation that recurrence of the disease usually occurred at those anatomical sites, which were previously affected by the disease.
The high rate of recurrence of PsA was also unexpected given the strict inclusion criteria we employed in this observational study. Patients had to be without musculoskeletal symptoms, such as joint tenderness, joint swelling, as well as signs of enthesitis or dactylitis for the last 6 months. Also, no change in DMARD medication was allowed during the last 6 months, which excludes inclusion of patients with unstable remission. Furthermore, skin disease was absent or minimal with a mean PASI of less than 0.3 at baseline. Although no formal remission criteria in PsA have been defined to date, the continuous absence of musculoskeletal complaints with no or only minimal psoriatic skin disease can considered as ambitious treatment goal in patients with PsA. Conditions resembling clinical remission of PsA have been reported previously. Their frequency ranges from 18% to as high as 58%, which is most likely based on the different populations studied, differences in the treatment and the criteria used to define remission. It is also important that remission at one point of time in disease does not entirely reflect continuous remission, which needs to be documented during several sequential visits. Recently, Coates and colleagues defined the term minimal disease activity in PsA, which permits minor residual disease and is intended to define a treatment target for rheumatologists in patients with PsA. The criteria for minimal disease activity in PsA were however not intended to define PsA patients, which are eligible to stop their DMARD medication. Such patients will have to be in true remission without any residual disease activity to justify cessation of treatment.
Our data do not support that discontinuation of DMARD treatment is a feasible option in patients with PsA, even if in remission for more than 6 months. Since the duration of remission did not predict the likelihood of recurrence of disease, we do not have data in support of the concept that the susceptibility to develop PsA changes even in cases of long-term remission. The observation that longer disease duration and synovial hypertrophy by ultrasound are more often associated with the recurrence of PsA suggests that joint damage in conjunction with inflammation may prime these joints for disease and enhance their susceptibility to become affected again. Such concept would further strengthen the importance of early intervention in PsA, which may not only enhance the likelihood of remission of disease as nicely shown by Theander and colleagues but also raises the perspective to induce drug-free remission and even cure.
Discussion
Due to earlier diagnosis, tighter management and the broader armamentarium of DMARDs, an increasing number of patients with inflammatory arthritis experience sustained clinical remission. This situation attributes to both RA and PsA patients and represents a future challenge for rheumatologists since patients question the need for ongoing drug therapy despite the absence of musculoskeletal symptoms . High costs of biological DMARD therapy as well as the controversial data on efficacy of MTX in patients of PsA further raise the importance of this question. As a matter of fact, two different concepts can be envisioned: (i) long-term successful management of inflammatory disease could lead to a reset of the entire underlying process of immune activation, which allows for cure of disease and successful cessation of treatment. In opposition to this view, (ii) current antirheumatic therapy, despite successfully suppressing the inflammatory response, may not cure the underlying cause of disease. This scenario would imply that once treatment has been stopped, disease and, in consequence, also clinical symptoms return.
We were surprised by the extraordinary high rate of recurrence of disease in patients with PSA in continuous remission after stopping treatment. More than two-thirds of the patients had to restart their original medication within the first 6 months of cessation of treatment. One additional patient developed disease activity only 30 days after the 6-month follow-up visit, suggesting that recurrence of PsA can occur even after a 6 months of symptom-free interval. This observation clearly favours the latter of the aforementioned scenarios, suggesting that neither MTX treatment nor TNFi fundamentally change the susceptibility of the patients to develop PsA. The reasons for this situation are unclear, but several explanations may be envisioned: first, genetic susceptibility to develop disturbed barrier function and/or altered immune response with activation of the IL-23/IL-17 axis in the skin may persist lifelong in patients with PsA and cannot be corrected by current antirheumatic interventions. Second, the joints of patients with PsA may be altered and become primed by the inflammatory tissue, possible due to damage of the entheseal organ, the bone and the cartilage. Affected joints may repeatedly and effectively home inflammatory tissue. This memory function of the tissue is supported by the observation that recurrence of the disease usually occurred at those anatomical sites, which were previously affected by the disease.
The high rate of recurrence of PsA was also unexpected given the strict inclusion criteria we employed in this observational study. Patients had to be without musculoskeletal symptoms, such as joint tenderness, joint swelling, as well as signs of enthesitis or dactylitis for the last 6 months. Also, no change in DMARD medication was allowed during the last 6 months, which excludes inclusion of patients with unstable remission. Furthermore, skin disease was absent or minimal with a mean PASI of less than 0.3 at baseline. Although no formal remission criteria in PsA have been defined to date, the continuous absence of musculoskeletal complaints with no or only minimal psoriatic skin disease can considered as ambitious treatment goal in patients with PsA. Conditions resembling clinical remission of PsA have been reported previously. Their frequency ranges from 18% to as high as 58%, which is most likely based on the different populations studied, differences in the treatment and the criteria used to define remission. It is also important that remission at one point of time in disease does not entirely reflect continuous remission, which needs to be documented during several sequential visits. Recently, Coates and colleagues defined the term minimal disease activity in PsA, which permits minor residual disease and is intended to define a treatment target for rheumatologists in patients with PsA. The criteria for minimal disease activity in PsA were however not intended to define PsA patients, which are eligible to stop their DMARD medication. Such patients will have to be in true remission without any residual disease activity to justify cessation of treatment.
Our data do not support that discontinuation of DMARD treatment is a feasible option in patients with PsA, even if in remission for more than 6 months. Since the duration of remission did not predict the likelihood of recurrence of disease, we do not have data in support of the concept that the susceptibility to develop PsA changes even in cases of long-term remission. The observation that longer disease duration and synovial hypertrophy by ultrasound are more often associated with the recurrence of PsA suggests that joint damage in conjunction with inflammation may prime these joints for disease and enhance their susceptibility to become affected again. Such concept would further strengthen the importance of early intervention in PsA, which may not only enhance the likelihood of remission of disease as nicely shown by Theander and colleagues but also raises the perspective to induce drug-free remission and even cure.
