Joint-Specific Memory and Sustained Risk for New Joint Accumulation in Autoimmune Arthritis

Abstract

Objective: Inflammatory arthritides exhibit hallmark patterns of affected and spared joints, but in each individual, arthritis affects only a subset of all possible sites. The purpose of this study was to identify patient-specific patterns of joint flare to distinguish local from systemic drivers of disease chronicity.

Methods: Patients with juvenile idiopathic arthritis followed without interruption from disease onset into adulthood were identified across 2 large academic centers. Joints inflamed at each visit were established by medical record review. Flare was defined as physician-confirmed joint inflammation following documented inactive disease.

Results: Among 222 adults with JIA, 95 had complete serial joint examinations dating from disease onset in childhood. Mean follow-up was 12.5 years (interquartile range 7.9-16.7 years). Ninety (95%) of 95 patients achieved inactive disease, after which 81% (73 patients) experienced at least 1 flare. Among 940 joints affected in 253 flares, 74% had been involved previously. In flares affecting easily observed large joint pairs where only 1 side had been involved before (n = 53), the original joint was affected in 83% and the contralateral joint in 17% (P < 0.0001 versus random laterality). However, disease extended to at least 1 new joint in ~40% of flares, a risk that remained stable even decades after disease onset, and was greatest in flares that occurred while patients were not receiving medication (54% versus 36% of flares occurring with therapy; odds ratio 2.09, P = 0.015).

Conclusion: Arthritis flares preferentially affect previously inflamed joints but carry an ongoing risk of disease extension. These findings confirm joint-specific memory and suggest that prevention of new joint accumulation should be an important target for arthritis therapy.

Figure 1.. Patient cohort.

Flowchart indicating patients with JIA seen in the Center for Adults with Pediatric Rheumatic Illness (CAPRI) who were followed longitudinally from Boston Children’s Hospital (BCH) Rheumatology.

Figure 2.. Time to first episode of inactive disease.

(A) Time from first visit in rheumatology clinic to the first documented normal physical exam. n=95 patients, including 5 who never attained remission. (B) Time to first inactive disease for patients diagnosed with JIA before 2005 (pre-biologic era, n=60) and after 2005 (biologic era, n=30), among the 90 patients who attained inactive disease. 2005 is the year that 25% of the patient cohort had received biologic therapy. p=0.001 Mantel-Cox test.

Figure 3.. Arthritis flares preferentially in previously inflamed joints.

(A) Timing of flare from diagnosis. n=253 flares in JIA patients who attained inactive disease (n=90). (B) Number of new joints per flare. (C) Distribution of joint inflammation in 53 flares involving paired large joints of which only one had been affected prior to a period of inactive disease. p<0.0001 from two-tailed exact binomial test against a stochastic 50/50 distribution.

Figure 4.. Arthritic joints accumulate over time during disease flares.

(A) Illustrative patients from each JIA subtype followed for at least 10 years, exhibiting a gradual increase in the number of affected joints with time. Each line represents an individual patient; each data point reflects an encounter for arthritis diagnosis or disease flare. (B) Total number of arthritic joints involved over time. (Left) Each patient contributes multiple data points and each dot represents an encounter for arthritis diagnosis or flare (n=348 encounters). (Right) Linear regression curve for each JIA subtype. Spearman correlation p<0.05 for all subtypes except enthesitis related arthritis (ERA). (C) Proportion of flares that recruit new joints over time (n=102 new joints, 253 flares). RF, rheumatoid factor.

Figure 5.. Joint accumulation hypothesis.

Over the course of arthritis, the number of joints currently inflamed varies with disease activity (blue line) but the number of joints ever involved increases stepwise, leaving each patient with a progressively greater number of joints at elevated risk for subsequent flare (joints marked red in homunculus during periods of inactive disease). Rapid, sustained disease control that prevents accumulation of at-risk joints may render arthritis easier to control in the long term, irrespective of any “window of opportunity” in the underlying autoimmune process.