Preclinical Rheumatoid Arthritis

Definition and Characteristics

Preclinical rheumatoid arthritis, also known as pre-rheumatoid arthritis (pre-RA), represents the phase of rheumatoid arthritis (RA) development before symptoms appear, i.e., before inflammatory arthritis becomes clinically apparent. Beyond this basic definition, the precise features or characteristics of this phase remain poorly defined. In one early attempt at delineating the phases of disease development, European League Against Rheumatism (EULAR) proposed six distinct phases (Figure 19-1): A) genetic risks factors; B) environmental risk factors; C) systemic autoimmunity associated with RA; D) symptoms without clinical arthritis; E) unclassified arthritis; and F) RA.

In the EULAR schema, pre-RA is broadly equivalent to phase C; however, another proposed model of RA development also includes local autoimmunity, i.e., a stage after an inferred local trigger event and before systemic autoimmunity. At the current level of understanding, it is prudent to use terms like preclinical RA or pre-RA only retrospectively, since not everyone with RA-associated risk factors or autoimmunity will develop clinical RA.

Preclinical RA is characterized by abnormalities including autoantibodies and/or other biomarkers. The most common autoantibodies in pre-RA are rheumatoid factor (RF) and anti- cyclic citrullinated peptide (CCP) antibodies (ACPA), but antibodies to post-translationally modified proteins, including acetylated and carbamylated proteins, have also been identified in pre-RA. Other (non-antibody) biomarkers associated with pre-RA include the apoptosis inhibitor surviving, the signal transduction protein 14-3-3η, and changes in B cell and T cell subsets.

Although the initial trigger for the development of autoimmunity remains unknown, evidence is accumulating in support of the mucosal origins hypothesis, which posits that it starts at one or more anatomical locations in mucosal tissue. Several immunity-related changes have been documented in mucosal sites of individuals at risk for RA, including ACPA production in the periodontium, lung, intestine and cervicovaginal mucosa, airway inflammation in the lungs and systemic presence of antibodies to Porphyromonas gingivalis, a typically oral bacterium that synthesizes an enzyme capable of protein citrullination and is a major cause of periodontitis. One small study found a higher prevalence of periodontitis in patients at risk of RA with ACPA (35/48 individuals; 73%) and those with early RA (14/26 individuals; 54%) than in healthy subjects (12/32 individuals; 38%), as well as greater P gingivalis abundance in healthy dental sites in patients at risk of RA, compared to healthy individuals and patients with early RA. Although more research is needed to elucidate the ultimate triggers of autoimmunity, the infection- and mucosa-related processes may play a role in the evolution of pre-RA into clinical RA, “resurrecting” in part the old view of RA as an illness caused by infection.

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Primary Prevention Trials

Despite the lack of a clear definition, the presence of distinct and identifiable biomarkers, particularly ACPA, in patients with pre-RA opens the possibility of primary prevention for RA. A number of clinical trials, including PRAIRI, ARIAA, APIPPRA, Treat Earlier and StopRA, were designed and undertaken to test the preventive efficacy of established RA treatment modalities applied during the pre-RA phase.

The PRAIRIE trial was a randomized, double-blind, placebo-controlled trial of rituximab for RA prevention in subjects seropositive for RF and ACPA without inflammatory arthritis history. A total of 82 patients were randomized (1:1) to receive a single infusion of 1000 mg rituximab or a placebo. Of the 81 to receive treatment (one patient in the placebo group withdrew), 30 (37%) developed arthritis. The relative risk of arthritis development was 55% and 53% lower at months 12 and 18, respectively, among rituximab-treated subjects than in those who received the placebo. Although this did not reach statistical significance, rituximab did significantly (12 months; P <0.0001) delay the time point at which 25% of the subjects developed arthritis. These results suggest that B cells (the targets of rituximab) have a pathogenetic role during pre-RA, and that it is possible to delay the onset of RA with pharmacological intervention. Rituximab was well tolerated in this context, with all safety events deemed non-treatment related.

The ARIAA trial was a randomized, double-blind, placebo-controlled study of the effects of abatacept on the development of RA during the pre-RA stage. Subjects seropositive for ACPA and showing signs of inflammation on MRI were eligible for recruitment. A total of 100 eligible patients were randomized (1:1) to receive either abatacept 125 mg weekly or placebo for 6 months, followed by a 12-month post-treatment follow-up. The primary endpoint was improvement in inflammation on MRI after 6 months; this was achieved by 61% of subjects in the abatacept group, compared to 31% in the placebo group (P = 0.0043). At six months, the secondary endpoint of progression to RA occurred in 8.2% of patients in the abatacept group, compared to 34.7% in the placebo group (P = 0.0025). A significant difference in the rate of progression to RA was maintained by month 18 (one year after cessation of treatment), with 35% and 57% of subjects in the abatacept and placebo group, respectively, developing RA (P = 0.0421). These results implicate T cell activation (the target of abatacept) in the development of RA. Abatacept was well tolerated in the pre-RA context, with only one serious adverse event (pneumonia) deemed to be treatment-related.

Another trial of abatacept in the pre-RA context is APIPPRA. This randomized, double-blind, placebo-controlled trial assessed the effects of treatment with abatacept on preventing or delaying the onset of RA in subjects with clinically suspicious arthralgia who are seropositive for ACPA and RF (or seronegative for RF but with high ACPA concentrations [≥3x ULN]). A total of 213 patients were randomized (1:1) to receive weekly subcutaneous injections of abatacept 125 mg (n = 110) or placebo (n = 103) for 52 weeks, after which the study included a further 52 weeks of follow-up. The primary endpoint was the time to development of ≥3 swollen joints or to fulfilment of the 2010 ACR/EULAR criteria for RA using swollen but not tender joints. At week 52, a primary endpoint event occurred in 6% of patients in the abatacept group and 29% of patients in the placebo group. At the end of the follow-up period, fewer patients in the abatacept group experienced a primary endpoint event (25%) compared to those in the placebo group (37%), with a mean arthritis-free survival time difference of 99.2 days (P = 0.002). During the 52-week treatment period, patients in the abatacept group also had lower tender joint counts and pain scores. The incidence of serious adverse events was numerically lower in the abatacept group (4) than in the placebo group (10).

The effects of methotrexate (MTX) and glucocorticoids in the pre-RA phase were assessed in the Treat Earlier trial. This randomized, double-blind, placebo-controlled trial enrolled subjects with arthralgia clinically suspected to progress to RA and subclinical joint inflammation (by MRI). A total of 236 eligible patients were randomized (1:1) to receive either a single injection (120 mg) of methylprednisolone followed by oral methotrexate (up to 25 mg/week) for a year, or placebo. At 2 years of follow-up, 19% of subjects in the treatment group and 18% in the placebo group developed arthritis. Thus, glucocorticoids and methotrexate had no effect on the development of arthritis, although the treatment did significantly improve physical functioning, pain, morning stiffness of joints, presenteeism and joint inflammation (assessed by MRI). The two groups showed a comparable incidence of adverse events.

The StopRA trial was a study of the effects of hydroxychloroquine (HCQ) on RA prevention during pre-RA. Like PRAIRI, StopRA enrolled patients with ACPA and no history of inflammatory arthritis; unlike in Treat Earlier, arthralgia was not used as a criterion. A total of 144 subjects were randomized (1:1) to either HCQ 200-400 mg/day (weight-based dosing) or placebo for a year, with 3 years of total follow-up. In an interim analysis, the Kaplan-Meier probability of RA development was 34% with HCQ and 36% with placebo. The trial was halted because the interim analysis revealed no benefit of HCQ for the prevention of RA. Safety events were comparable between the two groups.

The Future of Primary Prevention in RA

The positive results from at least some of the initial, proof-of-principle pre-RA intervention trials described above open the possibility for effective RA prevention in the future. At present, agents with demonstrated benefits are the B and T cell modulators rituximab and abatacept; future trials may reveal other efficacious strategies. Neither rituximab nor abatacept are currently approved for the treatment of preclinical RA by the FDA or any other regulatory agency.

Many completed and ongoing RA prevention trials have had recruitment difficulties; suggested solutions include a careful definition of what is pre-RA(i.e., does it include patients who already show inflammation on advanced imaging including ultrasound or MRI), strategies to educate potential participants, limiting the burden of the study on participants and training physicians to promote trial enrolment. Many other challenges to implementation of an RA prevention strategy remain, including agreement on terminology related to pre-RA and RA development more broadly, identification of appropriate molecular targets and development of more accurate models of progression to RA. If RA prevention is to be implemented in practice, a cost-effective, multidisciplinary screening infrastructure must be also developed.