Long-term outcomes of destructive seronegative (rheumatoid) arthritis – description of four clinical cases

Classification criteria for rheumatoid arthritis (RA) have evolved over the decades. Positive serology receives special emphasis in the current criteria [1]. In addition to rheumatoid factor (RF) and anti-cyclic citrullinated peptide (aCCP) antibodies, other RA-related antibodies have recently been identified. These include antibodies against carbamylated proteins (aCarP) [2] and malonaldehyde-acetaldehyde [3], albeit none of these are currently included in classification criteria or used in routine clinical practice.

Autoantibodies are believed to have a pathogenetic role in RA [4]. In studies examining predictors, associating factors, or prevention of RA, seropositive and seronegative groups of patients seem to behave differently [5‐7]. In treatment recommendations for RA, seropositivity is recognized as an indicator of severe disease and in these patients, the thresholds for earlier and more intensive/potent disease-modifying treatment are lower [8]. It has become increasingly apparent that our knowledge concerning the pathogenesis, treatment responses and clinical course of seronegative RA, is limited [9, 10].

Up to 20-30 % of patients recruited into RA cohorts and clinical trials are seronegative [11, 12]. An exception is the Finnish Heinola Rheumatism Foundation Hospital early RA cohort from the middle 1970’s, which included long-term (25 years) follow-up of seropositive patients only, as experienced rheumatologists were convinced that seropositive disease (positive RF alone at that time) is the only true presentation of the disease [13]. This formed the basis of our interest in observing the clinical presentation of seronegative RA.

Observations in our early RA cohorts indicate that long-term radiographic outcomes are different between seropositive and seronegative patients [14]. The natural course of seropositive disease is that of progressive erosions [15], while even in the long-term (e.g. over 20 years), seronegative patients do not present with marked erosions [16]. However, among >3000 patients included in the Jyvaskyla Central Hospital clinical RA database since the 1990’s we identified a few consistently RF and aCCP negative individuals with a particular presentation of aggressive, destructive disease. Four cases are presented in detail herein.

These cases all share a common feature: that of a severe, destructive disease in seronegative RA with involvement primarily of the wrists, sub-talar and ankle joints, as well as large joints. All these patients were negative with regard to RF, aCCP, and aCarP. Two cases were HLA-B27 positive but despite this, the clinical presentation (signs and symptoms) and radiographs of the sacro-iliac joints did not support a diagnosis of ankylosing spondylitis (AS) or other spondyloarthritides in these individuals.

Seronegative RA has been in focus of only a few cohorts and rarely in detail, to reveal various aspects of outcomes [9]. Again, an exception is from the Heinola group, which reported long-term outcomes of non-specific seronegative oligoarthritis in patients with a 23 year follow-up [16]. Based on patient history, radiographs and clinical status at the follow-up visit, they re-classified the 64 patients and found one case each of RA, systemic lupus erythematosus and ankylosing spondylitis, two cases of post-traumatic arthritis, four cases of osteoarthritis, and six cases of possible reactive arthritis. Of the remaining 49 patients, 15 were HLA-B27 positive and 16 had at least one of the psoriasis-related HLA antigens. Seven patients had minor erosions in their hands or feet joints. One HLA-B27 positive patient had developed bilateral sacroilitis by the evaluation at 23 years. Functional capacity of the patients was well retained. Compared to this Heinola seronegative cohort, our patients present a more severe destructive disease, and to date, remain un-classified.

To our experience, patients with destructive seronegative (RF, aCCP negative) RA - as this disease entity can be referred to - are rare. Among our approximately 3000 RA patients, of whom 30 % are seronegative, only a few seem to present with such degree of destructive disease. However, over the years it is possible that similar cases have been missed, as prior to the era of aCCP analyses, a proportion of RF negative cases demonstrated a typical RF positive course and were later revealed to be aCCP positive. Although destructive seronegative RA is rare, it can have devastating consequences and early recognition and intensive treatment is paramount.

The current clinical status of the patients presented in this report indicates considerable functional loss with a HAQ > 1.5 in three of the four patients. Despite this, disease activity appears to be under at least some degree of control with DAS28 values between 2.1 to 3.4. Current treatment in all four patients includes prednisolone, methotrexate and biologic agents (combination of two biologic agents in Case 4).

The radiological progression of joint damage in these patients presents major cartilage destruction and loss and with minor bony erosions of joints. In fact, it could even be argued that the radiographic destruction seen in these cases resembles that of advanced seronegative juvenile polyarthritis.

Through a detailed description of four destructive seronegative (for RF, aCCP and aCarP) RA cases from disease-onset and up to 35 years from diagnosis, this report could shed more light on the disease presentation, course and outcomes of such patients. We hope to inform the reader of this particular sub-type of inflammatory arthritis which can result in devastating patient outcomes and therefore needs prompt identification and treatment, similar to seropositive disease. This report justifies the undertaking of further research on the pathogenesis and identification of possible biomarkers for this type of arthropathy, which could be invaluable in firstly understanding disease behavior and course and secondly in treatment stratification.

aCarP, anti-carbamylated protein antibodies; aCCP, anti-cyclic citrullinated peptide antibodies; CRP, C-reactive protein; DAS, disease activity score; DMARD, disease modifying anti rheumatic drug; ESR, erythrocyte sedimentation rate; HLA, human leucocyte antigen; IM/i.m, intra muscular; MCP, meta carpo phalangeal; RA, rheumatoid arthritis; RF, rheumatoid factor.