Could it be Rheumatoid? A Case of Elevated Anti-CCP Antibodies in a Patient with Symmetric Polyarticular Arthritis and MAC infection

Summary: Background Anti-citrullinated protein antibodies (ACPAs) are a group of autoantibodies that have been found in up to two-thirds of rheumatoid arthritis (RA) patients with a specificity of around 98%. The most common commercial assay detects cyclic citrullinated peptide antibodies (CCP antibodies) and has been shown to correlate with early and more aggressive disease. In addition to RA, anti-CCP antibodies have been found in other autoimmune and infectious disease processes such as hepatitis C, psoriasis, and tuberculosis (TB). Case A 67-year-old Hispanic female presented for evaluation of symmetric polyarticular joint pain in the hands and knees. There was no associated joint swelling or synovitis on clinical examination. The patient denied smoking history, personal or family history of rheumatic disease. Radiographic images of the hands showed mild multifocal degenerative changes without erosions or inflammatory changes. Radiographic images of the knees showed mild tricompartmental joint space narrowing without erosions. Initial laboratory analysis revealed elevated anti-CCP antibody at >250 units (strongly positive range at >59 units). C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF) were all within normal range. Clinical examination and radiographic evidence were suggestive of generalized osteoarthritis without evidence of inflammatory arthritis. Review of systems was otherwise negative. Eighteen months later, the patient was found to have an incidental 2.2 cm irregular nodular density within the right lower lobe on a CT Thorax with contrast. She underwent a right lower lobe wedge resection and pathology of the lung parenchyma showed necrotizing granulomatous inflammation. Acid fast culture and smear was positive for Mycobacterium Avium Complex (MAC). No other organisms were visualized. The patient was successfully treated with six-month course of Ethambutol, Azithromycin, and Moxifloxacin. Clinical examination and radiography during this time remained suggestive of primary osteoarthritis without development of inflammatory arthritis. Discussion To our knowledge, this is the first report of MAC association with a significantly elevated anti-CCP antibody where other lab and clinical findings were unremarkable. ACPAs are found in up to two-thirds of RA patients and are included in the 2010 ACR/EULAR RA classification standard. There are statistically significant correlations seen between anti-CCP positivity, higher CRP, ESR, and disease activity measurements; establishing diagnosis of RA occurs in majority of cases within 2 years after initial anti-CCP elevation. Additionally, cigarette smoking was also associated with a positive anti-CCP test and increased disease activity. Over the course of 4 years, our patient continued to show signs and symptoms suggestive of primary osteoarthritis without development of inflammatory arthritis based on radiography and clinical examination. Anti-CCP antibodies have been found in other autoimmune and infectious disease processes such as hepatitis C, psoriasis, and TB. Anti-CCP was found in 37% of TB patients and in 43% of RA patients in Japan. Interestingly, many anti-CCP-positive TB sera also reacted with Arginine containing peptide (CAP), and anti-CCP: anti-CAP ratios in TB sera were low, which is a significant difference from the RA sera findings. Anti-unmodified arginine-containing peptide (anti-CAP) levels were higher in patients with active TB infections compared to RA patients. Thus, Anti-CCP/anti-CAP ratio could be used for differentiating TB arthritis from RA. It is important to note that ACPAs have been shown to participate in bone destruction directly or indirectly and accumulated citrullinated proteins trigger production of ACPAs; there are various types of ACPAs depending on different antigens and antibody isotypes. Over 100 potential autoantigens in RA have been studied, and it was suggested that the pattern of autoantibody recognition may form a basis for subgrouping anti-CCP-positive RA patients and anti-CCP-negative patients that rightfully should be considered ACPA-positive. Conclusion Additional studies are warranted to explore types of ACPAs, antigen arrays, compare reactivity patterns with clinical phenotypes, optimize anti-CCP antibody testing to better diagnose patients, and to tailor future treatment strategies.