What is the best treatment approach for an elderly female patient with a history of three flares of generalized aches and inability to walk, positive Rheumatoid Factor (RF) at 16, negative Cyclic Citrullinated Peptide (CCP), elevated C-Reactive Protein (CRP) at 3.28, and no joint swelling?

Treatment Approach for Seronegative Inflammatory Arthritis with Recurrent Flares

This patient requires immediate initiation of methotrexate 15-25 mg weekly combined with a short course of prednisone to control her recurrent inflammatory flares and prevent progressive disability. 1

Diagnostic Clarification

This presentation does not meet criteria for definite rheumatoid arthritis but represents seronegative inflammatory arthritis requiring aggressive treatment:

• RF of 16 is borderline/low-positive (typically significant when >40-60 IU/mL depending on lab), and negative anti-CCP antibodies argue against classic seropositive RA 1, 2
• CRP of 3.28 mg/dL is significantly elevated (normal <0.5 mg/dL), confirming active systemic inflammation 1, 3
• Three flares with generalized aches and inability to walk represent severe functional impairment requiring immediate intervention to prevent permanent disability 1
• Absence of joint swelling does not exclude inflammatory arthritis—elderly patients may have less obvious synovitis, and generalized inflammatory myalgias can occur in seronegative disease 1

Immediate Treatment Algorithm

Step 1: Initiate Prednisone for Rapid Symptom Control

• Start prednisone 10-20 mg daily immediately to achieve rapid control of systemic inflammation and restore mobility 4
• Prednisone provides defervescence and symptom control within 2-5 days in patients with active systemic features 4
• This is bridging therapy only—the goal is to taper and discontinue once DMARD therapy takes effect 1, 5

Step 2: Start Methotrexate Concurrently

• Initiate methotrexate 15 mg weekly (oral or subcutaneous) as soon as prednisone is started 1
• Do not wait for prednisone to work—methotrexate takes 6-12 weeks for full effect, so early initiation is critical 1
• Aggressive early management improves patient functioning, quality of life, and survival even in seronegative disease 1
• Subcutaneous administration may be considered if oral bioavailability is questioned 1, 6

Step 3: Monitoring and Dose Escalation

• Reassess at 6-8 weeks: if minimal response, escalate methotrexate to 20-25 mg weekly 1
• Formal assessment at 3 months using composite disease activity measures (SDAI or CDAI preferred over DAS28 as they are more stringent) 1
• Target low disease activity (SDAI ≤11 or CDAI ≤10) or remission (SDAI ≤3.3 or CDAI ≤2.8) by 6-12 months 1

Step 4: Treatment Intensification if Inadequate Response at 6-12 Months

If disease activity remains moderate-high (SDAI >11 or CDAI >10) despite optimized methotrexate:

• Add sulfasalazine 2 g daily + hydroxychloroquine 400 mg daily for triple-DMARD therapy 1
• Alternatively, add a TNF inhibitor or abatacept if triple-DMARD therapy fails or is not tolerated 1
• In seronegative patients with inadequate anti-TNF response, prefer abatacept or tocilizumab over rituximab (rituximab works best in RF/anti-CCP positive patients) 1

Step 5: Prednisone Taper

• Begin tapering prednisone once methotrexate shows clinical effect (typically 6-12 weeks) 1, 5
• Taper by 2.5 mg every 2-4 weeks as tolerated 5
• Goal is complete discontinuation to minimize long-term glucocorticoid toxicity (osteoporosis, cardiovascular disease, infections) 1, 4

Critical Pitfalls to Avoid

• Do not use NSAIDs alone or delay DMARD therapy—this patient has had three flares with severe functional impairment requiring aggressive disease-modifying treatment 4
• Do not withhold methotrexate because anti-CCP is negative—seronegative inflammatory arthritis still causes progressive disability and requires the same aggressive approach 1
• Do not continue prednisone long-term without concurrent DMARD therapy—this leads to glucocorticoid toxicity without addressing underlying disease 1, 5
• Do not assume absence of joint swelling means mild disease—inability to walk represents severe functional impairment requiring immediate intervention 1
• Monitor for methotrexate toxicity: obtain baseline CBC, hepatic panel, creatinine; repeat every 4-8 weeks initially 6
• Elderly patients require closer monitoring for hepatic, bone marrow, and renal toxicity with methotrexate 6

Additional Considerations

• Folate supplementation 1 mg daily reduces methotrexate toxicity without compromising efficacy 6
• Consider alternative diagnoses if no response to appropriate therapy: polymyalgia rheumatica (though typically responds dramatically to low-dose prednisone alone), crystal arthropathy, or paraneoplastic syndrome 4
• Assess for comorbidities: screen for hepatitis B/C before starting immunosuppression, ensure age-appropriate cancer screening, assess cardiovascular risk 6