You see a 29-year-old female business executive with complaints of joint pains and stiffness affecting both hands and wrists, both feet and her left knee. She has reported these symptoms for the past 3 weeks. According to the patient her symptoms are worse when she first gets up in the morning and it takes a few hours before her joints seem to loosen up. She notes over the past week she has experienced difficulty opening jars and holding a toothbrush. Her medical history is otherwise unremarkable. What pertinent findings should be sought on physical examination?
The most important aspect of this initial visit is to determine if she has an inflammatory arthritis. Her history indicates morning stiffness lasting several hours and pain in multiple joints that limits her ability to perform simple activities of daily living with her hands.
The physical examination should document whether she truly has synovitis (synovial inflammation -tenderness, swelling, warmth, possibly redness, and restricted range of motion) and therefore an inflammatory arthritis or just tenderness in the joints without physical evidence of joint inflammation.
When synovitis is documented we think of rheumatoid arthritis (RA) as the principal diagnosis, but other diseases such as viral arthritis, psoriatic arthritis, polyarticular gout, systemic lupus erythematosus (SLE) and other connective tissue diseases may present in the same way.
The presence of arthralgia alone, with or without joint tenderness, but no other signs of joint inflammation broadens the differential to include non-inflammatory conditions such as fibromyalgia, joint hypermobility syndrome, and viral arthralgia without arthritis. In the absence of synovitis we cannot make a definitive diagnosis of RA. Physical examination shows warmth and swelling over her wrists, left knee, and the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of her hands with a positive “squeeze” test of the MCP and metatarsophalangeal (MTP) joints. What is the differential diagnosis at this point?
We have now documented the presence of synovitis and are therefore dealing with an inflammatory arthritis. The most likely diagnosis is “early RA” (RA of disease-onset under 2 years). The features in favor of this diagnosis are the prolonged morning stiffness and the presence of synovitis in the wrists, MCP and PIP joints, left knee and the MTP joints.
A positive “squeeze” test of the MCP and MTP joints is a useful screen for early RA as synovitis causes the joint capsules to swell and squeezing these inflamed joints together provokes pain as the positive response. These are the joints most commonly affected in early RA.
We recommend evaluating a patient for early RA if she has morning stiffness lasting longer than 30 minutes, 3 or more swollen joints, and the presence of MCP or MTP joint involvement. I would not venture to definitively diagnose RA at this visit since she has only a 3-week history of joint symptoms. Ideally we like the duration of symptoms to be 6 weeks or longer for a firm diagnosis of RA since most viral arthritis would have resolved by 6 weeks.
It is important to ask the patient about fatigue, fever, weakness, weight loss, malaise and flu-like symptoms. If these are prominent, we worry about severe RA with systemic features, viral arthritis, prodromal hepatitis, SLE and other connective tissue diseases such as polymyositis and a paraneoplastic syndrome.
A history of hair loss, photosensitivity, malar rash, oral ulcers and pleuropericardial symptoms suggest SLE. Prominent GI symptoms suggest an inflammatory arthritis associated with inflammatory bowel disease. A history or physical evidence of psoriasis suggests psoriatic arthritis (PsA.) Unlike RA, PsA is often asymmetric in joint distribution and may affect the axial joints manifesting as neck, thoracic, lumbar or sacroiliac pain.
Inflammatory back pain is typically made worse by bed-rest and inactivity and causes early morning awakening such that the patient cannot sleep comfortably through the night. Prominent back symptoms in a patient with an inflammatory arthritis will point away from the diagnosis of RA. The presence of a swollen finger or toe (dactylitis) suggests PsA rather than RA. Our patient has a relatively symmetric arthritis and the absence of signs or history of psoriasis.
A recent history of urethritis may suggest gonococcal arthritis or a reactive arthritis in response to chlamydia infection. Patients with reactive arthritis typically have only a single affected joint such as the knee and rarely present in this fashion. Patients living in endemic regions of Lyme disease should be questioned about an antecedent history of erythema migrans but Lyme disease rarely affect the small joints of the hands and feet. What would be the initial laboratory work-up?
I typically would order a complete blood count (CBC), comprehensive metabolic panel, ESR, CRP, CK and urinalysis. Since her presentation is classic for early RA I would also obtain a rheumatoid factor and an anti-cyclic citrullinated peptide (anti-CCP) antibody. In anticipation of using methotrexate (MTX) I might also order hepatitis B and C panels to screen for prior exposure. How would you initially manage the patient’s symptoms?
Although RA is the most likely diagnosis it is still possible that she has a self-limiting viral arthritis since her symptoms are present for only 3 weeks. I would initially treat her with an NSAID at the anti-inflammatory dosage and might give her a short tapering course of prednisone over a week starting at 20 mg daily. I would plan to see her in 3 weeks. When would you begin a rheumatic disease work-up, and what tests would you order?
I have already ordered RF and anti-CCP with the first visit. If the CBC, comprehensive metabolic panel and urinalysis show significant abnormality such as leukopenia, lymphopenia, severe anemia, thrombocytopenia, raised BUN or creatinine and reduced eGFR, active urinary sediment or proteinuria then I would worry about SLE and order an ANA screen.
If positive, I would then order an ANA panel consisting of anti-DNA, anti-Sm, anti-RNP, anti-SSA and anti-SSB and serum C3 and C4. If CK is elevated I typically repeat it and order aldolase to confirm an inflammatory myopathy. Either or both ESR and CRP should be elevated in this patient to support systemic inflammation and the diagnosis of RA. The patient’s RF titer is 1:1280 and her anti-CCP titer is strongly positive as well. What are the clinical implications of these findings?
RF is positive in 70 to 80% of patients with RA but it may be a late marker and may only show positive after 12 to 18 months into the course of the disease. If positive in the setting of an inflammatory arthritis, it confirms the diagnosis of RA. It is a poor screening test since it is positive in 5% of healthy people and may be seen in 10% of the elderly population. If the initial RF is negative but I am sure this is RA I may repeat the test periodically in the next 12-18 months since it may turn positive later. A positive RF confers increased risk for a more aggressive, deforming arthritis and a higher risk for disease involvement in other organs such as pericarditis.
Anti-CCP (anti-cyclic citrullinated peptide) is seen in about the same percentage of patients with RA as the RF but it is a more specific marker since it is not seen in arthritis caused by other diseases (such as hepatitis C-induced arthritis which is typically RF positive but anti-CCP negative, especially in the setting of cryoglobulinemia.) If positive at high titer it implies a more aggressive form of RA with rapid progression to joint damage, deformity and disability within 5-10 years.
While there is considerable overlap of the two antibodies in RA patients, with some showing both positive RF and anti-CCP, it is worthwhile ordering both antibodies in evaluating RA patients since some will only be positive with one but not the other antibody.
Patients with both positive RF and anti-CCP (double positives) are prone to develop the most severe and destructive arthritis and need to be aggressively treated with a DMARD (disease-modifying antirheumatic drug) right from the beginning.