ANSWERS
CASE 14: STIFF AND PAINFUL HANDS
A 28-year-old legal assistant presents to her GP after being bothered by stiffness in the joints of both of her hands for the past few weeks. The stiffness is most prominent on awakening and lasts approximately an hour before getting better through the day. She denies any other musculoskeletal problems or any other joints being affected. Her only medical history is mild asthma. Her family history is positive for type 1 diabetes in her brother.
Examination
Physical examination reveals a well-looking, slim woman. Her metacarpophalangeal joints are slightly swollen bilaterally and mildly tender, and there is some pain on palpation over a few of the interphalangeal joints in both hands. Metacarpal squeeze test is positive bilaterally.
QUESTIONS
1. Based on the history and examination findings, suggest a differential diagnosis.
Which diagnosis is most likely and why?
2. What further investigations are required, and which tests are most predictive for the likely diagnosis?
3. Summarise the pathophysiology of the underlying diagnosis. What extra- articular complications may arise with this condition?
DOI: 10.1201/9781003242697-15 37
100 Cases in Clinical Pathology and Laboratory Medicine 38
ANSWERS
The clinical picture in this case is very suggestive of an inflammatory arthropathy with the findings of joint swelling, morning stiffness and evidence of synovitis. The key differential diagnoses therefore include:
• Rheumatoid arthritis (RA)
• Seronegative spondyloarthropathies (e.g., psoriatic arthritis, arthritis associated with inflammatory bowel disease)
• Post-viral or post-infectious arthropathy
• Connective tissue diseases (such as lupus and scleroderma)
• Crystal arthropathy (gout and pseudogout)
• Degenerative joint disease (osteoarthritis)
The most likely diagnosis is RA, which is the most common inflammatory arthropathy and typically affects adults between the ages of 30 and 50. This is because the history of bilateral joint problems, mainly in the small joints of the hand, as well as morning stiffness lasting longer than 1 hour, is very suggestive of an inflammatory rather than a degenerative process (in the latter, symptoms tend to get worse throughout the day, and stiffness generally lasts less than an hour). Similarly, the absence of any background medical history or other symptoms makes seronegative arthritis, post-viral arthritis and connective tissue disease unlikely.
The diagnosis of RA requires the following, based on American College of Rheumatology/
European Alliance of Associations for Rheumatology (ACR/EULAR) criteria:
• Inflammatory arthritis involving three or more joint areas
• Seropositivity for rheumatoid factor or anti–citrullinated protein (CCP)
• Elevated levels of inflammatory markers (ESR or CRP)
• Exclusion of other diseases such as crystal arthropathy, post-viral arthropathy, pso
riatic arthritis and lupus
• Duration of symptoms lasting >6 weeks
This patient meets three of these criteria from history and examination alone, and refer
ral to a rheumatology specialist would be warranted. Further investigations would include basic blood tests (full blood count—possible anaemia of chronic disease, renal and hepatic function—which may guide medication choice) and tests of inflammatory activity. The lat
ter include CRP and ESR along with more specific tests for RA, namely rheumatoid factor (RF) and anti-CCP antibodies. Anti-CCP has a similar sensitivity (65–85%) but much higher specificity (>95% vs. 80%) for RA in patients with suspected rheumatic disease than RF, and anti-CCP positivity is also associated with a more severe clinical course. Radiographs of the hand would also be useful to look for evidence of joint damage.
The pathophysiology of RA is incompletely understood, and the cause remains unknown.
It is an autoimmune disease triggered by the exposure of a genetically susceptible individ
ual to an as-yet unidentified antigen. Interplay of genetic (e.g., human leukocyte antigen [HLA]-DR4 allele) and environmental (e.g., smoking, infection) factors lead to altered post- transcriptional regulation of proteins and citrullination of self-proteins. Loss of tolerance to these new epitopes leads to the formation of autoantibodies (e.g., anti-CCP) and the stimula
tion of B-cell and CD4 T-cell responses, which act against unknown target antigens in joints and mediate joint injury via production of inflammatory cytokines such as tumour necrosis factor alpha (TNF-α) and interleukin (IL)-1. These stimulate proliferation of synovial cells and the production of matrix metalloproteinases, which assist in the destruction of articular cartilage, and the inflammatory-rich hyperplastic synovium adheres to and grows over the articular surfaces, forming pannus.
Case 14: Stiff and Painful Hands 39
RA is also associated with an increased risk of cardiovascular disease, resulting from endo
thelial activation by inflammatory cytokines. This generalised inflammatory response may also account for the other systemic manifestations of RA, involving the lungs (fibrosis), bones (osteoporosis) and brain (reduced cognition), as well as a higher risk of lymphoma.
KEY POINTS
• Morning stiffness is a common rheumatologic symptom, and the key to distin
guishing whether it is inflammatory or degenerative in origin is seeing whether it gets better or worse through the day.
• RA typically affects the small joints of the hands bilaterally and is associated with positivity for anti-CCP antibodies.
• It is believed to arise from the immune system reacting against as-yet unidenti
fied antigens, provoking the formation of an inflammatory pannus over articular surfaces.