60-year-old male with discoloration of fingers and pain in the left hand and both KNEES – 18/05/2022

The elderly male patient had Raynaud's phenomenon with persisting cyanosis on both sides of the fingers for the past 6 months. History also revealed dry skin, mild breathlessness on exertion especially on climbing stairs, episodes of headache, reduced appetite, and sleep disturbance. In addition, he had knee pain with backache persisting for the past 2 years and recurrent oral ulcers for the past 20 years. No additional co-morbidity like hypertension, diabetes, or IHD was reported.

Based on these presentations, the probable clinical diagnosis could be primary Raynaud's phenomenon, secondary Raynaud's due to connective tissue disease, vascular insufficiency, or hyperviscosity syndromes.

Differentiating between primary and secondary Raynaud's

The onset of primary Raynaud's is more common in younger patients. The primary and secondary Raynaud's can be differentiated using the following criteria:

Criteria for diagnosing primary Raynaud's phenomenon¹

1. Vasospastic attacks precipitated by cold or emotional stress
2. Symmetric attacks involving both hands
3. Absence of tissue necrosis or gangrene
4. No history or physical findings suggestive of a secondary cause
5. Normal nail-fold capillaries
6. Normal erythrocyte sedimentation rate
7. Negative serologic findings, a particularly negative tests for antinuclear antibodies

In the present case, the patient had episodes of cyanosis precipitated by cold and stress, symmetrical and minimal arthralgia/arthritis suggestive of osteoarthritis, and degenerative spine disease. There were no ischemic changes and no history or physical examination consistent with definitive evidence of connective tissue disease (CTD). No nail-fold capillaries or elevated ESR was reported. ANA profile was positive for SSA and it was borderline (1+ is not definitive proof). It is recommended to conduct an extensively work-up for secondary causes if Raynaud develops after the age of 30 years.

However, a meta-analysis has reported that the positive predictive value of ANA in indicating a secondary CTD for Raynaud's phenomenon is only 30%.² The predictable association is much stronger with the presence of subtypes like SCL-70, centromere, and Ro-52.^3,4 Given positive ANA, it is significant to consider the possibility of CTD In the present case. However, the joints involved were both knees and the X-ray indicates the occurrence of osteoarthritis with no other associated features of CTD. Since SSA is 1+ positive, the possibility of CTD can be considered.

The other probable diagnosis could be hyper-viscosity syndrome. A careful evaluation of the patient history and current hemogram indicate the occurrence of persistently elevated platelets. Elevated platelets can be considered as a part of inflammatory response or essential thrombocytopenia. Inflammatory parameters like CRP and ESR were normal. The total WBC count and hemoglobin were normal. These clinical findings indicate the possibility of essential thrombocythemia. The following criteria are recommended for confirming the diagnosis.⁵

Diagnostic criteria for essential thrombocythemia (Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Medicine), Revised Edition, 2017): requires either all major criteria or the first 3 major criteria plus the minor criterion

Major

• Criterion #1: sustained platelet count ≥ 450 x 10⁹ / L
• Criterion #2: megakaryocyte proliferation, large and mature with hyperlobulated nuclei (atypical), no or little granulocyte or erythroid proliferation; very rarely a minor (grade P) increases in reticulin fibers
• Criterion #3: does not meet WHO criteria for chronic myeloid leukemia, polycythemia vera, primary myelofibrosis, myelodysplastic syndrome, or other myeloid neoplasms
• Criterion #4: demonstration of JAK2 V617F or CALR or MPL mutation

Minor

• Presence of a clonal marker
• Absence of evidence of reactive thrombocytosis

Final diagnosis

Further evaluation by a hematologist, based on the beforementioned criteria, has confirmed the diagnosis as essential thrombocythemia. The patient was treated with an anti-platelet drug and pentoxyphyllin medicine. Anti-osteoarthritis drug was given to improve the joint pain. The presence of ANA needs to be monitored, which could be due to possible naturally occurring antibodies or myeloproliferative diseases.

References

1. LeRoy EC, Medsger TA Jr. Raynaud's phenomenon: a proposal for classification. Clin Exp Rheumatol 1992;10:485-8.
2. Spencer-Green G. Outcomes in primary Raynaud phenomenon: a meta-analysis of the frequency, rates, and predictors of transition to secondary disease. Arch Intern Med 1998;158:595-600.
3. Kallenberg CG. Early detection of connective tissue disease in patients with Raynaud's phenomenon. Rheum Dis Clin North Am 1990;16:11-30.
4. Kallenberg CG, Wouda AA, Hoet MH, van Venrooij WJ. Development of connective tissue disease in patients presenting with Raynaud's phenomenon: a six-year follow up with emphasis on the predictive value of antinuclear antibodies as detected by immunoblotting. Ann Rheum Dis 1988;47:634-41.
5. Bone marrow - neoplastic myeloid, Myeloproliferative neoplasms (MPN), Essential thrombocythemia, https://www.pathologyoutlines.com/topic/myeloproliferativeET.html