Three cases of rheumatoid arthritis (RA), presenting with refractory
anaemia, thrombocytopenia and peripheral lymphocytosis respectively,
were observed. In all the cases haematological manifestations were
unrelated to disease activity or drug toxicity. These patients were
detected to have pure red cell aplasia (PRCA) (normocytic normochromic
anaemia, reticulocytopenia and absence of erythroid precursors in the
bone marrow), immune thrombocytopenia (IT) (absence of splenomegaly and
presence of increased megakaryocytes in the bone marrow) and multiple
myeloma (MM) (lytic lesions on skull, paraproteinaemia and bone marrow
plasmacytosis) respectively. PRCA and IT responded to glucocorticoids.
Association with these three haematological alterations has rarely been
reported. Our report highlights the need to regularly monitor blood
counts in patients with RA

Agarwal V, Sachdev A, Lehl S, Basu S

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60 J Postgrad Med March 2004 Vol 50 Issue 160 CMYKUnusual haematological alterations in rheumatoidarthritisAgarwal V, Sachdev A, Lehl S, Basu S*Department of Medicine,*Haematology andTransfusion Medicine,Government MedicalCollege & Hospital, Sector32, Chandigarh, IndiaCorrespondence:Vikas Agarwal, MDC1221, Sector 32B,Chandigarh - 160030, IndiaE-mail: vikasagr@yahoo.comABSTRACTThree cases of rheumatoid arthritis (RA), presenting with refractory anaemia, thrombocytopenia and peripherallymphocytosis respectively, were observed. In all the cases haematological manifestations were unrelatedto disease activity or drug toxicity. These patients were detected to have pure red cell aplasia (PRCA)(normocytic normochromic anaemia, reticulocytopenia and absence of erythroid precursors in the bonemarrow), immune thrombocytopenia (IT) (absence of splenomegaly and presence of increased megakaryocytesin the bone marrow) and multiple myeloma (MM) (lytic lesions on skull, paraproteinaemia and bone marrowplasmacytosis) respectively. PRCA and IT responded to glucocorticoids. Association with these threehaematological alterations has rarely been reported. Our report highlights the need to regularly monitorblood counts in patients with RA.KEY WORDS: Pure red cell aplasia, immune thrombocytopenia, multiple myeloma, refractory anaemia,lymphocytosisatients with rheumatoid arthritis (RA) may presentwith haematological abnormalities either at the timeof diagnosis, or during the course of their illness. Anaemia,thrombocytosis and eosinophilia are observed commonlywhereas neutropenia, thrombocytopenia, large granular lym-phocytosis (LGL) and malignancies are uncommon.1 We de-scribe three rare haematological disorders, namely pure red cellaplasia (PRCA), immune thrombocytopenia (IT) and multi-ple myeloma (MM).Case HistoriesCase 1A 48-year-old female presented with anaemia of 3 months duration.She had seropositive RA for 6 years and was receiving sulfasalazine(SSZ, 1 gram) and indomethacin (100 mg) daily for 12 months. Dur-ing this period her haemoglobin (Hb), total (TLC) and differentialleucocyte counts (DLC) and platelet counts, done 3 monthly, re-mained normal. Examination confirmed severe anaemia, basalcrepitations, hepatomegaly and tender joint count (TJC) of 14 with-out any swollen or deformed joints. The rest of the examination wasunremarkable. Investigations revealed Hb 3.6 gm/dl, normochromicred blood cells, corrected reticulocyte count 0.3%, and erythrocytesedimentation rate (ESR) 80 mm. Haemogram, liver and renal func-tion tests, Coombs test, serology for antinuclear antibody (ANA),HIV-1 and HIV-2, X-ray chest and urinalysis were normal. Stool foroccult blood was negative. X-ray hands showed juxta-articularosteopenia (JAO). SSZ was discontinued and three units of packedred blood cells were transfused. She remained transfusion-depend-ent despite treatment with oral iron, folic acid and parenteral vita-min B12. Bone marrow (BM) examination 3 months later, revealedwww.jpgmonline.comReceived : 05-12-03Review completed : 16-12-03Accepted : 25-12-03PubMed ID : 15048003J Postgrad Med 2004;50:60-61absence of erythroid precursors without other abnormalities, con-firming the diagnosis of pure red cell aplasia (PRCA). Anaemia im-proved with prednisolone (1 mg/kg/day).Case 2A 52-year-old male presented with symmetric, inflammatory polyar-thritis of 3 months duration. The patient was Steinbroker functionalClass III (activities restricted, required assistance) and had early morn-ing stiffness (EMS) of >6 hours. There was no history to suggestSjogren’s syndrome, systemic lupus erythematosus or inflammatorymyositis. Examination revealed TJC of 18, swollen joint count of 10and left-sided carpal tunnel syndrome. The rest of the examinationwas unremarkable. Investigations revealed ESR 40 mm and plateletcount 47,000/µl. Haemogram, renal and liver function tests, serum vi-tamin B12 and folate levels and urinalysis were normal. Rheumatoidfactor (RF) was positive. X-ray hands showed soft tissue swelling andJAO at metacarpo-phalangeal (MCP) and proximal-interphalangeal(PIP) joints. Ultrasonogram of the abdomen was normal. Serology forANA, anticardiolipin, lupus anticoagulant, anti Ro and HIV-1 and HIV-2 was negative. BM examination revealed increased megakaryocytes.Platelet count normalized with prednisolone (1 mg/kg/day).Case 3A 65-year-old female presented with deforming RA of 40 years dura-tion. She received glucocorticoids for the entire period and denieduse of disease-modifying anti-rheumatic drug (DMARD) ever. Ex-amination showed deformities of hands and fingers with restrictedmovements at wrists, knees and elbows. The spine was diffusely ten-der. The rest of the examination was unremarkable. Investigationsrevealed TLC 13,900, lymphocytes 66%, ESR 50 mm and Hb 8.4 gm/dl. Urinalysis, renal and liver function tests, serum calcium, phos-phorus, protein and albumin were normal. Test for RF was negative.PCase Report61J Postgrad Med March 2004 Vol 50 Issue 1 CMYK 61ANA was positive (2+, diffuse at 1: 40). Serum immunoglobulin,IgG, IgM and IgA were 308 mg/dl (normal 800-1500), 30 mg/dl (nor-mal 45-150) and 795 mg/dl (normal 90-325) respectively.Radiologically, there were erosions and deformities of the hands andknees, atlanto-axial subluxation, generalized osteopenia and lytic le-sions in the skull. Immunoelectrophoresis of serum revealed IgA-λmonoclonal protein. Trephine biopsy of the BM showed 18% plasmacells with increased lymphocytes. She is presently receiving melphalanand prednisolone.DiscussionAll the three patients fulfilled the Americal College of Rheu-matologist 1987 criteria for the diagnosis of RA.1Case 1 highlights a distinctly rare cause of anaemia i.e. PRCA.2Drugs (fenoprofen, D-penicillamine, azathioprine, indometh-acin and SSZ),3,4 Parvovirus B19 infection or RA are known tocause PRCA.5 The possibility of Parvovirus B19-induced PRCAwas however less likely in our patient as she was immunocom-petent. Yet, in the absence of serological workup it cannot beexcluded. Insidious onset of anaemia following 1 year of therapywith SSZ and indomethacin, which did not remit after with-drawal of the drugs, favours PRCA due to RA in our patient.3PRCA may represent an extra-articular manifestation of RA.5PRCA occurs due to maturation arrest of erythroid precursorsby IgG inhibitor,3 natural killer cell or CD 4+ T-cell dysfunc-tion,5 or due to lyses of precursors by LGL.6 Expansion of LGLhas been reported in RA. 1 Glucocorticoids, cytotoxic agentsand immunosuppressive drugs have been tried in the manage-ment of PRCA with variable success.3Immune thrombocytopenia in RA is extremely unusual as ex-emplified by Case 2. He had IT at the onset of RA, which is incontrast to earlier reports.7,8 There are studies in favour,8 andagainst,7 the association between IT and disease activity in RA.Both the diseases share a common immunological profile.7,9The use of non-steroidal anti-inflammatory drugs andDMARDs carry the risk of worsening of thrombocytopenia andbleeding. However, IT in RA is responsive to glucocorticoids,immunosuppressive agents or danazol.7,8There is an increased risk of malignancy (Hodgkin’s disease,non-Hodgkin lymphoma, leukaemia and MM) in RA independ-ent of immunosuppressive therapy.1,10 As in Case 3, IgA-λ lightchain MM is reported more frequently,11 however, MM of otherimmunoglobulin isotypes may occur.12  Increased exposure toradiation may predispose to MM.10Haematological manifestations in RA can be broadly catego-rized into areas of; anaemia, neutropenia, thrombocytopenia,thrombocytosis, eosinophilia, and haematological malignan-cies.13  Anaemia in RA is multifactorial— disease activity, drug-induced, nutritional, gastrointestinal bleed, BM suppression,and ineffective erythropoesis.1 Autoimmune haemolytic anae-mia and PRCA are rare. Neutropenia is generally drug-inducedor due to Felty ’s or T-cell LGL syndrome.13 Thrombocytope-nia in RA is usually drug-induced or due to Felty’s syndrome.1IT is extremely rare.13 Thrombocytosis is related to disease ac-tivity. Eosinophilia in RA reflects active disease or hypersensi-tivity to drugs. Patients with RA and secondary Sjogren’s syn-drome may be predisposed to developing MALT lymphoma. 13Since all the haematological alterations discussed above arerare associations with RA, a possibility of chance phenomenoncannot be discounted.References1. Harris ED. Clinical features of rheumatoid arthritis. In: Kelley WN, Ruddy S, HarisED, Sledge CB, eds. Textbook of Rheumatology. Philadelphia: WB . Saunders Com-pany; 1998. p. 898-932.2. Baer AN, Dessypris EN, Krantz SB. The pathogenesis of anaemia in rheumatoidarthritis: A clinical and laboratory analysis. Semin Arth Rheum 1990;19:209-23.3. Dessypris EN, Baer MR, Sergent JS, Krantz SB. Rheumatoid arthritis and pure redcell aplasia. Ann Intern Med 1984;100:202-6.4. Anttila PM, Valimaki M, Pentikainen PJ. Pure-red-cell aplasia associated withsulphasalazine but not 5-aminosalicylic acid. Lancet 1985;2:1006.5. Tsai CY, Yu CL , Tsai YY, Kung YY, Wu TH, Tsai ST. Pure red cell aplasia in a man withRA. Scand J Rheumatol 1997;26:329-316. Handgretinger R, Geiselhart A, Moris A, Grau R, Teuffel O, Bethge W, et al. Purered-cell aplasia associated with clonal expansion of granular lymphocytes express-ing killer-cell inhibitory receptors. N Engl J Med 1999;340:278-84.7. Ustun C, Kallab A, Loebl D, Jillela A, Majewski B, Mazzella F, et al. Rheumatoidarthritis and immune thrombocytopenia:a report of two cases. Clin Rheumatol2002;21:543-48. Blanco R, Martinez-Taboada VM, R odriguez-Valverde V, Sanchez-Andrade A,Gonzalez-Gay MA. Successful therapy with danazol in refractory autoimmune throm-bocytopenia associated with rheumatic diseases. Br J Rheumatol 1997;36:1095-99. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med2002;346:995-100810. Eriksson M. Rheumatoid arthritis as a risk factor for multiple myeloma:a case-control study. Eur J cancer 1993;29A:259-63.11. Matsumori A, Nishiya K, Chijiwa T, Tahara K, Hosokawa T, Kumon Y, et al. Twocases of rheumatoid arthritis associated with IgA-l type multiple myeloma.Ryumachi 2000;40:26-31 (Abstract)12. Itoh T, Ohmae Y. Rheumatoid arthritis terminating in multiple myeloma. RinshoKetsueki 1994;35:547-51 (Abstract)13. Bowman SJ. Haematological manifestations of rheumatoid arthritis. Scand JRheumatol 2002;31:251-9.Agarwal et al: Rheumatoid Arthritis and haematological abnormalities

Unusual haematological alterations in rheumatoid arthritis

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