Bone Marrow Transplantation (2000)

Bone Marrow Transplantation (2000) 26, 673–675  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Case report First manifestations of seronegative spondylarthropathy following autologous stem cell transplantation in HLA-B27-positive patients

B Koch2, N Kranzho¨fer1, M Pfreundschuh1,2, HW Pees1 and L Tru¨mper1

1Dr Mildred-Scheel Unit for Blood Stem Cell Transplantation and 2Saarland University Rheumatology Center, Department of Internal Medicine I, Saarland University, Homburg, Germany

Summary: usually disappear after recovery and restoration of physical fitness and are therefore probably related to immobilization Two male patients with non-Hodgkin’s lymphoma and/or medication such as drugs used in conditioning regi- (NHL, follicular NHL, diffuse large B cell NHL, both mens, steroids or total body irradiation. We describe three in 2nd complete remission) and one female patient with patients who presented with rheumatic symptoms after acute myeloid leukemia in 1st complete remission autologous SCT. These were shown to be primary manifes- developed arthralgias and enthesopathy following auto- tations of an HLA-B27-associated rheumatic disorder. logous stem cell transplantation. In 2/3 patients, sacroiliitis could be demonstrated on X-ray. In both patients, the rheumatic symptoms were classified as manifes- Case reports tations of a spondylarthropathy. All three patients were subsequently shown to be HLA-B27-positive. The During regular follow-up at our transplant unit, arthralgias patients were successfully treated with non-steroidal were observed in 3/140 consecutive patients following anti-inflammatory drugs. The differential diagnosis of autologous PBSCT. All three were shown to be HLA-B27- joint pain following autologous stem cell transplantation positive. Details of the patients are listed in Table 1. 114 should include HLA-B27-associated spondylarthropath- autologous transplant patients and 26 allogeneic transplant ies in addition to the more commonly seen bone and patients were included in this series. 78 were male and 62 joint pain due to immobilization and medication. Bone female. The median age at transplant was 40 years. The list Marrow Transplantation (2000) 26, 673–675. of diagnoses included NHL (n = 59), ALL (n = 6), AML Keywords: autologous stem cell transplantation; HLA- (n = 20), CML (n = 9), MDS (n = 1), HD (n = 20), multiple B27; spondylarthropathy; enthesopathy; non-Hodgkin’s myeloma (n = 8) and solid tumors (n = 17). 105 patients lymphoma; late effects received peripheral blood stem cells and 35 bone marrow as the stem cell source. The data were retrieved from our data base (Stemsoft, Vancouver, BC, Canada). All trans- plants were registered with the EBMT-G. Joint pain is a common finding in patients after bone marrow or stem cell transplantation. Following allogeneic bone marrow (BMT) or blood stem cell transplantation (SCT), Case 1 rheumatic manifestations such as arthralgias and arthritis A 39-year-old male with relapsed follicular NHL achieved have been reported previously. These are thought to be due a 2nd complete remission (CR) following treatment with to avascular necrosis of the bone or are interpreted as an two cycles of the Dexa-BEAM regimen (dexamethasone, early clinical sign of imminent chronic graft-versus-host- carmustine, etoposide, cytosine arabinoside, and 1–3 disease, respectively. During the course of chronic graft- melphalan8) and abdominal bath irradiation with 20 Gy. versus-host disease characteristics similar to several auto- The patient underwent conditioning with the BEAM-regi- immune diseases such as scleroderma, Sjo¨gren’s syndrome, men9 and received 2.5 × 106 CD34-positive cells/kg body 3–6 and polymyositis may be seen. In the follow-up of auto- weight. Hematological recovery was uneventful logous SCT autoimmune events such as thyroiditis, throm- (neutrophils Ͼ1000 on day 12, platelets Ͼ20 000 on day bocytopenic purpura, and hemolytic anemia have been 19). Neutropenic fever and slight pulmonary infiltrates in 7 described, and in the early post-transplant period, joint and the second week after transplant resolved with standard bone pain are relatively common events. However, these broad spectrum antibiotics. Serology for common infections and blood cultures was negative. No other infectious complications occured during the first month. After a period Correspondence: Dr L Tru¨mper, Department of Internal Medicine I, Dr Mildred Scheel Unit for Stem Cell Transplantation, Saarland University, of 3 months, he developed arthralgias in the knee-joints and D–66421 Homburg, Germany wrists and heel pain, and 3 months later low back pain and Received 5 November 1999; accepted 20 May 2000 tenderness of the sacroiliac joints. X-rays revealed minimal Spondylarthropathy in HLA-B27-positive patients B Koch et al 674 Table 1 Characterization of patients with rheumatic symptoms fol- of pain in his heels and in his shoulder joints worsened by lowing autologous stem cell transplantation exercise and receives regular medication with NSAID.

Case 1 2 3 Case 3 Sex Male Male Female A 29-year-old female was diagnosed with acute myeloid Diagnosis NHL, NHL, DLBC AML, FAB follicular M4 leukemia (FAB M4 subtype) in 1984. After induction ther- Source of stem cells Peripheral Peripheral BM apy with HAM she was transplanted in 1st CR after con- Cond/HD-CT BEAM BEAM TBI/Cy ditioning with total body irradiation and cyclophosphamide. Status at SCT Second CR Second CR First CR In 1985 she acquired an infection with Yersinia enterocoli- Age at SCT (years) 40 39 29 Current hematological status Third relapsea CR CR tica proven by stool culture. A few months later, she Onset of rheumatic +3 months +4 months +1 year developed low back pain, arthralgias in the knee-joints, symptoms after SCT ankles, wrists, heel pain and tenderness of the sacroiliac Enteritic infection −−Yersinia joints. Grade III sacroiliitis and a heel spur on the right enterocolitica were demonstrated by X-ray examination 6 years after Arthralgias +++ Joint swelling −−−onset of the rheumatic symptoms. Bone scans with tech- Low back pain +−+netium 99m showed increased uptake in the knee joints, Enthesopathy +++wrists, ankles, and in the right heel. The patient responded X-ray: sacroiliitisb grade II ND grade III to treatment with NSAID. She is in continuous 1st CR of X-ray: heel spur + ND + (right) Bone scan-technetium 99m heels + ND right heel + the hematological disease 15.5 years following SCT. How- HLA-B27 +++ever, she still needs treatment with NSAIDs to relieve Response to NSAID +++her symptoms. Time from SCT (years) 4.5 4 15.5 Current rheumatic symptoms + (+) + Discussion SCT = stem cell transplantation; cond/HD-CT = conditioning/high dose- chemotherapy; BEAM = carmustine, etoposide, cytosine arabinoside, melphalan; TBI/Cy = total body irradiation/high-dose cyclophosphamide; According to the preliminary criteria proposed by the Euro- CR = complete remission; NSAID = non-steroidal antirheumatic drugs; pean Spondylarthropathy Study Group10 the rheumatic ND = not done. symptoms in two of the three patients described here could a At age 43 years. be classified as classical features of a spondylarthropathy. bGrading based on European Spondylarthropathy Study Group preliminary criteria. In the third patient (case 2) the symptoms could be classified as features of an incomplete undifferentiated spondylarthropathy fitting into the ARMOR classification of spon- dylarthropathias.11 In all three patients the rheumatic bilateral grade II sacroiliitis and heel spurs 6 months after symptoms evolved in the early post-transplant period. One transplant with bone scintigraphy activity at the heels and of the three patients presented with a pulmonary infiltrate at the wrists. He received non-steroidal-anti-inflammatory during the early post-transplant period (case 1), the second drugs (NSAID). After treatment for 4.5 years he is still patient suffered from an enteritic infection with Yersinia complaining of pain in the knees and heels. A Schober test enterocolitica before the onset of rheumatic symptoms of the lumbar spine revealed a 3 cm increase in distance (case 3), while the third patient did not report any enteritic, after maximal forward bending, and chest expansion was genito-urinary or other infection (case 2). None of the 2 cm compatible with restricted spine flexibility. Continu- patients had experienced symptoms of a rheumatic disease ous treatment with NSAID for symptomatic relief is neces- before the transplant. After autologous PBSCT, develop- sary and recently, treatment with azulfidine had to be ment of a polyarthritis has been described secondary to a started. Four years after PBSCT, the patient’s low grade CMV infection.12 However, in our cases no evidence for NHL relapsed. a CMV infection was found. Whether the immunological changes associated with autologous SCT favor the manifes- Case 2 tation of rheumatic symptoms in HLA-B27-positive individuals is not clear. Since HLA-typing had not been per- A 39-year-old male was diagnosed with relapsed high- formed regularly in our autologous transplant group, the grade non-Hodgkin’s lymphoma (diffuse large B cell lym- incidence of rheumatic symptoms in HLA-B27-positive phoma of the mediastinum according to the REAL patients cannot be judged with certainty. In our patient classification) in 1995. After treatment with two cycles of group, the prevalence of HLA-B27-associated rheumatic Dexa-BEAM, he achieved a 2nd CR and was subsequently disease was 2.1%, which is similar to the 1.9% incidence transplanted with 2.1 × 106 CD34 positive cells/kg body calculated for a German population.13 An increased preva- weight after BEAM conditioning. Four months after SCT, lence of spondylarthropathies could not be detected in our he complained of arthralgias in both knee joints, and post-transplant group. However, it is remarkable that the shoulder joints, and heel pain. With symptomatic treatment, first manifestations of rheumatic disease started in the post- all his symptoms disappeared after a few weeks. After an transplant period. To address the question of whether auto- observation period of 4 years he is in continuous CR from logous transplantation leads to an increased risk for primary the hematological disease. However, he is still complaining manifestations of rheumatic diseases in HLA-B27-positive

Bone Marrow Transplantation Spondylarthropathy in HLA-B27-positive patients B Koch et al 675 patients, one would have to perform pre-transplant HLA- 2 Wagener P, Schulte D, Link H et al. Musculoskeletal manifes- typing in a larger cohort of patients undergoing autologous tations in patients after bone marrow transplantation. Initial PBSCT. A review of data available in the EBMT data base clinical rheumatologic observations. Z Rheumatol 1991; 50: is planned. 199–203. Immunosuppression following autologous transplan- 3 Socie´ G, Selimi F, Sedel L et al. Avascular necrosis of bone after allogeneic bone marrow transplantation: clinical findings, tation is a well-known phenomenon. Following autologous incidence and risk factors. Br J Haematol 1994; 86: 624–628. transplantation, the regeneration of the CD4+ subset is + 4 Sherer Y, Shoenfeld Y. Autoimmune diseases and auto- markedly delayed and the absolute number of the CD4 immunity post-bone marrow transplantation. Bone Marrow cells may be reduced for a period of up to several months.14 Transplant 1998; 22: 873–881. In the case of HLA-B27-associated rheumatic disease, par- 5 Shulman HM, Sullivan KM, Weiden PL et al. Chronic graft- ticipation of T cells in transferring the rheumatic disease versus-host syndrome in man. A long-term clinicopathologic has been demonstrated. In animal experiments it could be study of 20 Seattle patients. Am J Med 1980; 69: 204–217. shown that CD4+ cells particularly are highly efficient in 6 Tse S, Saunders EF, Silverman E et al. Myasthenia gravis and transfer of the disease.15 It is tempting to speculate that the polymyositis as manifestations of chronic graft-versus-host transient immunosuppression following autologous SCT disease. Bone Marrow Transplant 1999; 23: 397–399. 7 Lambertenghi-Deliliers GL, Annaloro C, Della-Volpe A et al. and bacteremias and/or infections in the immediate post- Multiple autoimmune bone marrow transplantation. Bone transplant period may trigger the initiation of rheumatic dis- Marrow Transplant 1997; 19: 745–747. eases in susceptible patients. The disease may become 8 Pfreundschuh MG, Rueffer U, Lathan B et al. Dexa-BEAM manifest once T cell numbers and function have returned in patients with Hodgkin’s disease refractory to multidrug to pre-transplant levels, usually 3 to 6 months after the chemotherapy regimens: a trial of the German Hodgkin’s Dis- transplant. It is at present unclear whether reconstitution ease Study Group. J Clin Oncol 1994; 12: 580–586. above a certain threshold of CD4+ cells is necessary to 9 Mills W, Chopra R, McMillan A et al. BEAM chemotherapy favor initiation of the rheumatic process. A wide range of and autologous bone marrow transplantation for patients with infections especially with intracellular bacteria have been relapsed or refractory non-Hodgkin’s lymphoma. J Clin Oncol shown to be involved in the pathogenesis of spondylarthro- 1995; 13: 588–595. 16 10 Dougados M, van der Linden S, Juhlin R et al. The European pathies and reactive arthritis. One of our cases suffered Spondylarthropathy Study Group preliminary criteria for the from an infection with Yersinia enterocolitica, which is classification of spondylarthropathy. Arthr Rheum 1991; 34: known to favor the outbreak of rheumatic symptoms in 1218–1227. HLA-B27-positive individuals. In the other patients no 11 Armor B, Dougados M, Mijiyawa M. Crite`res de classification infections known to trigger the development of spondyl- des spondylarthropathies. Rev Rhum Mal Osteoartic 1990; 57: arthropathies could be demonstrated. However, the exact 86–89. source of bacterial or viral infections in the neutropenic 12 Burns LJ, Gingrich RD. Cytomegalovirus infection presenting period cannot always be identified. It is therefore conceiv- as polyarticular arthritis following autologous BMT. Bone able that infections trigger the onset of rheumatic diseases Marrow Transplant 1993; 11: 77–79. after SCT. 13 Braun J, Bollow M, Remlinger G et al. Prevalence of spondylarthropathies in HLA-B27 positive and negative blood donors. The cases presented here demonstrate that in patients Arthr Rheum 1998; 41: 58–67. undergoing autologous SCT for leukemia or lymphoma an 14 Koehne G, Zeller W, Stockschlaeder M, Zander AR. Pheno- arthropathy may arise in the post-transplant period as the type of lymphocyte subsets after autologous peripheral blood first manifestation of seronegative rheumatic disease. The stem cell transplantation. Bone Marrow Transplant 1997; 19: appearance of rheumatic symptoms should make HLA-B27 149–156. assessment mandatory. The differential diagnois of rheu- 15 Breban M, Fernandez-Sueiro JL, Richardson JA et al. T cells, matic symptoms following autologous SCT should there- but not thymic exposure to HLA-B27, are required for the fore include the entity of HLA-B27-associated rheumatic inflammatory disease of HLA-B27 transgenic rats. J Immunol disorders. The prognosis does not seem to differ from 1996; 156: 794–803. patients with de novo HLA-B27-associated spondylarthro- 16 Sieper J, Braun R. Pathogenesis of spondylarthropathies. Arthr Rheum 1995; 38: 1547–1554. pathies. Further studies involving the late effects registries 17 Dougados M, Revel M, Khan MA. Spondylarthropathy treat- of the EBMT or ABMTR should be undertaken. Treatment ment: progress in medical treatment, physical therapy and of these diseases in the post-transplant period should follow rehabilitation. Baillie`res Clin Rheumatol 1998; 12: 717–736. standard guidelines.17

References

1 Naranjo-Hernandez A, Mataix R, Rodriguez-Lozano C. Chronic polyarthritis and graft-versus-host disease. Br J Rheu- matol 1996; 35: 297–298.

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