Seronegative inflammatory arthritis in the myelodysplastic syndromes

Seminars in

ARTHRITIS

AND RHEUMATISM

VOL 21, NO 6

Seronegative

JUNE

Inflammatory Arthritis Syndromes

1992

in the Myelodysplastic

By Stephen W. George and Eric D. Newman The myelodysplastic syndromes (MDS) are a group of therapeutically refractory anemias resulting from a clonal stem cell disorder often associated with cytogenetic abnormalities. Immunologic abnormalities and occasionally vasculitis have been reported although no series has characterized an associated arthritis. All cases of MDS diagnosed in 1990 by bone marrow biopsy and followed up at the authors’ institution were reviewed. Df the 28 consecutive patients, 8 had acute seronegative inflammatory arthritis temporally related to the initial discovery of cytopenia. Five patients had a symmetric polyatihritis resolving only with use of steroids or upon evolu-

T

HE MYELODYSPLASTIC syndromes (MDS) are a heterogenous group of poorly understood refractory anemias resulting from a clonal abnormality in the pluripotential stem cell. The French-American-British (FAB) classification subdivides these into five distinct types based on bone marrow morphology.’ The frequently detectible cytogenetic abnormalities confirm the clonal nature of these disorders, and a variable percentage of cases eventually undergo malignant transformation to acute leukemia.2 The onset of the condition is insidious and asymptomatic until gradually progressive cytopenia and cell line dysfunction eventually manifest as fatigue, dyspnea, recurrent infection, and/or bleeding problems. A number of prognostic features have been identified, including FAB classification, number of cytogenetic abnormalities, degree of hypodiploidy, blast count, and degree of hypocellularity.2 Mortality is caused either by complications of chronic cytopenia or by evolution to acute myelogenous leukemia @ML). An increased frequency of immunologic abSeminars in Arthritis andRheumatism,

tion to leukemia, and 3 had episodes of oligoarthritis with systemic features including fever, pleuritis, pericarditis, and hemolytic anemia. Arthrocenteses in 2 cases did not show crystals or infection. Serological studies were nondiagnostic. The arthritis and systemic features responded to steroids in all 5 treated patients. Inflammatory arthritis appears to be common in MDS. Most compelling is the apparent bone marrow response to steroids in 2 cases, possibly identifying a treatable subgroup. Copyright o 1992 by W.B. Saunders Company INDEX WORDS: Myelodysplastic syndrome; thritis; seronegative; anemia; leukemia.

ar-

normalities have been reported in patients with MDS, generally ascribed to immune dysregulation and/or clonal involvement of the lymphocytic cell line.3-5 Reports have also suggested a direct role of autoimmunity in the multistep pathogenesis. In spite of the acceptance of an immune disturbance, few reports describe associated rheumatic conditions and none focus on a related arthritis. Our observation of several patients with MDS whose disorder was heralded by an acute seronegative inflammatory arthritis prompted us to review our hospital’s recent experience with MDS. The following is a summary of 8 such cases of arthritis among 28 From the Department of Rheumatology, Geisinger Medical Center, Danville, PA. Stephen W. George, MD: Fellow; Eric D. Newman, MD, FACP: Associate. Address reprint requests to Eric D. Newman, MD, Department of Rheumatology, Geisinger Medical Center, Danville, PA 17822. Copyright Q I992 by W B. Saunders Company 0049-0172/92/2106-0001$5.00/0

Vol 21, No 6 (June), 1992: pp 345-354

345

GEORGE AND NEWMAN

346

patients with MDS diagnosed in 1990. A review of the world literature follows. MATERIALS

Table 1: Features of 28 MDS Patients With or Without Arthritis

AND METHODS

review of our hospital’s computerized pathology records, all bone marrow biopsies confirming MDS in 1990 were retrieved. Twentyeight consecutive cases of MDS were diagnosed and followed up at our institution between January 1,1990, and December 31,199O. Information was obtained by chart review. In addition, we prospectively followed up cases 1, 3, and 7. A diagnosis of myelodysplasia was based on the FAB morphological classification and categorized as refractory anemia (RAn), RAn with ring sideroblasts (RARS), RAn with excess blasts (RAEB), RAn with excess blasts in transformation (RAEB-T), or chronic myelomonocytic leukemia (CMML). Patients with nutritional deficiencies, cytotoxic chemotherapy within 8 weeks of presentation, or insufficient criteria for a diagnosis of MDS and those not followed serially were not included. Cytogenetic analysis was performed using the G banding technique. Medical records were reviewed for demographics, history (malignancy, chemotherapy, radiation exposure, toxin exposure), presenting features, associated processes, laboratory abnormalities, bone marrow characteristics, and articular features. Articular and hematologic responses to steroids were also reviewed. By

Features

Arthritis

No Arthritis

(Group 1)

(Group 2)

3:5

Male:female

71 t2

Age fvr)”

Of the 28 cases of MDS confirmed in 1990,8 had seronegative inflammatory arthritis, with onset in all occurring within 18 months of the first recognition of significant cytopenia. Table 1 compares MDS cases with associated arthritis (group 1) to th ose without arthritis (group 2). Sixty-two percent of group 1 were women, compared with 20% of group 2. Six patients (30%) in group 2 had a known major risk factor for development of MDS (prior radiation, chemotherapy, and/or lymphoproliferative malignancy) and could be classified as having secondary MDS. No patients in group 1 had these risk factors for MDS, possibly suggesting an alternative pathogenesis. Arthralgias were the presenting complaint at the time of recognition of significant cytopenia in most (62%) of the cases in group 1. In group 2, cytopenias were discov-

16:4 70 t 3

Known risk factors for 0

6

Arthralgias

5 (62)

0

Fatigue Febrile illness

1 (12) I(121

7 (35) 0

Bleeding/ecchymosis

0

3 (15)

Unrelated*

1 (12)

5 (25)

0

5 (25)

MDSt Presenting symptoms*

Asymptomatic Associated processes Acute pleuritis and

2 (25)

0

Hemolytic anemia New onset hypothy-

2 (25)

1 (5)

roidism Inflammatory

2 (25)

1 (5)

pericarditis

bowel

disease

0

1 (5)

Panniculitis Vitiligo

0

1 (5)

f(12)

1 (5)

Leukocytoclastic vasculitis lmmunoglobulin

studies

Normal

0 4

1 (5) 15

2 (50)

g (60)

1 (25)

1 (7)

Monoclonal gammopa-

W Polyclonal gammopa-

1 (25)

3 (20)

0

1 (7)

0

1 (7)

thv

RESULTS

20

8

N

IgA deficiency Panhypogammaglobulinemia Duration of follow-up

ho)

54 * 21

23 rfr 6

NOTE. Data represent n (%) or mean + SEM. *At time of recognitionof cytopenia.

Xoexistent lymphoma (n = 2); thymoma (n = 1); head/neck cancer, S/P 1600 rads (n = 1); cervical cancer, S/P chemotherapy and radiation (n = 1); solvent (Xylol) exposure (n = 1). $Dyspnea due to congestive heart failure (n = 1); abdominal pain due to peptic ulcer disease (n = 2); lymphadenopathy

due

to coexistent lymphoma (n = 2); sequelae of a stroke (n = 1).

ered either incidentally or by symptoms related to their hematologic abnormalities. Aside from synovitis, a number of associated systemic autoimmune features were seen in both groups (Table 1). The onset of these processes either corresponded to the observa-

ARTHRITIS IN THE MYELODYSPLASTIC SYNDROMES

tion of pancytopenia or preceded it by 2 years or less. Overall, 46% had clinically evident immunologic disturbances. Laboratory evaluations were variable. Of 13 patients in whom rheumatoid factor (RF) was assessed, only 1 was positive at 1:lO (a patient in group 2). Of 18 ANA (antinuclear antibody) titers, 5 (3 in group 1,2 in group 2) were positive (all I 1:320), although only 2 remained positive (2 1:40) when repeated. The mean uric acid level in group 1 was 4.9 mg/dL (range, 2.9 to 8.0 mg/dL) compared with 5.6 mg/dL in group 2 (range, 3.0 to 7.8 mg/dL). The mean sedimentation rate was 77 mm/h in patients with arthritis. It was not assessed in patients without arthritis. On comparing bone marrow features between the two groups we were unable to identify a particular subtype, cytogenetic abnormality, or pathological description that might correlate with the presence of arthritis or other rheumatic features, but there were differences between the groups (Table 2). There seemed to be a relative lack of patients with RARS in the group with arthritis. There were no cases of CMML associated with arthritis although the 1 patient with CMML in group 2 did have leukocytoclastic vasculitis with mixed cryoglobulins. Four patients (50%) in group 1 had hypocellular marrows. This feature is atypical; hypercellularity is generally the rule in MDS. Overall, 9 of 24 (38%) had abnormal cytogenetics: 2 of 7 with arthritis and 7 of 17 without arthritis. The characteristics of the inflammatory arthritis are displayed in Table 3. The onset of synovitis was observed early in the development of MDS, occurring in each case within 18 months of first recognition of progressive cytopenia. It preceded the recognition of cytopenia in 5 cases; patients 1, 5, and 8 had cytopenias discovered during initial evaluation of newonset arthritis, and patients 3 and 7 were followed up for 9 and 13 months, respectively, for their polyarthritis before the first observation of new-onset progressive pancytopenia. Two patterns of arthritis were seen. Patients 2,3,5,7, and 8 developed symmetric peripheral polyarthritis involving the wrist, metacarpophalangeal, proximal interphalangeal, shoulder, and occasionally knee joints. Patients 1,4, and 6 had an asymmetric oligoarthritis limited to the large joints involving knees, elbows, hips, and ankles.

347

Table 2: Bone Marrow Characteristics

of 28

MDS Patients With or Without Arthritis Arthritis (Group 1) Classification

8

No Arthritis (Group 2) 20

RAn

3 (38)

6 (30)

RARS

1 (12)

8 (40)

RAEB

2 (25)

5 (25)

CMML

0

1 (5)

RAEB-T

2 (25)

0

Cytogenetics

7

Normal

5

17

Abnormal*

2 (29)

J

Monosomyt

2

4

TrisomyS

0

2

Partial deletion§

0

1

Partial duplication11

1

1

Translocationll

0

3

(71)

10 (59) (41)

Cellularity Increased

2 (25)

Normal

2 (25)

11 (55)

J

Decreased

4 (50)

2 (10)

(35)

Data represent n (X). Abbreviations: sideroblasts;

RAn, refractory anemia; RARS, RAn with ring RAE& RAn with excess blasts; CMML, chronic

myelomonocytic leukemia; RAE&T, RAn with excess blasts in transformation. ‘No consistent chromosomal aberrations were identified. tSingle chromosomal deletion involved chromosome 7 (n = 2)

or Y In = 1) multiple chromosomal

deletions included

>5

chromosomes without a consistent pattern (n = 3). *Single chromosomal duplication involved chromosome 8. IDeletion of 5q only. IlDuplication of 17p or 15~. llTranslocations included g-12.4-14,

or 12-19.

Effusions were observed in patients 1 and 4 with aspiration limited because of bleeding tendencies. Only patient 1 had volumes quantified (see Case Report). Four synovial fluid samples taken from this patient showed acute inflammation without evidence of infection or crystals. Systemic features were also seen in this group coinciding with the episodes of arthritis. Serologies, often repeated multiple times, were unrevealing in every case. Radiological studies showed no erosive disease. Patient 1 had soft tissue swelling seen on elbow radiographs. An ankle film showed generalized osteopenia with mild subtalar narrowing. Hip radiographs were normal. A knee radiograph performed during an episode of acute ankle and knee arthritis in patient 2 showed

-9*

18


RAEB-T

RAn

RARS

RAn

RAEB-T

RAn

3

4

5

6

7

8 arthritis

ripheral poly-

Weeks flares

Recurrent

resolution

Symmetric pe-

arthritis

Persistent then

Monocyclic

flares

Recurrent

gradual

9 wk

10d

Months

ripheral poly-

Symmetric pe-

goarthritis

Large joint oli-

arthritis

ripheral poly-

Symmetric pe-

None

None

anemia

Hemolytic

None

roidism

mia; hypothy-

hemolytic ane-

pericarditis;

pleuritis; acute

effusions

Fever, unknown origin; acute

Monocyclic

Hypothyroidism

None

oligoarthritis

17d

resolution

arthritis Large joint

then gradual

Persistent

flares

recurrent

Initial

ripheral poly-

Symmetric pe-

Months

months

ripheral polyarthritis

Weeks to

Symmetric pe-

vitiligo

pericarditis;

origin; acute

Fever, unknown pleuritis; acute

migratory

Episodic

effusions

l-5wk

goarthritis

large joint oli-

Asymmetric

-

-

NR

(1:160)

+

-

-

-

-

ANA

-

-

NR

-

-

-

-

-

RF

Other

-; -;

-; -;

-; C’, normal

CIC, CRYO, -;

SSAISSB,

DNA, -; CRYO, -

Sm/RNP,

SSAISSB,

C’, normal

CIC, CRYO, -;

Sm/RNP,

SSAISSB.

Studies

4.6

6.1

8.0

2.9

6.0

4.5

4.0

3.0

(mg/dL)

Uric Acid

ESR

60

64

NR

33

131

110

84

60

(mm/h)

Initial

SNIP

SNIP

SNIP

SLE

Early SLE

SNIP; PMR

Early SLE

Diagnosis

*Arthritis preceded cytopenia (see text).

polymyalgia rheumatica; SNIP, seronegative inflammatory polyarthritis; NR, not reported.

Abbreviations: RAn, refractory anemia; RAEB, RAn with excess blasts; RAEB-T, RAn with excess blasts in transformation: RARS, RAn with ring sideroblasts; ANA, antinuclear antibody; RF, rheumatoid factor; ESR. erythrocyte sedimentation rate; CIC, circulating immune complexes; CRYO, cryoglobulins; C’, complement levels; SLE, systemic lupus erythematosus; PMR,


-13’

5

18

RAEB

2


RAEB

1

Features

Systemic

Time

Episodes

Distribution

Recognition

Diagnosis

‘atient

Concurrent

of

Cytopenia

Pattern Over

Duration Joint

Months After

Bone

of Acute Arthritis in Patients With MDS

Marrow

Table 3: Characteristics

$

5

i?~

ARTHRITIS IN THE MYELODYSPLASTIC SYNDROMES

349

CASE

only changes of osteoarthritis. She underwent no studies during the earlier episodes of symmetric polyarthritis. Patients 3 and 4 showed soft tissue swelling of the involved joints. Radiographs in patients 5 and 7 were normal. Patients 6 and 8 underwent no radiographic studies. The clinical course varied (Table 4). Patient 3 had spontaneous resolution of synovitis coinciding with evolution to AML. The synovitis in patient 6 was self-limiting without recurrence. Patient 5 seemingly responded to salicylates. The remainder continued with persistent synovitis in spite of nonsteroidal antiinflammatory agents until institution of steroid therapy. Four patients given high-dose steroids showed rapid resolution within 48 to 72 hours. One patient given low-dose prednisone showed progressive improvement over the ensuing 2 to 3 weeks. Four patients had serial blood counts assessed during the steroid course. Interestingly, 2 of these showed hematologic improvement. Patient 4 had a 2-g increase in hemoglobin during a prednisone course with moderate anemia recurring during the taper. In patient 1, thrombocytopenia, anemia, and peripheral smear abnormalities resolved and the transfusion dependency was abrogated for the entire period of steroid use. During the taper, the platelet and hemoglobin levels progressively declined once again and transfusion dependency resumed. This case is discussed in greater detail. Table 4:

Patient 1

Response

Treatment

to Treatment

REPORT

Patient 1 is a 75-year-old woman with a 2-year history of generalized vitiligo who developed recurrent left hip pain and stiffness. Serial blood counts showed progressive pancytopenia. At the subsequent hematologic evaluation, the leucocyte count was 1.4 x 103/~L, hemoglobin 8.4 g/dL, and platelets 84 x 103/kL. Vitamin B12 level was >2,000 pg/mL. Paraprotein profile, Ham test, folate, ANA, and RF were negative or normal. Bone marrow biopsy showed dyspoietic erythrocyte and granulocyte precursors with marked hypocellularity. Cytogenetic studies showed mostly hypodiploid cells with multiple chromosomal deletions. MDS was diagnosed and classified as RAEB. Weekly blood and biweekly platelet transfusions were necessary to maintain counts above symptomatic levels. She was later hospitalized with an acute febrile illness and neutropenia. Progressive dyspnea and pleuritic pains were noted. Serial cultures of blood and urine were negative. Peripheral smears showed extreme pancytopenia with multiple dyspoietic neutrophils and immature cells. Moderate pericardial and bilateral pleural effisions were discovered. On the 11th hospital day, she developed left hip and right sacroiliac pain and later right elbow synovitis. Aspiration of the tense elbow effision yielded 10 mL of cloudy fluid with 20,000 white blood

of MDS Patients With Arthritis

Clinical

Hematologic

Response/ Recurrence

Response/ Recurrence

lndomethacin

Minimal

High-dose prednisone

Complete resolution/Yes,

2

High-dose prednisone

Rapid improvement/No

None

3

Diclofenac

None*

None

4

High-dose prednisone

Rapid improvement/No

HGB improved; WBC, PLT unchanged/

5

Salicylates

Gradual improvement/Yes

None

6

-

Gradual spontaneous resolution/No

None

7

Naproxen

Minimal

None

Hydroxychloroquine

Minimal

Low-dose prednisone

Gradual improvement/Yes,

High-dose IM steroids

Rapid improvement/Yes

None with tapers

Normalization of smear, HGB, and PLT, transfusion holiday/Yes,

Yes, with taper

8

None with taper

None Unknown

Abbrevletlons: IM, intramuscular; HGB, hemoglobin; WBC, white blood count; PLT. platelets. *Spontaneous resolution upon transformationto acute leukemia.

with tapers

350

GEORGE AND NEWMAN

SVNWITIS

PERIPII.

DVSPOIETIC

PLATELET

CELLS

1

-1

cl

1

TRANSFUSION

RBC TRANSFUSION

I I1

(

1 (

I

I

I

400

Fig

1:

Patient

1. Re-

sponse of several hematologic

parameters

and

synovitis to prednisone in a patient with RAEB and multiple

cytogenetic

normalities.

ab-

Day 0 refers

to the day of initiation of

-20

-10

0

10

20

30

40

60

DAVS

cells (WBC)/uL (predominately neutrophils). Reaccumulation necessitated serial aspirations (ranging between 5 and 13 mL and 18,000 to 45,000 WBC/~.LL). Synovial fluid analyses, immune complex assay, cryoglobulins, repeat ANA, SSA/SSB, Sm/RNP, C3, C,, CH50, and multiple Lyme serologies were negative or normal. Uric acid measured 3 mg/dL and the sedimentation rate was 60 mm/h. Cultures for mycobacteria, fungi, aerobes, and anaerobes remained negative. Antibiotics were discontinued after 7 afebrile days. One week later the fevers returned and she developed synovitis of the left ankle and painful metatarsophalangeal joints. Indomethacin was minimally effective. A prednisone trial was given and tapered over 12 days. She reported complete resolution of joint symptoms by the fourth

60

70

60

60

100

prednisone;

*intraarticu-

lar injection

with 40 mg

triamcinolone

hexace-

tonide.

day. Surprisingly, her hemoglobin remained stable and platelets increased from 43,000 to 213,000 during the prednisone course. On the 10th day of her steroid taper, arthritis of both elbows, left ankle, and left toe recurred. After injection of the ankle and reinstitution of prednisone (10 mgid), all symptoms and objective findings resolved within 72 hours (Fig 1). The patient remained asymptomatic for the next 3 months while prednisone was slowly tapered. During this interval, hemoglobin and platelet counts plateaued somewhat then progressively decreased coincident with the prednisone taper. The circulating dyspoietic neutrophils and blasts present on all smears before steroid administration never recurred. The transfusion requirement was eliminated for 85 days, returning once the dose reached 5 mg/d. Ulti-

ARTHRITIS IN THE MYELODYSPLASTIC

SYNDROMES

mately, acute inflammation of the costochondral junctions developed and responded to increasing the prednisone once again.

351

tients with MDS.17 Four of these had associated systemic features (not described), and their vasculitis responded dramatically to steroids.

DISCUSSION

Immunologic Abnormalities

Arthritis

Immunologic disturbances in MDS have been known for some time. Given the stem cell nature of these disorders it is not surprising that there may be some aberrancy of the lymphoid series as well, with resultent immune dysregulation. In 1979 Barnard et al first described CMML with paraproteinemia.(j Solal-Celigny et al substantiated this in a review of 35 CMML cases.’ Abnormalities in natural killer cells, diminished T-helper cells, and generalized impairments in T-cell, B-cell, and polymorphonuclear cell functions have been shown separately.5,s-10In a prospective analysis of 52 MDS patients, Economopolus et al found that 12% had monoclonal gammopathies, 33% had polyclonal gammopathies, and 6% had reduced immunoglobulins.4 Autoantibodies occurred much less frequently than in an age-matched control population. Mufti et al observed monoclonal gammopathies in 13%, polyclonal gammopathies in 28%, and reduced immunoglobulins in 17% of 96 patients with MDS compared with 5%, 10% (P < .OOOl), and 10% of controls, respectively.3 Aside from the subset with CMML, autoantibodies were again much less common than in controls. The frequency of immunoglobulin abnormalities in our series and the rarity of identifiable autoantibodies are consistent with these previous reports.

Isolated cases of arthritis in MDS are rarely reported in the literature. Refractory sideroblastic anemia has resulted in an arthropathy caused by synovial hemosiderosis, reflecting total-body iron overload similar to that seen in hemochromatosis.18-20Acquired exocrine gland hemosiderosis resulting in a sicca syndrome due to transfusion dependency in a patient with RAEB has also been described.*l Chronic arthropathy caused by synovial infiltration of dysplastic monocytes has been seen occasionally in CMML.22,23This arthropathy was refractory to the usual antiinflammatory medications, including steroids, and responded to cytotoxic chemotherapy aimed at the underlying neoplastic clone much as the infiltrative synovitis of leukemia.24 Neither synovial hemosiderosis nor presence of dysplastic monocytes could explain arthritis in our patients for numerous reasons. None of these patients had CMML. The arthritis was inflammatory in all, monocyclic in two, and steroid responsive in five of five patients so treated. It resolved upon evolution to AML in one case, contrary to what one might expect in a leukemic synovitis. Patients 1 and 4 clearly had a systemic process with an acute febrile illness, maculopapular rash, pleuritis, pericarditis, and synovitis in association with pancytopenia. Both were initially believed to have systemic lupus erythematosus although repeated serological assessment was negative and bone marrow examination confirmed dyshematopoiesis. Complement, immune complex, and cryoglobulin assays were also repeatedly negative. A lupuslike syndrome has been seen in association with underlying malignancy, although such patients have had positive serologies. 25,26Patient 3 was considered clinically to have lupus in light of her persistent symmetric small joint arthritis without erosions or deformity, associated with midphalangeal erythema and with transient thrombocytopenia evolving into pancytopenia. However, the abnormal bone marrow morphology, cytogenetic re-

Autoimmune Phenomena

A number of autoimmune phenomena have been seen in the setting of MDS. Hemolytic anemia (with or without identifiable erythrocyte autoantibodies) has been described”-l4 and was seen in 3 of 28 patients in this series. DeCoteau et al reported a case of RARS (with Coombsnegative hemolytic anemia) recognized 1 year after the diagnosis of primary Sjogren’s syndrome.15 Ponge described coexistence of CMML and Sjogren’s syndrome and speculated about the role of monocyte clonal proliferation on the polyclonal activation of B cells.16 Recently, cutaneous vasculitis has been described in six pa-

352

suit, and negative serologies suggested otherwise. Our review of the world literature has identified four cases of inflammatory arthritis in the setting of myelodysplastic syndrome. Saxne et al (Sweden) described a case of symmetric polyarthritis associated with fever, maculopapular and livedoid rashes, Raynaud’s phenomenon, pleuritis, low-titer ANA, and pancytopenia.27 An initial bone marrow biopsy showed ring sideroblasts without dyspoietic changes; however, as pancytopenia persisted in spite of prednisone therapy, a repeat study confirmed myelodysplasia. Cytogenetic abnormalities were present, and the patient ultimately developed AML. Mimura et al (Japan) reported a 65-year-old woman with a 2-month history of peripheral polyarthritis and pancytopenia whose bone marrow aspirate confirmed RAEB with multiple cytogenetic abnormalities.28 An ANA titer was low positive, but all other serological results were negative. Synovial fluid aspiration showed acute inflammation with negative cultures and crystal analyses. There are two points of interest in this case. First, the use of prednisolone (and three doses of cytosine arabinoside) resulted in improvement in articular complaints and a decrease in transfusion frequency. As steroids were tapered, progressive anemia and thrombocytopenia recurred. This finding is similar to the response in our first case. Second, as acute leukemia later evolved there was a diminution in the arthritis. A similar observation was made in our third case. Marti et al (Spain) described a 62-year-old man with polyarthritis followed by progressive anemia, monocytosis, and a bone marrow biopsy showing CMML.14 The patient developed Coombs-negative hemolytic anemia, cutaneous vasculitis, and positive circulating immune complexes. An ANA titer was low positive, but all other serological results were negative. Steroid therapy failed, but there was a complete response to cytotoxic chemotherapy with resolution of the rheumatic and hematologic abnormalities. Nakayama et al (Japan) described a 69-yearold man with a 4-year history of pancytopenia due to refractory anemia and accompanying cytogenetic abnormalities who developed symmetric hand arthralgias and a maculopapular rash.29 ANA and anti-DNA antibodies were

GEORGE AND NEWMAN

positive. Systemic lupus erythematosus accompanying refractory anemia was diagnosed. Institution of prednisolone, 30 mg/d, resulted in a prompt hematologic response in all three cell lines coincident with resolution of the rash, arthralgias, and abnormal serologies. Pancytopenia recurred with subsequent steroid tapering. Other cases of a lupuslike syndrome occurring in the setting of myelodysplasia have been alluded to but not well described.30,31 In a review of 151 patients with preleukemic syndrome, Weber et al mentioned seven patients with “signs suggestive of SLE,” but no elaboration was given regarding the presence or character of arthritis.31 The Mayo Clinic’s experience regarding rheumatic manifestations in MDS has been published recently. 32Thirteen cases of recent-onset rheumatic processes temporally related to the diagnosis of MDS were described. These included cutaneous vasculitis, peripheral neuropathy, and lupuslike syndrome. Only one patient had serologically proven SLE. Five had synovitis. The majority of cases improved with prednisone. Hematologic response to steroids is not mentioned. The possibility of coexistent unrelated diseases exists in each of the reported cases as well as in our series. A number of factors suggest otherwise, however, including (1) the temporal relationship between the onset of hematologic and rheumatologic features, (2) the frequent lack of immunopathologic, microbiologic, or biochemical evidence for a definable rheumatic disease, (3) the stem cell involvement in MDS with resultent dysfunction in the lymphocytic cell line and associated immunologic abnormalities, and (4) the multiple similarities between this association and the described lupuslike paraneoplastic phenomenon associated with malignancy.25,26The temporal relationship has diagnostic importance because many cases initially manifest as arthritis. Thus, the myelodysplastic syndromes need to be considered in the differential diagnosis of any case of new-onset seronegative arthritis accompanied or subsequently followed by persistent cytopenias. Steroid Responsiveness

The pathogenesis of myelodysplasia appears to be multistage, with evidence suggesting an

ARTHRITIS IN THE MYELODYSPLASTIC

353

SYNDROMES

initial clonal B-cell-activation stage followed by subsequent generation of chromosomal changes in the genetically unstable clone.33T” Numerous steps might then follow resulting in loss of immune surveillance and eventual clonal expansion. The initial insult might be a cytotoxic agent, radiation, malignancy, viral infection, or an immunologic stimulus. Given that the rheumatic features tended to occur early in the clinical recognition of MDS, it is conceivable that one of the earlier stages in the course of this disease in some patients is immune dependent or related. Thus, there may be an unrecognized steroiod-responsive interval as clonal expansion progresses. The presence of rheumatic features may highlight this stage in this subset. Steroid therapy in MDS has met with anecdotal benefit.35 Its use on a large scale, even on a trial basis, has fallen into disfavor as adverse reactions have outnumbered the few who benefit. In an attempt to identify the steroidresponsive subset, Bagby et al developed as in vitro colony-enhancement assay.36 Clonal enhancement by cortisol in vitro was found in 5 of 34 patients with severe pancytopenia from MDS. Three of these 5 showed prompt responses to

oral prednisone therapy, with resolution of anemia in each, neutropenia in 2, and thrombocytopenia in 1. None of the 29 in vitro nonresponders had a hematologic response to steroids in vivo. Further study with larger numbers of all varieties of MDS is still needed to delineate this subset. The potential benefits to the few patients who are steroid responsive would include decreased transfusion frequency, decreased sequelae of severe pancytopenia (infection, hemorrhage, etc), and possibly delayed evolution to AML. We propose that a short therapeutic trial of high-dose steroids with close assessment of blood counts is reasonable in patients with rheumatic manifestations, particularly inflammatory arthritis, in association with MDS. It is hoped that prospective studies investigating rheumatic manifestations in myelodysplasia will follow and lead to better understanding of this association. ACKNOWLEDGMENT The authors thank Diane M. Keefer for her skillful assistance in manuscript preparation and Adel Z. Makary, MD, Department of Hematology.

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