Eosinophilic arthritis

C.-H. Tay

Mount Elizabeth Medical Centre, 3 Mount Elizabeth, #08-03, Republic of Singapore


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To report the clinical picture, laboratory findings and management of 10 patients presenting with acute polyarthritis and hypereosinophilia of unknown causation.

Methods. Patients presenting with acute arthritis and elevated eosinophil counts (>0.7x109 cells/l) or percentage (>11%) were studied during the period 1990–1997. Exhaustive investigations were carried out to exclude allergy, parasitic and infectious diseases, autoimmune disorders and malignancy. They were managed by standard treatment with oral non-steroidal anti-inflammatory drugs (NSAIDs), failing which, some were given oral corticosteroids. Those resistant to corticosteroids were treated empirically with diethylcarbamazine citrate or levamisole. All were closely monitored.

Results. Nine females and one male were found to have acute polyarthritis of 1–6 weeks duration. Most affected were the large joints: knees, ankles, elbows and shoulders. Except for localized urticarial rash, none had constitutional symptoms or extra-articular manifestations. Mild to moderate eosinophilia (absolute count 0.7–7.08x109 cells or 11–63%) was detected at the disease onset, but other laboratory findings were generally non-contributory. Treatment with oral NSAIDs did not relieve the joint symptoms nor reduce the hypereosinophilia, but oral prednisolone brought rapid recovery to five out of eight patients. Three of the corticosteroid-resistant patients were treated with an oral diethylcarbamazine, an anti-filarial drug. Complete resolution of arthritis and normalization of eosinophil count were observed after 2–3 weeks. Similar success was obtained in one patient after a single dose of levamisole. No side-effects or relapse were encountered. It was also observed that there was a good correlation between joint activity and the eosinophilic count, indicating the joint as the possible target end organ of these cells.

Conclusion. Ten patients were found to have an acute polyarthritis without systemic involvement, but with marked hypereosinophilia of unknown aetiology. They had clinical and laboratory findings which differed from other diseases with eosinophilia, especially the idiopathic hypereosinophilic syndrome (HES) and parasitic or infectious conditions. The response to NSAIDs, corticosteroids and, most interestingly, to anthelmintic drugs, like diethylcarbamazine citrate and levamisole, was noteworthy, although the basic mechanism remains unknown. The term eosinophilic arthritis (EA) is used here to describe this group of arthritides which has a benign course and is most likely a reaction to some occult allergen or agent.

KEY WORDS: Eosinophilic arthritis, Hypereosinophilia, Idiopathic hypereosinophilic syndrome, Diethylcarbamazine citrate, Levamisole


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In normal subjects, eosinophils account for only 1–3% of the total peripheral blood leucocytes, with a normal value of not more than 350 cells/mm3 of blood, i.e. <0.35x109 cells/l. Increased numbers of these cells (eosinophilia) have been found in a variety of clinical conditions, some with systemic manifestations [1]. When eosinophilia is detected in arthritic patients, the causes listed in Table 1Go may be responsible, the commonest being drug allergy and atopic diseases. Over the past few years, we have noted a number of patients presenting with acute polyarthritis with significant eosinophilia, but without systemic manifestations. Exhaustive investigations failed to reveal any known aetiology. They seem to have a disease pattern not previously described, and hence their clinical characteristics, laboratory findings and management are presented and discussed.


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TABLE 1.  Arthritis with eosinophilia: possible associations
 

    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Between January 1990 and December 1997, those patients attending our rheumatic clinic and found to have polyarthritis with eosinophilia, but without any known causes, were studied.

Besides a detailed present, past and personal history, patients were questioned regarding their allergies, ingestion of drugs, herbs or L-tryptophan-containing substances, travel to possible parasite-infested areas, contact with toxic oils, chemicals or infected pets, constitutional disturbance and symptoms related to their joints, spine and major organs.

Complete physical examination was followed by a detailed joint assessment.

The number of painful and tender joints was graded using the Ritchie articular index (RAI) [2].

Laboratory investigations included the following.

Management
All patients were treated with standard doses of oral non-steroidal anti-inflammatory drugs (NSAIDs) and those with a rash were given oral antihistamines. They were followed up with clinical and laboratory assessments, with special attention to their arthritic and laboratory status. Joint activity was measured, using the RAI, and serial blood tests, especially the percentage eosinophils and AEC, were performed at regular intervals during their treatment.

Patients found to be unresponsive to NSAIDs after 4 weeks or more were given a course of oral corticosteroid (prednisolone), after careful exclusion of infectious and parasitic diseases, especially strongyloides. Those who failed to improve with steroids after a period of time had a therapeutic trial of oral anthelmintics, either diethylcarbamazine citrate (Hetrazan) or levamisole (Ketrax). All were closely monitored from 6 months to 5 yr.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
During the 8 yr period January 1990–December 1997, 10 patients were found to have acute polyarthritis and significant eosinophilia, but without a known cause. As shown in Table 2Go, they were predominantly females (male:female ratio of 1:9) between the ages of 26 and 57 yr (median 41.5). Most were Chinese (8) and local residents (9). They gave no recent history of travelling or visiting parasite-infested places, ingestion of drugs, herbs or L-tryptophan-containing substances nor did they have contact with toxic oils, chemical compounds or infected pets. None had constitutional symptoms such as fever, weight loss, lethargy, muscular weakness or paralysis. A past history of allergy was obtained in three patients: one with rhinitis and two had previous drug hypersensitivity, but none had recent attacks.


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TABLE 2.  Clinical characteristics
 
The chief presentation was an acute joint pain with swelling with an onset of inflammatory symptoms from as early as 5 days to as long as 6 weeks (median 3.5 weeks). All except one had polyarticular and symmetrical joint involvement.

Affected joints were detected in both knees (7), ankles (8), metatarsophalangeal (MTP) joints (6), wrists (5), elbows (2) and shoulders (2). These were painful, swollen and tender with restriction of joint movement. Effusion was minimal and none developed joint deformity or contracture. No bursitis, joint nodules or bone erosions were found. The RAI measured at disease onset ranged from 2 to 19 (mean 11.2). This was regularly assessed at every visit during treatment.

Skin manifestations at onset were found in four patients. Three had localized urticarial eruptions confined to knees, legs and hands, and in one patient localized tissue oedema was present on hands and feet. This was transient and subsided spontaneously or with oral antihistamines.

Generalized urticaria, angioneurotic oedema, vasculitis, rheumatoid nodules, toxic erythema, scleroderma, fasciitis, myositis, cellulitis, lymphadenitis, lymphoedema and elephantiasis were not detected.

Patients were all in good general health without any evidence of pyrexia, wasting, anaemia or cyanosis. Examination of their vital major organs, including cardiovascular, respiratory, gastrointestinal, renal, hepatic and neurological systems, was all normal. The spine, bones and muscles were similarly not affected.

Laboratory findings
Haematological study.
As shown in Table 3Go, except for the eosinophilia, haematological findings were within normal limits in all patients at onset and on subsequent review.


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TABLE 3.  Laboratory findings
 
Mild anaemia was detected in one patient (no. 4) and leucocytosis in two (no. 1 and 9).

Studies of the peripheral blood films revealed morphologically matured eosinophils without any primitive forms and smears for microfilaria did not yield positive results after repeated tests. Likewise, the ESR and platelet counts were within the normal ranges throughout the disease.

Eosinophilia ranging from 11 to 63% (median 37%) and the elevated AEC ranging from 0.69 to 7.08x109 /l (median 3.88x109 /l) was the primary abnormality observed at onset of the disease. On subsequent visits, the state of hypereosinophilia, as measured by the AEC, appeared to correlate strongly with the severity of joint activity as measured by RAI. Both are useful in assessing the response to medication (Table 4Go and Fig. 1Go).


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TABLE 4.  Management: response to treatment
 


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FIG. 1.  Correlation between mean Ritchie articular index (RAI), mean absolute eosinophil count (AEC) and their response to treatment with NSAIDs, prednisolone and diethylcarbamazine citrate.

 
Arthritis study.
All patients had negative RF, ASOT, ANA, VDRL, CRP, LE cells, and normal values of anti-DNA antibody, serum calcium, blood uric acid and SCPK. Synovial fluid study in one patient was normal. It was clear and had predominantly mononuclear cells with no crystals, organisms or parasites.

Liver and renal function tests were also within normal limits.

Other studies.
Serial examination of stools was negative for ova or parasites in the nine patients tested.

Serum IgE estimation (modified RAST method) showed that two out of seven tested had raised values of 834 and 1000 IU/ml (normal: <120 IU/ml). Serological tests for other infectious diseases were negative (5).

Radiology study involving X-ray films of the chest (7) and affected joints [knees (7), ankles (5)] all showed normal findings. No bony erosion was detected.

The electrocardiogram was normal in all seven patients investigated.

Management: response to treatment (Table 4Go and Fig. 1Go)
Oral NSAIDs, e.g. diclofenac, naproxen or indomethacin in standard doses given for an average of 4 weeks, were administered to all 10 patients. The results were disappointing. Joint symptoms did not improve: the mean RAI at the fourth week was 9.8 compared with 11.2 at onset, and mean AEC was 3.31 compared with 3.75.

Only patient no. 5 with milder disease eventually made a full recovery, although after a 10 week course of oral diclofenac. Her E% rose from 11 to 14%, but later fell to 6% and absolute counts also fell from 0.69 to 0.40x109 cells/l. This was most likely a spontaneous remission with the passage of time.

Oral antihistamines were given to three patients with transient localized urticaria or diffuse soft-tissue swelling of the hands and feet. Dexchlorpheniramine and cetirizine in standard doses reduced itch and skin eruptions, but had no effect on the joint manifestations.

When oral NSAIDs failed, oral prednisolone 10– 15 mg daily was introduced in all except patients no. 5 and 10. Five out of eight patients registered a marked clinical and haematological improvement with complete recovery of all the affected joints and a sharp decrease in eosinophils mostly within 2 weeks of administration. The mean RAI fell from 9.8 to 0.2, while the mean AEC decreased from 3.31 to 0.47.

Oral diethylcarbamazine citrate 150 mg a day (13 mg/kg body weight) was administered to three patients resistant to oral steroids. Their mean RAI had remained high at 10.0 and the mean AEC was at 3.21. After 3–4 weeks of treatment, marked resolution of joint symptoms and reduction of the eosinophil population was observed. Mean RAI had fallen to 0.33 and mean AEC to 0.56. No side-effects were encountered and none experienced a relapse.

A single dose of 120 mg of oral levamisole produced a dramatic response in patient no. 10, who experienced a rapid resolution of her 5-week-old right ankle arthritis with eosinophils decreasing from 51 to 4% and AEC from 6.02 to 0.26x109 cells/l. Earlier treatment with oral NSAIDs for 5 weeks had not helped.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Elevated peripheral blood eosinophilia (>6% or absolute count >0.7x109 cells/l) is not uncommon in arthritis patients when they have associated drug reactions, allergies or helminthic infection [3, 4]. Rarely, they could have some of the disorders listed in Table 1Go.

Over the past 8 yr, we have found 10 patients who did not have the above-named association in spite of exhaustive investigations to exclude all known causes. This condition, not previously documented, is rare: about one new case a year. It affects predominantly females aged between 26 and 57 yr (median 41.5) and most were local Singapore citizens who had not recently travelled to parasite-infested countries. They had also not been exposed to drugs, herbs, toxic substances (including L-tryptophan) or infected pets, and had no recent allergic reaction or major systemic complaints apart from their joint pains.

Constitutional symptoms were minimal and physical examination revealed no major organ involvement. Extra-articular manifestations were confined to a few patients with localized urticarial rash on their limbs. This was transient and either cleared spontaneously or with oral antihistamines, denoting a minor localized allergic reaction. None progressed to a systemic allergy. They had no relationship to the disease nor the disease outcome.

The articular manifestation was an acute-onset polyarthritis, varying from 1 to 6 weeks (median 3.5 weeks) with symmetrical involvement of large joints such as the knees, ankles, wrists, elbows and shoulders. MTP joints were not spared. Synovial inflammation was disabling, but significant joint effusion and deformity were not detected, even at a later stage. Rheumatoid nodules were not seen. Axial joints, muscles, s.c. fascia, bones, nerves and other major body organs were not affected, thus excluding spondyloarthropathies, eosinophilic myositis [5], eosinophilic fasciitis [6] and the eosinophilia-myalgia syndrome [7].

Except for the eosinophilia, laboratory tests were unrewarding: autoimmune and arthritis studies were negative, and the active-phase reactants ESR and CRP were seldom elevated. No abnormality was detected in renal, liver and other bodily functions.

A study of synovial fluid in one patient was normal and no excess eosinophils, crystals, organisms or parasites were found. Unfortunately, a synovial biopsy was not available.

The hallmark of this disease at onset in all patients was a mild to moderately severe eosinophilia varying from 11 to 63% or AEC from 0.69 to 7.08x109 cells/l.

It was observed that the hypereosinophilia was closely correlated with the severity of joint activity as well as the progression of the disease, indicating a possible target end-organ damage by overproduction of these cells (Table 4Go and Fig. 1Go).

There was no evidence of bone marrow or glandular infiltration, and a search for allergy and parasitic infection was unsuccessful. Only two patients had raised serum IgE tests, but they had no history of systemic allergy, skin or chest diseases. Moreover, oral antihistamines, which helped the urticaria, had no effect in the management of the arthritis, although, in theory, they are able to inhibit the vacuolization, degranulation and accumulation of tissue eosinophils in target end organs [8].

A search for helminthic infections was also unsuccessful. Serial stool examination, blood and serological tests failed to identify any parasitic infestation.

Filariasis was especially looked for as the disease was endemic in Singapore 30 yr ago [9], but this has since been eradicated and no cases were found in this series. In filarial synovitis, patients are usually extremely ill with fever, lymphangitis, lymphadenoathy and elephantiasis [10]. Strongyloidiasis was excluded by negative stool and serological tests, as well as the lack of cutaneous, intestinal, pulmonary and other features [11].

Our patients differ from the idiopathic hypereosinophilic syndrome (HES) [12, 13] in many aspects (Table 5Go). Besides the female predominance (9:1), the duration of disease (eosinophilia) was short (<4 weeks), there was a lack of constitutional symptoms with no major organ involvement and little or no extra-articular manifestations except urticaria. They also had relatively normal laboratory findings (except eosinophilia), a benign course with complete arthritic and haematological resolution within 3 months, and an excellent prognosis.


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TABLE 5.  Differences between idiopathic hypereosinophilic syndrome (HES) and eosinophilic arthritis (EA)
 
Unlike HES, there was no requirement for high-dose corticosteroids or cytotoxic chemotherapy since there was little morbidity and no mortality in this series. Arthritis has been described in HES, but in addition, generalized systemic involvement and extra-articular manifestations are present [1416].

The response to oral NSAIDs was unsatisfactory in our patients and joint activity remained. The E% as well as the AEC rose or persisted in seven patients, while three patients registered a modest (5–20%) decrease after 3–10 weeks of medication. This was unexpected because NSAIDs have a marked anti-inflammatory effect by their action of inhibiting cyclooxygenase, the enzyme that transforms arachidonic acid via endoperoxides to prostaglandins, prostacyclin and thromboxanes [17]. A different mechanism might therefore be responsible for the production of the arthralgia.

Oral corticosteroids (prednisolone 10–15 mg daily) given to eight patients resistant to oral NSAIDs produced a dramatic clinical and cellular normality in five out of eight patients within 2 weeks. Glucocorticoids have been known to be the most effective agents in reducing eosinophilia by suppressing the transcription of a number of genes for inflammatory mediators, including genes for interleukin-3, interleukin-4, interleukin-5, granulocyte-macrophage colony-stimulating factor and various chemokines [18]. It is, therefore, unclear why these three were glucocorticoid resistant. It is postulated that these subjects may have had a reduced level of glucocorticoid receptors or an alteration in activator protein 1, a transcription factor [19].

The proposed alternative anti-eosinophilic therapy for steroid resistance includes the employment of myelosuppressive drugs like hydroxyurea, vincristine, interferon alpha and cyclosporin, but these have been used mostly in severe cases of HES [2, 20, 21, 22]. Newer drugs like the leukotriene and phosphodiesterase inhibitors [23, 24] are not available locally and, based on our experience with the treatment of tropical eosinophilia and filariasis, we decided to treat the three steroid non-responders empirically with oral diethylcarbamazine citrate (Hetrazan) [10], not as an anti-filarial medication but as an anti-eosinophilic drug. The response was surprisingly good with clinical remission and return to cellular normality in all patients after 3–4 weeks of therapy. No side-effects or relapse were observed.

The last patient (no. 10), with right ankle monoarthritis and without systemic or parasitic disease, made a dramatic recovery with a single dose of levamisole 120 mg. She had not had any improvement previously after 5 weeks of oral NSAIDs.

Levamisole has been used for treating rheumatoid arthritis as an immunostimulant drug [25], but its effect on hypereosinophilia is unknown. Others have employed anti-parasitic drugs (diethylcarbamazine citrate and thiabendazole) for HES without any demonstrable benefit [26, 27].

Diethylcarbamazine, a derivative of piperazine, is used as a cidal drug sensitizing the adult worms and making them susceptible to phagocytosis. Its anti-eosinophilic and arthritic effects have not been studied. Like levamisole, it may possess some immune cellular function or induce the production of anti-eosinophilic cytokines, e.g. transforming growth factor alpha, tumour necrosis factor alpha, macrophage inflammatory protein 1-{alpha}, etc. [13].

As this disease is relatively benign, remitting with time (patient no. 5) or with medication (steroids or anthelmintics), we believe that the eosinophilic arthritis could have resulted from a reaction to some occult agents or allergens yet to be discovered. More studies will be needed to elucidate the above observations.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 1 December 1998; revised version accepted 4 June 1999.