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REITER’S DISEASE IN WOMEN

DAVID L. SMITH, ROBERT M. BENNETT, and MARTHA G. REGAN

Reiter’s disease in its classic form is defined by the triad of arthritis, conjunctivitis, and urethritis and occurs predominantly in men. Recent descriptions have emphasized other ancillary findings: mucocutaneous lesions, plantar fasciitis, Achilles tendinitis, sausage digits, asymmetrical sacroiliitis, and an association with HLA-B27. This study describes 29 women followed over the past 4 years who have a rheumatic disorder most consistent with Reiter’s disease. All 29 patients were seronegative, 72% presenting with an asymmetrical pau- ciarticular arthritis, and the majority evidenced lower extremity involvement. During the course of their illness, 52% of the patients developed either eye and/or urinary tract involvement. Additional features were mucocutaneous lesions in 8 patients, heel pain or Achilles tendinitis in 15 patients, sausage digits in 20 patients, and clinical sacroiliitis in 20 patients. HLA-B27 was positive in 59% of patients, and radiographic bone and joint abnormalities were present in 52% of the patients. The recognition of this group of patients has both thera-

From the Departments of Rheumatology, Providence Medi- cal Center and the University of Oregon Health Sciences Center, Portland, Oregon.

Supported in part by the Betty Lou Margulis Rheumatology Fund, Providence Medical Center, Oregon Chapter of the Arthritis Foundation, and a Clinical Center Grant from the National Arthritis Foundation.

David L. Smith, MD: Fellow in Rheumatology, University of Oregon; Robert M. Bennett, MD, MRCP: Associate Professor of Medicine and Chief of Rheumatology, University of Oregon; Martha G . Regan, MD. Assistant Professor of Medicine, University of Ore- gon, Chief of Rheumatology, Providence Medical Center.

Address reprint requests to Martha G. Regan, MD, Chief of Rheumatology, Providence Medical Center, 700 N.E. 47th. Portland, Oregon 9726.

Submitted for Dublication June 26, 1979; accepted in revised form November I , 1979.

peutic and prognostic implications, because they preferentially respond to indomethacin or phenylbutazone and often pursue a chronic course, albeit without widespread joint destruction.

Reiter’s disease, as originally described by Hans Reiter in 1916, consists of polyarthritis, urethritis, and conjunctivitis ( I ) . Without a proven etiologic agent, Reiter’s disease is currently regarded as one of the rheumatic disorders within the spectrum of the seronegative spondylarthritides (2-7). Certain associated findings have been observed to occur during the course of Rei- ter’s disease that often aid in the diagnosis. They include skin and mucous membrane lesions, nail changes, plantar fascitis, and/or Achilles tendinitis and sausage digits (8- 12). Common investigational findings are: radiographic periostitis, sacroiliitis, enthesopathy, absence of rheumatoid factor, and a high prevalence of HLA-

An increasing awareness of these additional features has led to the recognition of Reiter’s disease in patients who do not fulfill the original triad. With the ac- ceptance of a broader definition and heightened clinical awareness, the concept of incomplete Reiter’s disease, consisting of a seronegative oligoarticular asymmetrical arthritis without conjunctivitis or urethritis, has recently emerged (17). The features of heel pain, periostitis, and sausage digits in association with HLA-B27 were emphasized as important adjuvant diagnostic aids.

Both classic Reiter’s and incomplete Reiter’s disease appear to be a disease usually confined to men, occurring infrequently in women (18,19). The purpose of this study is to report 29 women with a seronegative arthritis most compatible with Reiter’s disease.

B27 (7,13-16).

Arthritis and Rheumatism, Vol. 23, No. 3 (March 1980)

336 SMITH ET AL

Table 1. Distribution of arthritis at initial evaluation

Pattern* Type of arthritic

involvement, no. patients Symmetrical Asymmetrical

Monarticular, 1 0 I

Polyarticular, 14 7 7

Total, 29 7 22

Oligoarticular,t 14 0 14

* Fourteen patients had predominant lower extremity arthritis, 12 had predominant upper extremity involvement, and 3 patients had equal upper and lower extremity involvement.

t Defined as 4 or fewer inflamed joints.

PATIENTS AND METHODS Twenty-nine women were initially evaluated and fol-

lowed during the course of their disease by one of the princi- pal investigators at Providence Medical Center or the Univer- sity of Oregon Health Sciences Center. Inclusion into this series required: 1) initial objective evidence of peripheral joint inflammation; 2) one or more of the following discriminating clinical features during the course of their illness: a) nail changes either as hyperkeratosis or onycholysis, b) mucocutaneous lesions either as keratodermia blennorrhagica or oral lesions, c) sausage digits, d) enthesopathy presenting either as heel pain, plantar fasciitis, or Achilles tendinitis, and e) clinical sacroiliac joint involvement.

Initial laboratory data consisted of a complete blood count, sedimentation rate (Westergren), rheumatoid factor, antinuclear factor, and urinalysis. HLA-B27 testing was per- formed on all patients. Radiographs included sacroiliac joints and symptomatic peripheral joints. Treatment with nonsteroidal, antiinflammatory agents was monitored by both subjective difference in pain and stiffness and objective evidence of joint inflammation.

RESULTS Twenty-nine white women with a mean age of

36.7 f 13.5 years (1 SD) and age range from 13-71 years were evaluated over 2-year period. Followup was from 1 month to 4 years (mean 1.5 years). Family history was negative for psoriasis, spondylitis, and other forms of inflammatory adhritis. None of the patients

gave a history of recent venereal disease exposure, sig- nificant weight loss, or antecedent dysentery.

On initial evaluation peripheral arthritis was noted in all patients (Table 1). An oligoarticular (4 joints or less) asymmetrical arthritis was present in 14 patients (48%). Polyarticular involvement occurred in 14 patients (48%) and was asymmetrical in 7. Mon- articular involvement was seen in only one patient. A lower extremity distribution predominated; arthritis was present in 104 lower extremity joints and in 90 upper extremity joints. The mean number of affected joints per patient was 6.8.

There was initial diagnostic confusion in most cases. However, ongoing evaluation revealed the appearance of additional discriminating features. Fifteen patients (52%) displayed eye and/or urinary tract involvement. Ten of these patients (34%) had ocular inflammation witnessed by a physician; conjunctivitis was present in 9 and iritis in 1 (this patient was B27 positive). The conjunctival involvement preceded the arthritis by 2 months in one patient, and iritis occurred only after 3 years had elapsed in another patient. Objective evidence of urinary tract involvement occurred in 10 patients (34%) as sterile pyuria or unexplained hema- turia, occurring from 6 months prior to presentation to 2.7 years after presentation. Only 6 of these patients had dysuria. Both eye and urinary tract involvement evolved in 5 patients during the course of their illness.

At least one additional discriminating clinical feature was found either initially or on followup (Table 2). Mucocutaneous lesions occurred in 8 patients; hyperkeratosis or onycholysis of the nails was present in 5 patients, keratoderma blennorrhagica in 5 patients, and painless oral ulceration in 1 patient. Sausage digits (Fig- ure 1) were present in 20, heel tenderness or plantar fasciitis occurred in 15 (Figure 2), Achilles tendinitis in 15, and sacroiliac tenderness in 20 patients (15 of whom were B27 positive).

Laboratory determinations (Table 3) revealed rheumatoid factor and ANA to be negative in all pa-

Table 2. Diagnostic features of Reiter’s disease in women occurring over the course of the illness

Time of documentation with reference Diagnostic features No. of patients to presentation for arthritis

Minus 2 months to 3 years Minus 6 months to 2.7 years

10 10

Ocular involvement Urinary tract involvement

5 Presentation to 2 years Nail changes Keratoderma blennorrhagica 5 Presentation to 2.8 years Sausage digits 20 Presentation to 2 years Heel paidplantar fasciitis 15 Presentation to 2 years Achilles tendinitis 15 Presentation to 4 years Sacroiliac joint tenderness 20 Presentation to 4 years

REITER’S DISEASE IN WOMEN 337

Figure 1. “Sausage” digit with radiographic evidence of periositis. *Tc diphosphate shows uptake into juxtaarticular tissues.

tients. The mean sedimentation rate was 34 mm/hour. HLA-B27 was positive in 17 patients (59%). Radio- graphic abnormalities were seen in 15 patients; sacroiliac changes were present in 5 patients, periostitis in 6 (Figure 3A), erosive joint disease in 7 (Figure 4A), and marked cartilage loss in 2 patients.

Knee arthrocentesis in 4 patients yielded synovial fluid with white blood counts ranging from 6,800 with 46% polymorphonuclear leukocytes (PMN) to 56,000 with 97% PMN. Synovial biopsy in 1 patient showed synovial cell proliferation with mononuclear in- filtration. Plantar fascia biopsy in 1 patient demon- strated plantar fibromatosis. Extensive keratoderma blennorrhagica was seen in 1 patient (Figure 5) who

Table 3. Investigational features of Reiter’s disease in 29 women ~. - -

Investigation No. of patients

Rheumatoid factor Antinuclear antibodies

Radiographic abnormalities Sacroiliac joint changes Penostitis Erosive joint disease

HLA-B27

~~ .~

0 0

17 (59%) 15 (51%)

5 6 7

also had sterile pyuria, and a skin biopsy showed changes indistinguishable from pustular psoriasis,

Indomethacin (1W200 mg) and phenylbutazone (600-800 mg) were effective in controlling symptoms and decreasing joint inflammation in 19 patients (65%); the use of other nonsteroidal antiinflammatory drugs was effective in 6 patients (20%). Healing of periostitis of the second toe (Figure 3B) and healing of an erosion of the metatarsophalangeal joint of the great toe (Figure 4B) occurred in the same patient while she was on phenylbutazone. A short course of 6-mercaptopurine was effectively employed to clear extensive keratoderma in 1 patient. One patient received intramuscular gold therapy (totaling 2,835 mg) with a good clinical result, in- cluding healing of an erosion at the interphalangeal joint of the great toe. Eight patients underwent treatment with corticosteroids, but in no instance was there a beneficial response.

The course of this group of patients has been characterized by three basic patterns: 1) an acute arthritis of short duration (3 patients); 2) a relapsing arthritis (5 patients); and 3) a chronic arthritis (21 patients). Of the 21 patients who experienced chronic disease, I 1 pa-

Figure 2. A. Sclerosis and subchondral osteopenia at the insertion of the Achilles tendon into the calcaneum-an example of “enthesopathy.” B. Opposite calcaneum (uninvolved) for comparison.

Figure 3. A. Florid periostitis of the second proximal phalanx of l e right foot. B, Resolution of the periosteal reaction after 5 months therapy with phenylbutazone.

338 SMITH ET AL

Figure 4. A, Bony erosion at the base of the first metatarsophalangeal joint. B, Healing of the erosion after therapy with phenylbutazone.

tients had at least one period of remission and sub- sequent flare.

DISCUSSION The seronegative spondylarthritides include an-

kylosing spondylitis, enteropathic arthropathies, psoriatic arthritis, and Reiter’s disease (7). Each condition is characterized by certain distinctive clinical features, and aLl exhibit some degree of axial skeleton inflammation. Thus, some overlap exists between each condition, forming a disease continuum. An association with HLA-B27 has proved useful in distinguishing these seronegative arthritides from other forms of inflammatory arthritis (20-24).

The women in this study showed certain features characteristic of the seronegative spondylarthritides, in particular Reiter’s disease. The usual pattern of arthritis was most commonly asymmetrical with either oligoarticular or polyarticular involvement. Although eye and/ or urinary tract involvement could be documented in only 15 patients (52%), the complete triad may have been more prevalent. History for these symptoms may be difficult to elicit, since mild conjunctival imtation may go unnoticed (9). Furthermore, “urinary tract involvement” in women is difficult to specifically classify. Symptoms of dysuria are most often attributable to cystitis or urethritis in young women; however, non-spe- cific cervicitis or mild vaginitis may also give symptoms of dysuria (26,27). The sterile pyuria is not explained in 9 of our patients, 6 of whom were symptomatic with dysuria, although a Chlamydia, T-strain mycoplasma,

or as yet unidentified infectious organism may be considered a possible etiologic agent, since an association may exist between these organisms and Reiter’s disease (8,28,29). Hemorrhagic cystitis was seen in one patient in this study and has been described previously (1 1). The classic Reiter’s triad was recognized in only one patient at presentation, though the complete triad developed in 4 other patients up to 2.7 years after presentation.

Certain distinctive ancillary features are crucial in triggering an awareness of Reiter’s disease. These do not necessarily occur at presentation; 19 patients (66%) developed them only on followup as long as 4 years after presentation.

The term “enthesopathy” has been used to con- note an inflammatory process at a ligamentous bony insertion (9,30). This was frequently seen in our patients as Achilles tendinitis, heel tenderness, or plantar fasciitis. “Sausage-shaped digits” has been used for the clinical appearance of combined inflammation of syno- vium, tendons, and ligamentous insertions (9). Twenty

Figure 5. Extensive keratoderma blenorrhagica (seen here on trunk), the onset of which coincided with acute arthritis, sacroiliitis, and sterile pyuria.

REITERS DISEASE IN WOMEN 339

patients (69%) developed sausage digits. Sacroiliac tenderness compatible with sacroiliitis was elicited on physical examination in 19 patients (65%), although radiographic changes occurred in only 5. These symptoms and signs may be present without radiographic change in Reiter’s disease (9). HLA-B27 was positive in 17 patients (59%). a finding in accordance with other series on Reiter’s disease (3 I). Although our series is small, we could not discern a major difference between B27 positive and B27 negative individuals for disease activity or clinical course.

The proper classification of patients with seronegative polyarthritis remains controversial. In this study the diagnosis of seronegative rheumatoid arthritis is unlikely, considering the characteristic asymmetrical articular distribution and the distinctive ancillary features seen on followup. Furthermore, the HLA-B27 po- sitivity in 59% of patients is inconsistent with its known incidence in rheumatoid arthritis (7).

The diagnostic category of seronegative spondylarthritides is more reasonable. Our patients had no history or evidence of inflammatory bowel disease on followup. Psoriatic arthritis was considered the less likely diagnosis because 24 patients (83%) lacked skin lesions. In one recent study of psoriatic arthropathy, joint involvement preceded skin involvement in 16% of patients by a mean interval of 6.6 years (23). It may be that on longer followup some of our patients will develop psoriasis. Of our 5 patients with keratoderma, 2 had sterile pyuria, considered to be a rare finding in psoriatic arthritis (24). The indistinguishable clinical and histologic findings in pustular psoriasis and keratoderma blennorrhagica (32) lend further confusion to the distinction between psoriatic arthropathy and Reiter’s disease in some patients.

The main thrust of the diagnostic dilemma sur- rounds classic Reiter’s disease, incomplete Reiter’s syndrome, and the emerging concept of mild ankylosing spondylitis in females. Lacking a definite causal agent on which to base a diagnosis, the concept of Reiter’s disease is solely dependent upon a characteristic con- stellation of clinical, radiographic, and laboratory features. If Reiter’s original definition is strictly adhered to, then only 5 patients in this study could be classified as having Reiter’s disease.

Female ankylosing spondylitis remains a possible alternative diagnosis (24,33-35). There is a grow- ing awareness of peripheral joint disease, enthesopathy, and high incidence of HLA-B27 in this forme fruste of ankylosing spondylitis (23). Yet, bilateral sacroiliitis is necessary for confirming this diagnosis (36). Radio-

graphic sacroiliac changes of sacroiliitis were asymmetrical in 4 of our 5 patients. The contention that the re- maining patients who are without current radiographic sacroiliac involvement represent early female ankylosing spondylitis is acknowledged.

It is apparent from the foregoing considerations that a dilemma will remain concerning the proper classification of our group of patients. Until there are valid scientific criteria akin to Koch’s postulates, semantic confusion will persist in establishing a diagnosis of the rheumatic disorders. In the case of Reiter’s disease, the confusion has largely been a function of the rigidity of the original definition.

The adoption of more widely based criteria for diagnosing Reiter’s disease, as suggested by Arnett ( 17) and expanded in the present study, has diagnostic, ther- apeutic, and prognostic implications. Heightened clinical awareness is important for diagnosis since the characteristic distinctive features of Reiter’s disease do not uniformly coincide with the presentation of arthritis. Furthermore, these patients preferentially respond to indomethacin and phenylbutazone. Although they may pursue a chronic course, they most commonly do not develop widespread destructive arthritis. These considerations indicate that the identification of Reiter’s disease in women has important practical implications ir- respective of current semantic bias.

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