A Wider Spectrum By Muhammad As in other

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Epidemiological studies have been hampered by incomplete definition of the clinical disease spectrum, and there is a need to use broad criteria that will include the patients that have been ignored because their diseases do not fit the current criteria. This difficulty in clearly categorizing some patients with SpA into specific subgroups occurs most often in early stages of these diseases.7-‘0 The characteristic signs and symptoms for such a subgroup may only become manifest after a long follow-up of the patient, and may sometimes require examination of the patient’s family members. For example. in a family with multiple cases of AS, reported by Gladman et a1,16 there were three brothers with B27-positive AS and two with B27-negative AS. In addition, a sister with B27-negative AS was

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by W.B. Saunders Company.

ERONEGATIVE spondyloarthropathy (SPA) is a heterogeneous clinical entity that includes ankylosing spondylitis (AS), the prototype of this group of interrelated disorders, reactive arthritis (including Reiter’s syndrome), psoriatic arthritis, and arthritis associated with chronic inflammatory bowel diseases.le3 As in other diseases of undetermined etiology, the diagnosis of AS and related diseases is based on

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clinical and roentgenographic features. The studies of Moll et al’ and the discovery in 1973 of the association of HLA-B27 with AS and related SPACED have clearly demonstrated that these diseases share clinical and radiographic features as well as genetic predisposing factors.le3 However, these observations have also raised questions about our perceptions of the clinical spectrum of SPAS, and it has become apparent that features typical of SpA may occur in different combinations so that the existing criteria for disease classification may be inappropriate for a subset of such patients.6-‘5

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Asim Khan and Sjef M. van der Linden

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From the Department of Medicine, Case Western Reserve University, Division of Rheumatology, MetroHealth Medical Center Cleveland, OH, and the Department of Medicine, Division of Rheumatology, University of Limburg, Maastricht, The Netherlands. Muhammad Asim Khan. MD: Professor of Medicine, Case Western Reserve University, Director. Division of Rheumatology, MetroHealth Medical Center, Cleveland, OH; Sjef M. van der Linden. MD: Professor of Rheumatology, Department of Medicine, Division of Rheumatology, University of Limburg. Maastricht, The Netherlands. Address reprint requests to Muhammad Asim Khan, MD, Professor of Medicine, Director, Division of Rheumatology. MetroHealth Medical Center, 3395 Scranton Rd. Cleveland. OH 44109-I 998. % 1990 by W.B. Saunders Company. 0049-0172/90/2002-0005%5.00/O

Seminars in Arthrihs and Rheumatism, Vol 20, No 2 (October), 1990: pp 107-l 13

107

108

found to have sacroiliitis. There was no genetic recombination or evidence of psoriasis or inflammatory bowel disease in this family. When first seen, this family appeared to illustrate a dissociation between “pure” AS and HLA-B27, but only after several years of follow-up did the first evidence of psoriasis appear. Radiological evidence of sacroiliitis is considered necessary for the diagnosis of AS according to the New York (and the modified New York) criteria and, except for rare instances, is also a requirement for the Rome criteria.11-14 But the current concept of the spectrum of AS seems to be too restricted, because arthritis involving the axial skeleton, including the sacroiliac joints, can be present in some patients without evidence of erosive disease roentgenographically.6’7.‘5 A family study showed evidence of spondylitic disease in up to 25% of B27-positive relatives of HLAB27 positive AS patients.16 Some of these relatives may have signs and symptoms of AS, including inflammatory back pain, but not show radiographic sacroiliitis6 Patients with symptomatic spondylitic disease may often have associated thoracic pain and stiffness.6’15 Sometimes, as has been found in family studies on AS, individuals may only have recurrent thoracic pain and stiffness with or without inflammatory back pain.15 The chest pain is often associated with tenderness over sternocostal or costochondral junctions, and the patient may initially be diagnosed as suffering from Tietze’s syndrome. The pain may be accentuated on coughing or sneezing because of the involvement of costovertebral joints. Radiographically detected sacroiliitis is extremely frequent in AS, but it may not be an obligate manifestation, especially in early stages of the disease.‘6a This point is well illustrated by the results of a prospective study published by Mau et a1.17 They followed 88 patients with “possible AS” (88% of them had chronic low back pain with at least one of the following features: peripheral arthritis, heel pain, anterior uveitis, or raised ESR; the remaining 12% did not have inflammatory back pain, but they had at least three of the four features mentioned). None of these 88 patients had unequivocal radiographic sacroiliitis, psoriasis, reactive arthritis, positive rheumatoid factor, or noninflammatory spine disease. After 5 years of follow-up, 24

KHAN AND VAN DER LINDEN

patients demonstrated definite AS, and 8 additional patients showed definite AS after another 5 years of follow-up. Thus, 32 patients (out of the 54 that were available for a complete 10 year follow-up) had demonstrated definite AS. This diagnosis could finally be excluded in 12 patients. The remaining 10 patients were assessed as having possible or undifferentiated SpA, and 6 of them (60%) were noted to possess B27, as compared with 91% of those who developed definite AS. Radiologic evidence of sacroiliitis became evident after 9 i 6 years of disease duration. This study, therefore, clearly demonstrates that not all patients with AS have radiologic evidence of sacroiliitis when they first consult a physician for their back pain. The current concept of the spectrum of AS as an arthritis of the axial skeleton (including the sacroiliac joints), should also emphasize the fact that the disease can be present in some patients without evidence of erosive disease roentgenographically. 6~‘7The prefix “ankylosing” in the term AS can be misleading, because it perpetuates the image of a stiff, deformed spine, when, in fact, many patients with the disease do not progress to a stage of ankylosis. Therefore, it may well be the time for a new name for AS.‘* We have suggested that “spondylitic disease” may be a more appropriate name,6 and it can be defined as a “group of processes which, via a mechanism which is facilitated by Hl.A-B27, and in the absence of sepsis or metabolic disease, leads to diffuse spondylitis” (Arnett F, personal communication). CARDIOVASCULAR

ABNORMALITIES

IN

SPONDYLOARTHROPATHIES

The extent of cardiovascular abnormalities seen in SpA patients may also have a much broader spectrum than previously realized.19V20 Studies in Sweden have shown that an HLA-B277 associated inflammatory disease process may be the probable underlying cause in 14% to 20% of patients with lone aortic incompetence.” The occurrence, in men, of complete heart block without SpA, and the cardiac syndrome of “lone aortic incompetence and pacemaker-requiring bradycardia” (emphasis added) are B27-associated inflammatory disease processes, because an increased frequency of B27 has been observed among such patients.” Presence of lone aortic

109

A WIDER SPECTRUM OF SPONDYLOARTHROPATHIES

incompetence in the absence of SpA and heart block is not associated with B27. In an earlier study from the United States” of 100 consecutive patients with “lone aortic incompetence,” 4 were found to have AS and 3 had Reiter’s syndrome. These 7 patients all possessed B27, versus only 5 of 89 patients with no evidence of SpA. Six of these 7 patients with aortic incompetence and SpA had cardiac conduction abnormalities, and 4 of them required permanent pacemaker insertion.” REITER’S

SYNDROME AN5

PSORIATIC

ARTHRITIS

The disease spectrum of Reiter’s syndrome has been broadened considerably and “incomplete” forms of Reiter’s syndrome are observed much more commonly than the classical triad of arthritis, conjunctivitis, and urethritis.2q3’2’ The term “B27-associated reactive arthritis” has been used in recent years to refer to SpA following enteric or urogenital infections, and the disease spectrum includes the clinical picture of typical Reiter’s syndrome. Despite many attempts, no viable organisms have been successfully cultured from the joints in these patients, although the presence of Chlamydia, Salmonella, and Yersinia antigens in the synovial white blood cells or synovial tissue has now been observed in some patients with reactive arthritis.22W24a Recent findings suggest that in genetically predisposed individuals, an arthritogenic immune response might be triggered by persisting infectious agents independent of their antigenic specificities, and Borrelia hurgdorferi (that causes Lyme disease) may join human immunodeficiency virus (HIV) among the growing list of infectious agents that must be considered for a patient with reactive arthritis or Rciter’s syndrome.25-29 The clinical spectrum of psoriatic SpA has been better clarified, and the clinical course of psoriatic spondylitis appears to be less disabling than that of primary AS.30,31 Psoriasis, psoriatic arthritis, and Reiter’s syndrome occupy an intriguing place in the spectrum of SpA; some HIV-infected patients have developed severe psoriasis (with or without psoriatic arthritis) and/or Reiter’s syndrome, usually at the onset of the development of acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC).27-29 There are reports of psoriatic pa-

tients developing arthritis after physical trauma. and also reports of occurrence of Reiter’s syndrome shortly after physical injury.32,33 However, a majority of these are anecdotal case reports, and it is not yet possible to conclude from the published data that physical trauma can trigger psoriatic arthritis or Reiter’s syndrome.29.34 UNDIFFERENTIATED

SPONDYLOARTHROPATHY

Some of the less well defined B27-associated clinical syndromes include seronegative oligoarthritis, polyarthritis, or dactylitis (“sausagelike” toes) of the lower extremities, and heel pain caused by calcaneal (and tarsal) periostitis.35-37 Such entities, however, do not fit into any of the clearly defined subcategories of SpA, and these undifferentiated SpA have been ignored in previous epidemiologic studies because of inadequacy of the existing classification criteria.29 Studies of Eskimos have shown that undifferentiated SpA may be as frequent as AS and Reiter‘s syndrome.29~38-39a A study of undiagnosed chronic monoarthritis has shown that a substantial subgroup of such patients (especially the one third who possess HLA-B27) may represent the first manifestation of a clinically occult SpA. HLA-B27--associated lower-limb oligoarthropathy, without evidence of any preceding enteric or genitourinary infection, or any clinical evidence of psoriasis or chronic inflammatory bowel disease, is often associated with Achilles tendinitis and calcalcaneal (or tarsal) periostitis.40,4i It is not uncommon to find some family members with other B27-associated diseases, such as AS, reactive arthritis, or acute anterior uveitis.2.3,8,’ ’ Results of a prospective study from Germany of 119 patients with B27-positive oligoarthritis have recently been reported.37 During a follow-up period of 2 to 6 years, 40 patients experienced complete remission, recurrences of oligoarthritis developed in 3 1 patients, 30 cases evolved into AS, 3 cases into psoriatic arthritis, and 3 cases into Reiter’s syndrome. Five patients were lost to follow-up, and in 7 patients the oligoarthritis evolved into rheumatoid arthritis. The 31 B27-positive patients with recurrent oligoarthritis were observed for another 6 years, :and 13 of them continued to have recurrent oligoarthritis. This study demonstrates that after many years of follow-up about 10% of B27-positive oligoarthri-

110

KHAN AND VAN DER LINDEN

tis patients continue to have recurrent oligoarthritis, almost 50% develop a well-defined SpA, and the remaining 40% obtain persistent remission.37 Prakash et a142 from India have reported their experience with 29 patients with “unclassifiable” SpA seen during a prospective study of 2 years. During this period they had also observed 51 patients with AS, 36 with Reiter’s syndrome, 11 with “inflammatory” low back pain without roentgenographic changes of sacroiliitis, 3 with ulcerative colitis and arthritis, and 3 with Behcet’s syndrome. All but 4 of their 29 patients with “unclassifiable” SpA were men, 25 had polyarthritis at a mean age of onset of 21 years. The arthritis was often asymmetric, mostly affecting joints of the lower extremities and frequently associated with enthesopathy and/or low back pain and stiffness. The only symptom of the remaining 4 patients was severe bilateral heel pain. HLA-B27 was present in 21 of the 25 patients (84%) with polyarthritis, and in 3 of the 4 patients (75%) with heel pain. JUVENILE SPONDYLOARTHROPATHIES

Juvenile onset of AS is quite common in developing countries of Asia and Latin America. 40-43Most Mexican patients with AS (54%) have juvenile onset, and the overall prognosis of the Mexican juvenile AS patients is much worse than that of their American counterparts.40,43*44 Clinical evidence of enthesopathy, along with family history of SpA, should always be obtained for children with arthritis.8*41,45 Children with juvenile-onset B27-associated “unclassifiable” SpA may also present with unilateral or bilateral heel pain. Some children, especially in Mexico, may have tarsal or digital arthritis and periostitis as the major early clinical manifestation of their SpA. 40.41,43,46 Some children with SpA present with seronegative oligoarthritis, mostly of the lower extremities, along with tenderness at ligamentous attachments to bone due to enthesopathy.41*45 This clinical presentation has been called seronegative enthesopathy and arthropathy (SEA) syndrome.45 Juvenile AS and SEA syndrome are both conditions that predominantly occur in HLA-B27 positive boys in late childhood,41s45 and many of these diseases progress to AS and related SPAS. Recently the results of a prospective Mexican study reports that SEA syndrome represents an

early stage of juvenile AS because, after 5 years, 92% of the patients had developed definite AS.40 The frequencies of peripheral arthritis and enthesopathy were much higher in juvenile-onset than adult-onset AS.40 LATE-ONSET SPONDYLOARTHROPATHY

Although AS rarely develops after 50 years of age, 10 such cases, all HLA-B27 positive, have recently been described who had little or no clinical involvement of the axial skeleton at the onsets of their diseases.47 Five of these patients later showed bilateral sacroiliitis and 4 of them demonstrated definite AS. This syndrome could represent up to 10% of seronegative polyarthritis in men older than 50, and its clinical recognition might prove helpful in its management4’ These patients often had moderate oligoarthritis with low cell counts in the synovial fluid, pitting edema of the lower limbs, constitutional symptoms, or an elevated erythrocyte sedimentation rate; and they resemble those with remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome described by Mcwith RS3PE were Carty et a1.48,48a Patients predominantly men older than 50 years who had polyarthritis, pitting edema, and low number of cells in the synovial fluid. They were frequently B7-positive in contrast to the patients with B27positive late-onset SpA. In addition, patients with RS3PE all had symmetrical involvement of the hands, which was absent among the patients with late-onset SpA. MISCELLANEOUS

ENTITIES

Osteoarticular manifestations of acne conglobata, acne fulminans, hidradenitis suppurativa, palmo-plantar pustulosis, Sterno-costo-clavicular hyperostosis, and chronic recurrent multifocal osteomyelitis include several features of SpA, such as seronegative asymmetrical oligoarthritis, sacroiliitis, syndesmophytes, enthesopathies, anterior chest-wall involvement, and an association (although relatively weak) with HLA-B27.4gW52 A new but somewhat clumsy name has been suggested for this syndrome, synovitis acne pustulosis hyperostosis osteomyelitis syndrome (SAPHO syndrome), and diagnostic criteria have been proposed.52 Some patients with renal failure treated with chronic hemodialysis have developed destructive

111

A WIDER SPECTRUM OF SPONDYLOARTHROPATHIES

SpA of a noninfectious nature,s’53 resembling erosive diskovertebral lesions and spinal pseudoarthrosis of AS.54-57 But this erosive SpA is not B27-associated and it results from secondary hyperparathyroidism, and possibly from deposition of hydroxyapatite and calcium oxalate crystals, and amyloid deposition associated with /3,-microglobulin.8.57

PRELIMINARY

CRITERIA

FOR CLASSIFICATION

OF SPONDYLOARTHROPATHY

It is important to distinguish between criteria for individual patients and criteria to classify groups of patients. The purpose of any set of criteria should, therefore, be clearly stated. We prefer to reserve the term diagnostic criteria for those that state the probability of disease for an individual. In contrast, the criteria to classify groups of patients, ie, the classification criteria, define a disease concept, help create homogeneity among patients, and facilitate comparison between groups of patients across different centers, regions, countries, or populations. The classification criteria, therefore, are conditions sine qua non for generalizability to other patients who are considered to have the same disease, or to conclusions drawn from clinical studies that deal with these disorders. No clear definition for the classification of the whole group of SpA patients had been proposed until recently. 29.58The European Spondylarthropathy Study Group (ESSG) has completed a study aimed at developing preliminary classification criteria for the whole group of SpA, with the specific intention also to encompass patients with undifferentiated SpA. 58 The rheumatology departments of seven European universities participated in this multicenter study. The diagnosis of SpA was based solely on the clinical judgement of the local expert. Controls used for this study had rheumatological disorders other than SpA. A whole spectrum of data comprising spinal involvement (spinal pain, buttock pain, anterior chest wall pain, spinal mobility, chest expansion), peripheral arthritis, enthesopathy, extraarticular involvement (eye, skin, gut, urogenital symptoms), and family history of features of SpA were collected for all patients and controls. Altogether 403 SpA patients and 674 controls participated in the study. Using clinical judge-

ment and logistic regression analysis, a set of clinical variables was determined that performed best in differentiating the whole group of SpA patients from controls. This was done in patients with and without inflammatory spinal pain to preclude the possibility of typical signs and symptoms of AS overshadowing other SpA features. The set of ESSG criteria resulting from the study is shown in Table 1. The sensitivity of the ESSG criteria was 77% and the specificity was 89% when applied to the whole group of 403 SpA patients and 674 controls. Adding sacroiliitis to the clinical criteria improved the sensitivity to 86% while the specificity was minimally affected (Table 1). The criteria also performed quite well in a subgroup of 102 patients considered to have undifferentiated SpA, demonstrating a sensitivity of 78% and a specificity of 89??‘~.~~Also, in a subgroup of 163 patients with SpA who did not show radiographic evidence of sacroiliitis, the ESSG criteria performed rather well with 74% sensitivity and 88% specificity. It is important to recall that classification criteria are primarily designed for investigative studies and clinical trials and are not aimed at establishing a diagnosis in individual patients, although such criteria

Table

1: ESSG

cation

of Spondyloarthropathy

Preliminary

Criteria

for Classifi____

Inflammatory Spinal

Pain

or Synovitis 0 Asymmetrical 0

Predominantly

andAny

One of the Following:

0

Positive Family History

0

Psoriasis

0

Inflammatory

0 Alternate 0

,

in the Lower Limbs

Bowel Disease

Buttock

Pain

Enthesopathy

Sensitivity

77%’

Specificity

B9%*

Ad?‘;;;;;

;;;;

*Based on 403 patients and 674 controls. tEased on 36 1 patients and 455 controls.

112

KHAN AND VAN DER LINDEN

might occasionally be helpful in diagnostic situations. Hussein et a159 have proposed diagnostic criteria for atypical SpA in children. In summary, the concept of SpA is now well established, and a better delineation of the separate diseases belonging to this whole group is slowly emerging. However, some patients may present at an early stage of their disease or with a persistently undifferentiated type of SpA. Such

patients have been ignored in epidemiological studies in the past because of the inadequacy of the classification criteria used, and this may have resulted in an underestimation of the prevalence of the full spectrum of SPA.~~ It is hoped that this situation may be rectified to a large extent if future epidemiological studies of SpA use the newly developed ESSG preliminary classification criteria.29T58

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spondylarthropathies.

Bull

3. Khan MA, Skosey JL: Ankylosing spondylitis and related spondyloarthropathies, in Samter M (ed): Immunolog ical Disease. Boston, MA, Little, Brown, 1988, pp 1509-1538 4. Brewerton DA, Hart FD, Nicholls A, et al: Ankylosing spondylitis and HL-A 27. Lancet 1:904-907, 1973 5. Schlosstein L, Terasaki PI, Bluestone R, et al: High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med 288:704-706, 1973 6. Khan MA, van der Linden SM, Kushner I, et al: Spondylitic disease without radiologic evidence of sacroiliitis in relatives of HLA-B27 positive ankylosing spondylitis patients, Arthritis Rheum 28:40-43, 1985 7. Zeidler H: Undifferentiated arthritis and spondylarthropathy as a major problem of diagnosis and classification. Stand J Rheumatol65:54-62, 1987 (suppl) 8. Khan MA: Newer clinical and radiographic seronegative spondyloarthropathies. Curr Op 1:139-143, 1989 9. Kidd BL, Cawley MI: Delay in diagnosis tis. Br J Rheumatol27:230-232, 1988

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10. Kaarela K, Mattila J, Lehtinen K, et al: Hidden psoriatic arthritis in seronegative oligoarthritis: A 14-year follow-up study. Clin Rheumatol8:504-506, 1989 11. Khan MA, Kushner I: Diagnosis of ankylosing spondylitis, in Cohen AS (Ed): Progress in Clinical Rheumatology (vol 1). Philadelphia, PA, Grune & Stratton, 1984, pp 145-178 12. Moll JMH, Wright V: New York clinical criteria for ankylosing spondylitis. A statistical evaluation. Ann Rheum Dis 32:354-363, 1973 13. van der Linden SM, Valkenburg HA, de Jongh BM, et al: The risk of developing ankylosing spondylitis in HLA-B27 positive individuals: A comparison of relatives of spondylitis patients with the general population. Arthritis Rheum 27:241249,1984 14. van der Linden SM, Valkenburg HA, Cats A: Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 27:361-368, 1984 15. van der Linden SM, Khan Chest pain without radiographic

MA, Rentsch H-U, et al: sacrioliitis in relatives of

patients with ankylosing spondylitis. J Rheumatol 15:836839,1988 16. Gladman DD, Urowitz MB, Anhorn KB, et al: Discordance between HLA-B27 and ankylosing spondylitis: A family investigation. J Rheumatol 13:129-136, 1986 16a. Khan MA (ed): Ankylosing spondylitis and related spondyloarthropathies. Spine. State of the Art Reviews 4:497-688, 1990 17. Mau W, Zeieler H, Mau R, et al: Clinical features and prognosis of patients with possible ankylosing spondylitis. Results of a IO-year followup. J Rheumatol 15:1109-l 114, 1988 18. Anonymous: Spondylitis: Time for a new name and a new approach to diagnosis. Lancet 2479-481, 1985 (editorial) 19. Bergfeldt L, Insulander P, Lindblom D, et al: An important genetic risk factor for lone aortic regurgitation and severe conduction system abnormalities. Am J Med 85:11-18, 1988 20. Qaiyumi S, Hassan ZU, Toone E: Seronegative spondylarthropathies in lone aortic insufficiency. Arch Intern Med 145:822-824, 1985 21. Wright V, Mall JMH (eds): Seronegative polyarthritis. North Holland Publishing, Amsterdam, Holland, 1976, pp l-483 22. Granfors K, Jalkanen S, von Essen R, et al: Yersinia antigens in synovial-fluid cells from patients with reactive arthritis. N Engl J Med 320:216-221, 1989 23. Schumacher HR Jr, Magge S, Cherian PV, et al: Light and electron microscopic studies on the synovial membrane in Reiter’s syndrome: Immunocytochemical identification of Chlamydial antigen in patients with early disease. Arthritis Rheum 31:937-946, 1988 24. Keat A, Thomas B, Dixey J, et al: Chlamydia trachomatosis and reactive arthritis: the missing link. Lancet 1~72-74, 1987 24a. Granfors K, Jalkanen S, Lundberg AA, et al: Salmonella lipopolysaccharide in synovial cells from patients with reactive arthritis. Lancet 335:685-688, 1990 25. Arnett FC: The Lyme spirochaete: Another cause of Reiter’s syndrome? Arthritis Rheum 321182-l 184, 1989 (editorial) 26. Weyand CM, Goroncy JJ: Immune responses to Borrelia burgdorferi in patients with reactive arthritis. Arthritis Rheum 32:1057-1064, 1989 27. Rowe IF, Keat ACS: Human immunodeficiency virus infection and the rheumatologist. Ann Rheum Dis 48:89-91, 1989

A WIDEA SPECTRUM OF SPONDYLOARTHROPATHIES

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