The undifferentiated arthritis (UA) includes the forms of diseases with manifestations that do not correspond or only partially correspond with estimated diagnostic (classification) criteria of defined nosological entities.
Diagnosis of Undifferentiated Arthritis
The UA may be presented as an initial diagnosis or represent a nosological entity of a joint process for a particular patient over a number of years. One of the initial diagnostic steps in case of any arthritis is a lesion variant definition of osteoarticular skeleton according to articular syndrome types: peripheral, central or mixed. The typical representative of peripheral type of the disease is rheumatoid arthritis. The central or mixed affections are more often associated with spondylarthritis group of diseases. There’s no doubt that the differential diagnosis doesn’t end here and the list of any possible nosological variants of debut arthritis forms should be continued. However, clear understanding of the modern diagnostic criteria for early (including undifferentiated) forms of rheumatoid and spondylarthritis, and discerning prognostically unfavorable characteristics allows reasonably narrowing down the extent of differential diagnostics, and justifying the prescription of basic and genetically engineered biologic drugs at an early stage of the disease. According to the analysis of foreign authors’ publications the occurrence of UA in patients with first diagnosed arthritis varies and amounts to an average of 33%. According to the data of Russian researchers study in a group of 366 patients with inflammatory joint diseases that lasted less than one year 36.3% of cases of arthritis were verified as undifferentiated. After 12 months 33.1% of patients from that group were diagnosed with rheumatoid arthritis, which generally speaks for a severe prognosis of undifferentiated arthritis . At the same time a development of spontaneous remission of the disease cannot be excluded in approximately same number of cases.
Diagnosing debut forms of either rheumatoid arthritis or spondyloarthritis is a complicated clinical task but it should be noted that the identification of the latter is more difficult. As a result, the frequency of wrong initial diagnoses reaches 72% in case of spondyloarthritis and most often occur in diagnosing women – 94%. Symptomatology of spondyloarthritis, especially of its axial forms, is not always sharply defined, is stretched in time, and prone to spontaneous long-lasting remissions. Oversimplified conception of back-pain problem, unreasonably frequent diagnosing with “osteochondrosis” (also in patients at the age of 25-35), and lack of knowledge of clinical symptomatics are the most frequent causes of tardy diagnostics. As a consequence, the final diagnosis is established after 8 year on average after the debut of articular syndrome and some 7-8 visits to distinct specialists.
Retaining the terminological similarity of the main definition, there are some differences in the interpretation of “early” and undifferentiated arthritis, debut “rheumatoid-like” and “spondyloarthritic” variants of articular syndrome. UA at the onset of rheumatoid arthritis (Ra) is considered to be a variant of the so-called “early rheumatoid arthritis” and is indicated with the term undifferentiated peripheral inflammatory arthritis, UPIA. This group includes patients with clinically significant swelling of one or more joints (synovial proliferation or synovial edema) revealed by a rheumatologist on examination and absence of correspondence to any diagnostic/classification criteria for specific rheumatic disease .
The development of clinically defined variant of arthritis is preceded by subclinically passing immuno-pathological process that debutes many months (or years) before the evident symptoms of RA. For example the cyclic citrullinated peptide antibodies (anti-CCP) may be identified in a patient’s serum 14 years earlier than first symptoms of RA (median 4 years), which is 4 to 5 years earlier than the manifestation of rheumatoid factor , while the signs of chronic synovitis could be found at the very beginning of disease not only in affected but also in “normal” joints according to the biopsy of synovium . Basing on the analysis of risk factors, four group of patients with high risk for RA can be identified, one of which is constituted by population with UPIA .
The application of that diagnostic algorithm gives the possibility to settle or reject the diagnosis of RA, in the early stages before all – “very early RA” and early estimated (full-scaled) RA”. «Very early RA» is a arthritis of first three months (first six months in case of gradual developing of symptoms), this period defines the tenacity of arthritis. This period is potentially reversible. “The early established (full-scaled) RA” is an arthritis of first 1-2 years, during which period the first symptoms of the disease progression can be assessed, e.g. presence/absence of typical erosive intraarticular process . “Classical” diagnostic criteria for RA (ACR) are used in the verification of full- scaled forms RA diagnosis, as they are characterized with quite high sensitivity (93%) and specificity (91%).
What allowed the increase of sensitivity of the new criteria for the diagnostics of initial forms RA? In the first place some changes in the articular syndrome description: now the evidences of synovitis include not only joint swelling but its soreness as well, which can be objectivised by positive “lateral constriction testing” of metatarsophalangeal and metatarsophalangeal joints. Besides swelling and soreness, the high ESR and high CRP were selected as symptoms confirming and substantiating active inflammation diagnosis. High RF level, increase of ESR and CPR level are associated with rapid progression of joint lesion. However, these parameters often conform to norms at an early stage.
The addition of anti-CCP test to serum diagnostics of RA should be emphasized, this test comes second after RF identification. Its specificity is rather high (75-90%), and its sensitivity at an early stage reaches 75%. The anti-CCP test is especially important for seronegative RF patients. Anti-CCR seropositive results and/or high titre are associated with faster developing intraarticular erosions, steady high activity of RA, increasing overall mortality and more frequent comorbidities so it gives an unmistakable value to the test.
Categorization of joints is essential for the practical application of the criteria established in 2010, and should be estimated at diagnostics along with the excluded joints.
Cases when symptoms of debut articular syndrome are similar to RA, but are not supported by ASAS 2010 criteria, UPIA can be diagnosed. In this cases an estimation of prognostic value of presenting clinical, laboratory and imaging results is important. According the EULAR 3e Initiative conclusion, the most likely predictors for RA in patients with UPIA are: anti-CCP, RF, erosions in joints revealed with X-ray, erosions and intraoseal edema on MR-image . Specific studies devoted the comparison of different methods for erosion identification have shown that radionegative erosions detected with the use of MRI and ultrasound can be considered as true erosions . No unified standardized system for assessment structural joint injury revealed on ultrasound examination exists at present time. Besides, sonography along with radiography and MRI are increasingly frequently used for diagnosis verification. R. Wakefield and coauthors reported that in comparison with routine roentgenography ultrasound examination reveals 6.5 times more erosions at an early stage and 3.4 times more in case of disease duration exceeding 2 years. Besides, the specific criteria suggested by A.H. Van der Helmvan Mil and colleagues in 2007 (“prediction rule”) have sufficient predictive validity (probability of developing of RA within one year. The main outstanding feature of these criteria is lack of limitations on duration of symptoms.
A necessary step before establishing a provisional diagnosis of RA (including UPIA) is performing differential diagnostics. Any idiopathic, autoimmune, degenerative, infectous, oncotic, trautomatic, metabolic reasons for RA should be excluded.
According to the current classification of spondyloarthritis, undifferentiated spondyloarthritis (USA) falls under the group of predominantly peripheral spondyloarthrites along with pcoriatic and reactive arthrites and arthrites associated with inflammatory bowel disorders, primarily with nonspecific ulcerative colitis and Crohn’s disease. As distinct from UPIA the USA in many cases represents as a separate nosological entity with clinical and roentgen symptoms of spondyloarthrites but with no correspondence to diagnostic criteria for “classical” forms of SA. The term “early SA” is used with regard to axial subtype SA with no roentgenologic signs, the final variant of which is ankylosing spondylitis.
Up to 43% of SA can be referred to the category “undifferentiated”. The study of Sampaio-Barros P.D. has shown the prolonged clinical development in patients with SA unlike RA: in a group of 68 patients with USA observed for 2 years for 75% of cases the disease remained undifferentiated, for 13% remissions occurred, 10% developed AS, 2% developed psoriatic arthritis. Disorders most frequently attributed to undifferentiated arthritis are: SAPHO syndrome (Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis); SEA syndrome (Seronegativ Enthesopathy and Arthropathy syndrome); isolated dactylitis; HLA-B27- associated uveitis /iridocyclitis; HLA-B27-associated cardiac disease, over- Lap-syndrome, «Late» spondyloarthritis and others. Moreover, the affiliation of some diseases to USA is not clear completely.
Before diagnosing with USA a screening for the correspondence of the signs to the cLassification criteria for axial and peripheral arthritis developed by the ASAS working group (The Assessment of SpondyloArthritis international Society) should be performed.
CLassification criteria for axial spondyloarthritis have two variants. One of them is based on the visual signs of sacroileitis (MRT or X-ray study), and the other is based on the HLA-B27 identification as well as clinical and Laboratory findings characteristic of the entire group of SA. The possibility for early pre-roentgen diagnostics of SA is a principal distinction of new criteria for mostly axSA .
Back pain is considered as inflammatory if at least 4 out of 5 features of the first or second criteria group listed below are present, the first one is more sensitive and the second one is more specific. The first group – gradual onset, age at onset <40, low back pain S 3 months, morning stiffness, improvement with exercises. The second group (ASAS, 2009) – gradual onset, age at onset <40, night pain, improvement with exercises, no improvement with rest. “Good response to NSAIDs” suggests reducing or absence of pain in 24-48 hours after application of NSAID full dose. MRT of sacroiliac joints and spine plays a special role not only for the early diagnostics but for the disease activity assessment. Active inflammatory changes are visualised best by T1-weighted sequence with fat saturation using contrast medium (gadolinium) and fat-saturated T2-weighted (STIR) sequence. Active inflammatory lesions of sacroiliac joints include bone marrow oedema (osteitis), capsulitis, synovitis and enthesitis. Chronic inflammatory lesions include sclerosis, erosions, fat deposition, bony bridges/ankylosis . MRT is much more sensitive than routine X-ray study for early identification of chondro-osseus destruction. The radiologically verified sacroileitis should suggest grade 2-4 bilaterally or grade 3-4 unilaterally according to the modified New-York criteria. Ultrasound study is used for revealing enthesopathy and inflammatory changes of hip joints. There are two criteria groups for the perSA diagnostics. For both variants the presence of peripheral articular or tendinous lesion (arthritis, enthesitis, dactylitis) is required. The diagnosis of perSA should be estimated in case of combination of articular or tendinous lesion with one feature of the first group or with two feature of the second group “other features”. Including monoarthritis and polyarthritis in addition to olygoarthtis to the list of diagnostically significant findings is one of the advantages of new criteria for peripheral SA that increases their sensitivity. Dactylitis is a separate sign of enthesopathy that represents a combination of finger flexor tendovaginitis with synovitis. The specific features: axial finger lesion and cyanotic color of skin (phenomenon “sausage-like finger”). Isolated dactylitis can be the only SA findings over a long time in some cases . The potential disadvantage of new criteria for peripheral SA is an exclusion of patients with onset after 45 years. If separate signs of SA manifest at age > 50-60 years the “late” undifferentiated variant of spondyloarthritis should be considered. The semiology of “late” SA could be similar to the SEA-symptome in children – asymmetrical olygoarthtitis of lower limbs and enthesitis with minimum spinal involvement. In some cases the onset starts with inflammatory thoracic and cervical spinal pain in combination with general symptoms: fever, weight loss and elevated ESR that requires differential diagnosis with paraneoplastic arthropathy and polymyalgia reumatica.
At the present the management in patient with early and undifferentiated arthritis and SA has undergone substantial transformation. What is most important now is not a dictatorial definition of articular disease but the treatment justification with application of the baseline therapy as early as possible, including genetically engineered biologic drugs. The tools within the modern diagnostic criteria for RA and SA allow to standardize the diagnostic approaches and personalize the management of disease in every clinical case.