BASIC CONSIDERATIONS

Normally, immune system does not react to self-antigens due to elimination of autoreactive B- and T-cells during their development. This self-tolerance is lost in rheumatic disorders due to:

• Cross-reactivity between a foreign and self-antigen due to striking molecular similarity;

• Alteration in host antigen due to some extraneous factor, e.g.

Genetic susceptibility as well as environmental factors have been identified to trigger these responses in rheumatic disorders.

Pathophysiologically, Non-recognition of self-antigen by own B and T-cells triggers an abnormal or exaggerated immune response against target tissues with—(a) recruitment of inflammatory cells, (b) immune complex formation, (c) complement activation, and (d) cytokine production; all leading to acute or chronic inflammation, tissue damage and constellation of clinical features.

Clinical spectrum of rheumatic disorders varies with the type, site and extent of immune injury. Possibility of rheumatic disease must be considered in presence of any one or more of the clinical indicators enumerated in Table 24.1, after exclusion of other common causes. Despite considerable overlap, rheumatic disorders may be broadly classified into three groups:

a. Predominantly arthritic syndromes, e.g. juvenile idiopathic arthritis (JIA).

b. Systemic connective tissue disorders, e.g. systemic lupus erythematosus (SLE), dermatomyositis, etc.

c. Systemic vasculitis syndromes, e.g. Henoch- Schonlein purpura (HSP), Kawasaki disease, etc.

TABLE 24.1: Clinical indicators of rheumatic disorders

• Unexplained prolonged fever

• Unexplained arthritis or arthralgia

• Unexplained muscular tenderness or weakness

• Enthesopathy, i.e. tenderness at ligamental insertions

• Recurrent or poly-serositis

• Unexplained skin rash or other acquired changes

• Unexplained multi-systemic disease

Laboratory diagnosis: No laboratory test is the gold standard in rheumatic disorders and diagnosis is usually based on constellation of clinical features (all of which may not be apparent at the time of first presentation, leading to delay in specific diagnosis) and laboratory evidences of chronic inflammation and immunological reactions.

a. Elevated acute phase reactants, e.g. ESR, CRP, Ferritin, etc. due to chronic inflammatory process, which are also useful to monitor the course of illness and efficacy of therapy. However, these tests have limited diagnostic value, as also deranged in many non-rheumatic conditions, e.g. infections..

b. Rheumatoid factor (RF) is an IgM antibody directed against Fc segment of IgG antibodies, usually detected by latex-agglutination test. However, a positive rheumatoid factor is not necessarily diagnostic of rheumatoid disorders, being also positive in many viral infections, tuberculosis, infective endocarditis or intrauterine infections. Conversely, gt;85% cases with juvenile idiopathic arthritis are RF negative.

c. Antinuclear antibodies (ANA) are large group of auto-antibodies directed against antigens in the nucleus of the host cells, usually detected by indirect immunofluoroscence. ANA are present in 97% cases of SLE, but may also be positive in many other rheumatological disorders, e.g., Oligoarticular JIA or Juvenile dermatomyositis and non-rheumatological conditions, e.g., EBV, HIV, Tuberculosis and malig­nancies. ANA may be also present with low-titers (1:40) in ~30% of normal individuals and with high titers (1:160) in ~5%.

Commonly used ANA test is a screening test, which detects presence of non-specific antinuclear antibodies. Tests to identify antibodies to specific extractable nuclear antigens (ENA) or ANA Blot/ profile are also available, e.g., anti-Sm antibodies in SLE, anti- Scl antibodies in scleroderma and anti-Pm- Scl antibodies in dermatomyositis.

d. Lupus cell (LE cell) is a modified polymorph, ready- for-phagocytosis, after reacting with anti-nuclear antibody against its deoxyribonucleoprotein (DNP). While not very sensitive, presence of LE cells indicates possibility of rheumatological disorders.

e. MHC (Major histocompatibility complex) or HLA (Human leukocyte antigen) identification is mainly useful to predict the risk of rheumatic disorders in a suspected case or family members, e.g,.

f. Other immunological tests, though not diagnostic, help to assess the severity of disease and response to therapy and include, e.g. complement levels (C₃-C₄) or hypergammaglobulinemia, etc. which are more useful to assess the severity of disease and response to therapy.

g. Radiological investigations, e.g., X-rays, USG, CT/ MRI, help to establish the diagnosis and evaluate the extent of musculoskeletal involvement. USG is very useful to assess synovitis, joint effusions and enthesitis, as well as to guide joint aspirations and intra-articular drug injections.

h. Tissue biopsies are required to confirm the diagnosis in selected cases, e.g. skin biopsy in atypical Henoch- Schonlein purpura, muscle biopsy in uncertain cases of dermatomyositis and renal biopsy in suspected lupus nephritis. Synovial biopsy or joint fluid examination is rarely required in rheumatic disorders.

Management of rheumatological disorders requires multidisciplinary team approach including—(a) medical therapy with NSAIDs, steroids, disease modifying anti- rheumatoid drugs (DMARDs) and biological agents, (b) physiotherapy with orthopedic and orthotic interventions, (c) psychological counselling regarding chronic nature of these disorders, and (d) rehabilitation services.

DMARDs re duce inflammation by acting on inflam­matory pathways and modulating the immune system, thus reducing the steroid requirements and include, e.g. methotrexate, cyclophosphamide, mycophenolate mofetil, sulfasalazine, etc.

Biological agents are target-specific monoclonal anti­bodies directed against various inflammatory agents, e.g. Rituximab (Anti-CD-20 antibody), Etanercept (TNF-#945; receptor antagonists), Anakinra (IL-1 receptor antagonists), etc.

24.2