Diagnosis And Treatment In Rheumatology

Spondyloarthropathies (SpA) are a group of chronic inflammatory arthropathies affecting the spine, sacroiliac joints, entheses and extra-articular sites. Clinical characteristics of spondyloarthritis are: peripheral arthritis, mainly in the lower limbs, asymmetrical, tendency for radiographic sacroilitis, no rheumatoid factor and presence of subcutaneous nodules. Significant familiar occurrence and association with HLA-B27 are characteristics for SpA. Diseases belonging to the group of spondyloarthritis are: ankylosing spondylitis, reactive arthritis (ReA), enteropathic arthritis (Crohn’s disease, ulcerative colitis), psoriatic arthritis (PsA), undifferentiated spondyloarthritis and juvenile chronic arthritis (juvenile onset ankylosing spondylitis). SpA occurs due to genetic predisposition especially in patients with positive test for major histocompatibility complex (MHC) class I molecule HLA-B27. Environmental factors are also involved in the pathogenesis. Extra-articular features include skin lesions in PsA, gut involvement in inflammatory bowel disease-related arthritis and the oculo-urethrosynovial triangle in ReA. NSAIDs and anti TNFα drugs are effective in the treatment of axial manifestations of AS. Acute episodes of ReA are treated using NSAIDs and is used as the first line treatment. In more severe cases including NSAIDs resistance, systemic or prolonged disease, systemic GCS may be used. Management of peripheral arthritis in PsA: NSAIDs, GCS, DMARDS: MTX, or Sulfasalazine or Ciclosporin or Leflunomide, anti –TNFα, new options for treatment includes inhibitor IL-17 (ixekizumab or secukinumab), ustekinumab – a fully human IgG 1k monoclonal antibody that binds to the common p40 subunit shared by interleukins 12 and 23, and apremilast – a phosphodiesterase inhibitor.

Juvenile Idiopathic Arthritis (JIA) is a group of diseases that starts before the age of 16 and is characterized by arthritis of at least one joint, lasting for more than 6 weeks and the origin of which is unknown. Symptoms of JIA include fever, rash, weakness, non-specific musculoskeletal pain and morning stiffness. Classification of JIA is based on symptoms that present during the first 6 months of the disease. Categories of JIA: systemic arthritis, oligoarthritis, a/persistent oligoarthritis b/extended oligoarthritis, polyarthritis (rheumatoid factor negative), polyarthritis (rheumatoid factor positive), psoriatic arthritis, enthesitis-related arthritis, undifferentiated arthritis. There are no serological markers which may indicate JIA at diagnosis, therefore it is important to exclude other conditions which may mimick arthritis. Initial treatment of children with arthritis begins with NSAIDs, intra-articular GCS and if these prove ineffective, methotraxate is used. Sulfasalazine, hydroxychloroquine or ciclosporin A may also be used. Biological therapies such as anti-TNFα, anti – IL1, IL6 blockade, abatacept show better improvement when they are added to methotrexate. Acute rheumatic fever is a systemic inflammatory disease which occurs 2-3 weeks after infection with group A β-hemolytic streptococci. The acute form is characterized by: fever, arthritis, which is usually migratory and affects predominantly large joints. Cardiac manifestations due to involvement of the pericardium, myocardium, endocardium and heart valves may also occur. Neurological involvement is in the form of Sydenham’s chorea. Bed rest and antimicrobial therapy with penicillin is essential. Salicylate doses of 4 g may be required in adults. GCS is used in patients with severe carditis.

Systemic lupus erythematosus (SLE) is an inflammatory disease involving many systems, with different clinical features and laboratory findings. The etiology of SLE is unknown. The pathogenesis of SLE may derive from genetic as well as environmental factors. Overproduction of autoantibodies causes cytotoxic damage and takes part in immune complex formation causing inflammation. Clinical features may be general or result from inflammation in different organ systems including skin and mucous membranes, joints, kidneys, brain, serous membranes, lungs, heart and occasionally the gastrointestinal tract. The morbidity and mortality is associated with the involvement of vital organs, especially the kidneys and central nervous system, and is due to direct tissue damage or as a result of therapy. Lupus management is based on disease activity. Antimalarial drugs are effective for acute and chronic lupus rashes. Most clinical symptoms of SLE respond to GCS, however the adverse effects of GCS cause an increase in morbidity and must be tapered and withdrawn. Severe lupus (e.g. proliferative lupus nephritis, CNS involvement or severe thrombocytopenia) is treated by pulse IV methylprednisolone (MP) followed by oral GCS (0.5 mg/kg/day) and MMF or IV CYC, followed by less toxic AZA, MMF. To diagnose antiphospholipid syndrome (APS), a patient must have both a clinical event (thrombosis or pregnancy loss) and an antiphospholipid antibody (aPL), documented by a solid-phase serum assay (anticardiolipin – aCL), an inhibitor of phospholipid-dependent clotting (lupus anticoagulant – LA), or both. APS is treated by anticoagulation such as warfarin, heparin, and low-molecular-weight heparin and often in association with low-dose aspirin.

Sjogren’s or sicca syndrome (SS), is a progressive, inflammatory autoimmune disease affecting the exocrine glands. Clinical features include mucosal dryness presented as xerophthalmia (keratoconjuctivitis sicca), xerostomia, xerotrachea and vaginal dryness, major salivary gland enlargement, non-erosive polyarthritis and Raynaud’s phenomenon. The symptoms are mild from dryness of mucosal surfaces in some patients to very severe with involvement of many organs in others. The disease has increased mortality, due to extraglandular systemic involvement and often accompanying lymphoma. Laboratory tests show positive antinuclear antibodies, rheumatoid factor and anti Ro/SSA, anti La/SSB antibodies. Biopsy of the minor salivary glands is a gold standard in the diagnosis of SS. The focus score in an area of 4 mm2 describes focal aggregates of at least 50 lymphocytes. One present focus score represents a positive result. Structural damage on the eye surface is evaluated using the Lissamine green test. Patients with SS have a 44 times higher risk of developing lymphoma than normal control population. Extraglandular symptoms may be treated with GCS and immunosuppresive drugs in severe cases (CYC, AZA or MMF in pulmonary alveolitis, glomerulonephritis or severe neurological features). Mikulicz’s disease (MD) is an IgG4-related disease. Criteria of MD are: increased IgG4 level (>135 mg/dl), tissue biopsy with infiltration of IgG4 plasmocytes with fibrosis and sclerosis. Differences between MD and SS: MD does not show the same female predominance. Allergic rhinitis and autoimmune pancreatitis are seen more often in MD. There is an increased improvement after GCS treatment in patients with MD than with SS.

Dermatomyositis and polymyositis are inflammatory myopathies with muscle inflammation and proximal muscle weakness. Skin examination, muscle enzyme measurement (creatinine kinase, aldolase) assessment of antinuclear and myositis-specific antibodies (MSA), muscle or skin biopsy, electromyography (EMG), magnetic resonance imaging (MRI) of skeletal muscle and exclusion of malignancy are very important. Histologic signs of DM and PM include degeneration, regeneration, inflammatory cell infiltration and ultimately, muscle fiber necrosis. In DM, the cellular infiltrate is perifascicular and perivascular with infiltration of B lymphocytes and plasmacytoid dendritic cells. In PM, the cellular infiltrate in muscle is in the fascicle, with cytotoxic CD8+ T cells. Skin changes characteristic of DM are Gottron’s papules, a heliotrope rash and V sign. EMG findings include spontaneous fibrillations, positive sharp waves, and complex repetitive discharges. DM is diagnosed in patients with symmetrical proximal muscle weakness, increased muscle enzymes and a specific rash. Biopsy is not required. EMG and muscle biopsy may be useful in patients who have atypical findings to exclude other diseases such as inclusion body myositis (IBM), metabolic myopathy, or muscle dystrophies. Exclusion of other diseases such as inflammatory myopathies, motor neuron disease, myasthenia gravis, muscular dystrophies, inherited, metabolic, drug-induced, endocrine, and infectious myopathies must be performed. Muscle strength and CK levels monitor disease activity. GCS are the main lines of treatment used. Combined therapy includes methotrexate, azathioprine and antimalarial drugs. Cyclophospamide and intravenous gamma-globulin have a role in life-threatening cases. Plasmapheresis is used only when the above mentioned therapies have failed.

Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis of the skin and internal organs, changes in the microvasculature and in cellular and humoral immunity. The types of disorders include: localized scleroderma (morphea, linear scleroderma, en coup de sabre) and systemic sclerosis (diffuse cutaneous systemic sclerosis [dsSSc], limited cutaneous systemic sclerosis [lcSSc] and systemic sclerosis sine scleroderma). LcSSc is a milder form with slow progression of skin involvement and visceral complications after 10-15 years, but with serious pulmonary arterial hypertension. DsSSc has fast progression of skin sclerosis, from weeks to months, and includes injuries to organs such as the lung, heart and kidney, which may lead to organ failure. The presence of ANA was found in more than 90% of patients with SSc, anti-Scl-70 antibodies in patients with dcSSc in 30-40%, anticentromere antibodies (ACA) in patients with lcSSc in 80-90%. Fibrosis is the end-stage representation of SSc pathogenesis. Severe forms of the disease and rapidly progressive diffuse SSc with pulmonary, cardiac, and renal involvement, are associated with very high mortality rates, estimated at 40-50% in 5 years. No treatment effective therapy exists to stop fibrosis and disease progression beside autologous haemopoietic stem cell transplantation (AHSCT). Cyclophospamide has moderate efficacy in patients with ILD. Methotrexate may be used for the treatment of arthritis. Oesophageal dysmotility and reflux are treated with promotility agents, and proton pump inhibitors. In PAH endothelin receptor antagonists, with PDE5 inhibitor and prostaglandins are used. The most important manifestation is scleroderma renal crisis and is now treated using ACE inhibitors.