Hypogammaglobulinemia & arthritis

A young adult presents with chronic large joint oligoarthritis and fever Diagnosed case of common variable immunodeficiency in view of recurrent respiratory tract infections Not on IVIG Mycoplasma isolated by special cultures Responds to antibiotics

- An 8 year old child presenting with subacute onset irritability, fever, myositis, facial rash fits into dermatomyositis - Initiated on high dose steroids, and methotrexate, later azoran..no improvement - Seizures and progressive deterioration - IVIg leads to improvement gradually - Enterovirus isolated - H/o recurrent ear and chest infections - Enterovirus induced pseudo- dermatmyositis ?

 A 6 year old female child presents with h/o recurrent infections, bronchiectasis, normal IgG levels, poor antibody response, normal mitogen induced T cell response, relative low B cell, T cell (CD4 & CD8) count Recurrent infections- stabilized on IVIG, later stopped Later polyarthritis, bronchitis- non infective work up, no response to IVIG, response to steroids Autoimmune workup suggestive of SLE Recurrent flares including arthritis, pancytopenia- no evidence of infection No response to IVIG, some reduction in infections, intolerating MMF and Azoran Finally good response to rituximab and IVIG !

Points to be discussed
1. Briefly types of gammaglobulins, their functions 2. When one is said to have hypogammaglobulinemia (hypoIg) ? 3. Primary hypoIg and arthritis, pathophysiology 4. Primary hypoIg and other autoimmune diseases 5. CVID & SLE 6. Secondary hypoIg 7. Drugs causing hypoIg 8. Approach to evaluation of hypoIg in rheumatology 9. Treatment of patients with hypoIg 10. Impact on our practice ? - Take home messages

Immunoglobulins

When do you say one has hypogammaglobulinemia?

Suspect with recurrent infections (more than 2 lobar pneumonias or 3-5 episodes of sinusitis/middle ear infection per year) Selective Class or subclass deficiency Total gamma globulin fraction less than 5g/L

Primary immune deficiencies

Cellular and SCID Humoral (the ones which present with hypogammaglobulinemia)

 PIDs typically manifest as recurrent infections that usually start in childhood. Among the other clinical manifestations, some are both highly specific and rare, whereas others are more common. Bone and joint abnormalities fall into latter category. They can arise from a variety of mechanisms and occur chiefly in humoral PIDs. Joint manifestations are more common than bone involvement and usually consist in arthralgia, although arthritis is relatively frequent. Joint manifestations occur chiefly in patients with humoral PIDs A few cases of arthritis have been reported in patients with chronic granulomatous disease, Wiskott-Aldrich syndrome or cellular or SCID syndromes

Primary hypogammaglobulinemia (mostly Humoral PIDs)

X linked hypogammaglobulinemia (Bruton) Aggamaglobulinemia (AR) Common variable immunodeficiency (CVID) IgA deficiency Hyper IgM syndrome (classified under cellular immunodeficiency) Good syndrome

Joint manifestations in PIDs

Mainly in humoral deficiencies 1) Septic arthritis (monoarthritis or rarely oligoarthritis) - Staphylococci, streptococci or other encapsulated organism - Mycloplasma - Viruses (Enterovirus) 2) Apparently aseptic oligo or polyarthritis - Seronegative polyarthritis resembling RA - Seronegative RA - Arthritis associated with other autoimmune diseases - Postinfectious or reactive arthritis

 In patients with humoral PID, the prevalence of joint manifestations before treatment has ranged across studies from 5% to 40%. Hansel et al identified 7 cases of monoarthritis and 1 case of oligoarthritis among 69 patients with agammaglobulinemia, as well as 1 case of monoarthritis and seven cases of oligoarthritis among 161 patients with CVID.

Hansel TT, Haeny MR, Thompson RA. Primary hypogammaglobulinemia and arthritis. BMJ 1987 Bone and joint disease associated with primary immune deficiencies Joint Bone Spine 72 (2005)

Septic arthritis
Encapsulated organisms (Streptococci, Staph., H.influenzae) Viruses (enterovirus 11 and adenovirus 1) Mycoplasma arthritis

Ackerson BK, Raghunathan R, Keller MA. Echovirus 11 arthritis in a patient with X-linked agammaglobulinemia. Pediatr Infect Dis 1987 Fraser KJ, Clarris BJ, Muirden KD. A persistent adenovirus type 1 infection in synovial tissue from an immunodeficient patient with chronic rheumatoid-like polyarthritis. Arthritis Rheum 1985

Mycoplasma and arthritis

Usually monoarticular, rarely oligoarticular, polyatricular very rare, predominantly large joints, chronic septic arthritis, joint destruction can occur Very common, Furr et al. found Mycoplasma in joint specimens from at least 38% of patients with arthritis and hypogammaglobulinemia. Ureaplasma urealyticum most common Pathophysiology Arthritogenic Isolation difficult, molecular methods may be required Treatment with macrolides, quinolones or cyclines, ?IvIg
1) Bone and joint disease associated with primary immune deficiencies ,Joint Bone Spine 72 (2005) 503514 2) Furr PM, Mycoplasmas and Ureaplasmas in patients with hypogammaglobulinaemia and their role in arthritis: microbiological observations over twenty years., Ann Rheum Dis 1994 3) Hypogammaglobulinemic Patient with Polyarthritis Mimicking Rheumatoid Arthritis Finally Diagnosed as Septic Arthritis Caused by Mycoplasma hominis

Apparently aseptic arthritis

About 1040% of arthritis cases in patients with humoral PIDs seem aseptic. Monoarthritis or oligoarthritis or polyarthritis which may resemble rheumatoid arthritis. May be more common among children and males, mostly those with agammaglobulinemia or profound hypogammaglobulinemia. Studies of affected families found no increase in the rate of joint manifestations among immunocompetent first-degree relatives

Features of apparently aseptic arthritis

Polyarthritis, rarely erosive, infection absent by definition (but low levels cannot be ruled out) Histology different - No plasma cell or lymphoid infiltration - CD8 T cells - Synovial biopsy can be helpful in diagnosis Pathophysiology - Post infectious, part of other syndrome - Actual RA without B cell involvement (CVID doesnt have B cell depletion) - RA developed before, it should then improve !

Treatment of apparently aseptic arthritis

IVIG Trial of antibiotics may be warranted if recent onset

CVID and other autoimmune diseases

CVID and SLE

Complex association B cell or T cell defect? TACI and BAFF mutations more related? Overlap? IgG and IgM levels who overlap Autoantibodies- higher IgG levels in patients with SLE and CVID as compared to patients with CVID alone Drug induced, nephrotic syndrome

Secondary Hypogammaglobulinemia
1) Excess loss - GI loss - Nephrotic syndrome 2) Decreased production - Drugs - Malignancies - Infections - Severe malnutrition

Drugs

 Corticosteroids 1. Usually CD4+ lymphopenia classical but, may also induce hypoIg 2. Generally the episodes are moderately severe and essentially concern IgG (IgG1 in particular). 3. These deficiencies have been reported in all types of corticosteroid therapy: low-dose long-term therapy (> 5mg/d for more than 2 years) or high-dose short-term therapy. 4. The prevalence o hypoIg in these populations was around 12 to 17%. 5. The mechanism is still unclear, corticosteroids may increase catabolism and reduce the synthesis of Ig via their action on intracellular pathways. 6. It seems that the infectious consequences of this deficiency are slight, even though there is sometimes an impaired response to vaccines, notably anti-pneumococcal vaccine .

References

 Cyclophosphamide Many case reports. Prevalence with low dose cyclophosphmaide ? Antiepileptics and in particular carbamazepine , phenytoin and clonazepam. The deficiency affects all classes of Ig and is usually reversible and disappears with cessation of the treatment. Complication due to infections are generally rare. D-penicillamine, gold salts and sulfasalazine. They principally cause IgA deficiency, but hypogammaglobulinemia has also been described, often with no clinically important consequences. Methotrexate - ?risk attributed-incidence very low?consequence Rituximab 10-40%, increase with repeat dosing

References

Impact of Rituximab on Immunoglobulin Concentrations and B Cell Numbers after Cyclophosphamide Treatment in Patients with ANCA-Associated Vasculitides Plos one 2011 20% of patients required Ig replacement

 i. ii. iii. iv.

Malignancies Multiple myeloma CLL and other leukemias NHL Thymoma

Infections i. HIV ii. Chronic parasitic infections

Rheumatologist approach Decision tree

Treatment principles of hypogammaglobulinemia

Treat infections with cidal antibiotics Treat primary causes with IVIG to maintain Ig level above 5g/L or 800mg/kg If primary causes associated with immune disease, maintain Ig levels, and treat immune disease with measures required Remove or try to correct offending causes in secondary IVIG, be judicious about replacement of IG, assess risk individually

Bone manifestations in primary immune deficiencies

Infectious osteomyelitis Recurrent fractures in hyper-IgE syndrome Metaphyseal bone lesions of the costochondral joints, acetabular roof, ischium, and vertebras in adenosine deaminase deficiency Birth defects associated with Di George syndrome (dysembryogenesis of the third and fourth branchial arcs) Spondyloepiphyseal dysplasia associated with humoral immunodeficiencies Schimke osseous immune dysplasia

Take home messages

Suspect hypoIg to diagnose, especially with relevant history Try to remove or change the offending drug when possible A case for baseline immunoglobulin patients in SLE or patients being planned on high dose immunosuppression? Do not underestimate nutrition !

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